Combined Dose Groups Research Articles

Combined exposure of polystyrene microplastics and benzo[a]pyrene in rat: Study of the oxidative stress effects in the liver

Microplastics (MPs) and benzo[a]pyrene (B[a]P) are prevalent environmental pollutants. Numerous studies have extensively reported their individual adverse effects on organisms. However, the combined effects and mechanisms of exposure in mammals remain unknown. Thus, this study aims to investigate the potential effects of oral administration of 0.5μm polystyrene (PS) MPs (1 mg/mL or 5 mg/mL), B[a]P (1 mg/mL or 5 mg/mL) and combined (1 mg/mL or 5 mg/mL) on 64 male SD rats by gavage method over 6-weeks. The results demonstrate that the liver histopathological examination showed that the liver lobules in the combined (5 mg/kg) group had blurred and loose boundaries, liver cord morphological disorders, and significant steatosis. The levels of AST, ALT, TC, and TG in the combined dose groups were significantly higher than those in the other groups, the combined (5 mg/kg) group had the lowest levels of antioxidant enzymes and the highest levels of oxidants. The expression of Nrf2 was lowest and the expression of P38, NF-κB, and TNF-α was highest in the combined (5 mg/kg) group. In conclusion, these findings indicate that the combination of PSMPs and B[a]P can cause the highest levels of oxidative stress and elicit markedly enhanced toxic effects, which cause severe liver damage.

Safety and efficacy of once-daily dexfadrostat phosphate in patients with primary aldosteronism: a randomised, parallel group, multicentre, phase 2 trial

Primary aldosteronism (PA) is caused by autonomous aldosterone overproduction and characterised by uncontrolled hypertension. There are currently no treatments that targetaldosterone synthesis. We evaluated the safety and efficacy of a novel aldosterone synthase inhibitor, dexfadrostat phosphate, in patients with PA. This multi-centre, randomised, phase 2 trial was conducted between November 2019 and May 2022 (NCT04007406; EudraCT code 2019-000919-85). Adults with PA and an office systolic blood pressure of 145-190mmHg were included. After a 2-week single-blind placebo run-in period, participants were randomised 1:1:1 to receive oral dexfadrostat phosphate 4, 8, or 12mg once daily for an 8-week double-blind treatment period, followed by a 2-week single-blind placebo withdrawal period. Randomisation was conducted centrally and stratified by centre and sex. At the beginning and end of the treatment period, 24h ambulatory systolic blood pressure (aSBP) was recorded. Blood samples were taken every 2 weeks. Primary endpoints were the change in aldosterone-to-renin ratio (ARR) and mean 24h aSBP from baseline to the end of the treatment period in the combined dose group of all participants receiving any dose of dexfadrostat phosphate. Safety endpoints were the occurrence of treatment-emergent adverse events (TEAEs) and serious adverse events over the entire study in all randomised participants who received at least one dose of dexfadrostat phosphate. In total, 35 participants received dexfadrostat phosphate and all participants completed the study. Twenty-six participants (74.3%) were male, the mean age was 51.9 years (SD 8.7), and most were White (n=32, 91.4%). The median ARR and the mean 24h aSBP significantly decreased from the beginning to the end of the treatment period in the combined dose group (ARR: 15.3 vs 0.6, least-squares mean [LSM] change in log-normal values-2.5, p<0.0001; aSBP: 142.6 vs 131.9mmHg, LSM change-10.7mmHg, p<0.0001). There were no safety concerns; all TEAEs were mild or moderate and there were no serious TEAEs. Dexfadrostat phosphate corrected the ARR and aSBP and was well tolerated in patients with PA, demonstrating the benefit of pharmacologically targeting the source of hyperaldosteronism. DAMIAN Pharma AG.

LB4. Casirivimab and Imdevimab for Treatment of Hospitalized Patients With COVID-19 Receiving Low Flow or No Supplemental Oxygen

LB4. Casirivimab and Imdevimab for Treatment of Hospitalized Patients With COVID-19 Receiving Low Flow or No Supplemental Oxygen

Comparison of Repeated Doses of C-kit-Positive Cardiac Cells versus a Single Equivalent Combined Dose in a Murine Model of Chronic Ischemic Cardiomyopathy

Using a murine model of chronic ischemic cardiomyopathy caused by an old myocardial infarction (MI), we have previously found that three doses of 1 × 106 c-kit positive cardiac cells (CPCs) are more effective than a single dose of 1 × 106 cells. The goal of this study was to determine whether the beneficial effects of three doses of CPCs (1 × 106 cells each) can be fully replicated by a single combined dose of 3 × 106 CPCs. Mice underwent a 60-min coronary occlusion; after 90 days of reperfusion, they received three echo-guided intraventricular infusions at 5-week intervals: (1) vehicle × 3; (2) one combined dose of CPCs (3 × 106) and vehicle × 2; or (3) three doses of CPCs (1 × 106 each). In the combined-dose group, left ventricular ejection fraction (LVEF) improved after the 1st CPC infusion, but not after the 2nd and 3rd (vehicle) infusions. In contrast, in the multiple-dose group, LVEF increased after each CPC infusion; at the final echo, LVEF averaged 35.2 ± 0.6% (p < 0.001 vs. the vehicle group, 27.3 ± 0.2%). At the end of the study, the total cumulative change in EF from pretreatment values was numerically greater in the multiple-dose group (6.6 ± 0.6%) than in the combined-dose group (4.8 ± 0.8%), although the difference was not statistically significant (p = 0.08). Hemodynamic studies showed that several parameters of LV function in the multiple-dose group were numerically greater than in the combined-dose group (p = 0.08 for the difference in LVEF). Compared with vehicle, cardiomyocyte cross-sectional area was reduced only in the multiple-dose group (−32.7%, 182.6 ± 15.1 µm2 vs. 271.5 ± 27.2 µm2, p < 0.05, in the risk region and −28.5%, 148.5 ± 12.1 µm2 vs. 207.6 ± 20.5 µm2, p < 0.05, in the noninfarcted region). LV weight/body weight ratio and LV weight/tibia length ratios were significantly reduced in both cell treated groups vs. the vehicle group, indicating the attenuation of LV hypertrophy; however, the lung weight/body weight ratio was significantly reduced only in the multiple-dose group, suggesting decreased pulmonary congestion. Taken together, these results indicate that in mice with chronic ischemic cardiomyopathy, the beneficial effects of three doses of CPCs on LV function and hypertrophy cannot be fully replicated with a single dose, notwithstanding the fact that the total number of cells delivered with one or three doses is the same. Thus, it is the multiplicity of doses, and not the total number of cells, that accounts for the superiority of the repeated-dose paradigm. This study supports the idea that the efficacy of cell therapy in heart failure can be augmented by repeated administrations.

SO086SNF472 CONSISTENTLY SLOWS PROGRESSION OF CORONARY CALCIFICATION IN PATIENTS ON HEMODIALYSIS: SUBGROUP ANALYSIS OF THE CALIPSO STUDY

Abstract Background and Aims In the CaLIPSO study, SNF472 significantly attenuated progression of coronary artery calcium (CAC) volume score compared with placebo. This pre-specified analysis examined the effect of SNF472 on CAC progression in key subgroups of patients in CaLIPSO. Method Patients with a CAC Agatston score of 100 to 3500 at baseline were randomized to SNF472 300 mg (n=92), SNF472 600 mg (n=91), or placebo (n=91), infused during hemodialysis (HD) thrice weekly for 52 weeks. Patients received standard of care therapy, including phosphate binders and calcimimetics as determined by investigator. The primary endpoint (change in log CAC volume score from baseline to week 52 in the combined dose groups vs placebo) was analyzed for patients who received SNF472 or placebo and had an evaluable CT scan post-randomization (modified ITT population). Sensitivity analysis was also performed for the per protocol population of patients that met entry criteria, received 80% of scheduled treatment, completed the study procedures, and had both a baseline and week 52 evaluable CT scan. The analysis plan pre-specified key subgroups: age, sex, diabetes, dialysis vintage, and arteriosclerotic cardiovascular disease (ASCVD), as well as baseline use of non-calcium phosphate binders, calcium-based phosphate binders, calcimimetics, activated vitamin D, warfarin, or statins. Results Demographics and disease characteristics were similar across the treatment groups. Age (mean±SD) at baseline was 63.6±8.9 years and 39% of the patients were female; 62% had diabetes and 41% had prior ASCVD. Median dialysis vintage was 42.4 months; 33% had received hemodialysis for ≥5 years. Concomitant medications at baseline were: non-calcium phosphate binders, 62%; calcium-based phosphate binders, 28%; calcimimetics, 31%; activated vitamin D, 51%; warfarin, 8%; and statins, 64%. CAC volume progression was 11% for the combined dose groups and 20% for placebo (p=0.016). Treatment differences for CAC volume score progression from baseline to week 52 were similar across the subgroups (FIGURE). All interaction p-values were non-significant, and comparisons favored SNF472 vs placebo in each subgroup for both the modified ITT and per protocol population. Conclusion SNF472 treatment for 52 weeks attenuated CAC progression compared with placebo in all subgroups of the CaLIPSO study. These results support the potential benefit of SNF472 across a broad population of patients with cardiovascular calcification. Future studies are needed to determine the effects of SNF472 on cardiovascular events in patients receiving HD.

Long-term safety and efficacy of erenumab in patients with chronic migraine: Results from a 52-week, open-label extension study.

This study reports the long-term safety and efficacy of erenumab in chronic migraine patients. This was a 52-week open-label extension study of a 12-week double-blind treatment phase study. During the double-blind treatment phase, patients received placebo or once-monthly erenumab 70 mg or 140 mg. During the open-label treatment phase, the initial monthly dose was erenumab 70 mg. Following protocol amendment, patients continued to receive erenumab 70 mg if they had already completed their Week 28 visit, otherwise, patients switched from 70 mg to 140 mg; if enrolled after the amendment, patients received 140 mg monthly throughout. In all, 451/609 (74.1%) enrolled patients completed the study. The exposure-adjusted patient incidence rate for any adverse event was 126.3/100 patient-years for the overall erenumab group. Overall, the adverse event profile was similar to that observed in the double-blind treatment phase. Adverse event incidence rates did not increase with long-term erenumab treatment compared with the double-blind treatment phase, and no new serious or treatment-emergent events were seen. Efficacy was sustained throughout the 52 weeks. Clinically significant reductions from double-blind treatment phase baseline (about half) were observed for monthly migraine days and migraine-specific medication days. Achievement of ≥50%, ≥75% and 100% reductions from the double-blind treatment phase baseline in monthly migraine days at Week 52 were reported by 59.0%, 33.2% and 8.9% of patients, respectively, for the combined dose group. A numerically greater benefit was observed with 140 mg compared with 70 mg at Weeks 40 and 52. Sustained efficacy of long-term erenumab treatment in patients with chronic migraine is demonstrated, with safety results consistent with the known safety profile of erenumab and adverse event rates comparable to placebo adverse event rates in the double-blind treatment phase. This study is registered at ClinicalTrials.gov (NCT02174861).

Time to Symptom Resolution in Ulcerative Colitis With Multimatrix Mesalazine Treatment: A Pooled Analysis

Patients with ulcerative colitis [UC] require rapid and complete relief of symptoms, particularly stool frequency and rectal bleeding. The aim of this study was to determine time to symptom resolution in patients with UC during induction treatment with multimatrix mesalazine, and the proportion of patients remaining symptom-free and in endoscopic remission after 12 months of maintenance. A pooled analysis of 5 pivotal clinical trials, including >1300 patients, evaluating multimatrix mesalazine for treatment of mild-to-moderate active UC was conducted. Time to symptom resolution was defined as the period between first drug dosage date and first 3 consecutive days of induction therapy when the patient achieved a score of 0 [normal] on a modified UC Disease Activity Index for stool frequency and/or rectal bleeding. Median [95% confidence interval] time to resolution of stool frequency was 52 (45-not estimable [NE]) days for placebo versus 38 [34-41] days for multimatrix mesalazine [combined dose groups, 2.4 or 4.8 g/day]; time to resolution of rectal bleeding was 35 [20-NE] days for placebo versus 15 [14-17] days for multimatrix mesalazine [combined dose groups]. Among those who achieved resolution of both stool frequency and rectal bleeding during induction, 67.4% maintained symptom scores of 0 at Month 12. No relationship was observed between rapidity of symptom resolution during induction treatment and achievement of endoscopic remission at Month 12. Induction with multimatrix mesalazine provided rapid and prolonged symptom resolution in addition to endoscopic remission at Month 12.

Effects of oral sildenafil on exercise capacity in children with pulmonary arterial hypertension: a randomised trial

ObjectiveThe 16-week, randomised, double-blind Sildenafil in Treatment-Naïve Children, Aged1–17 years, with Pulmonary Arterial Hypertension (STARTS-1) study assessed the effect of sildenafil on cardiopulmonary exercise testing (CPET) in treatment-naïve paediatric patients...

Antileishmanial Efficacy and Pharmacokinetics of DB766-Azole Combinations

Given the limitations of current antileishmanial drugs and the utility of oral combination therapy for other infections, developing an oral combination against visceral leishmaniasis should be a high priority. In vitro combination studies with DB766 and antifungal azoles against intracellular Leishmania donovani showed that posaconazole and ketoconazole, but not fluconazole, enhanced DB766 potency. Pharmacokinetic analysis of DB766-azole combinations in uninfected Swiss Webster mice revealed that DB766 exposure was increased by higher posaconazole and ketoconazole doses, while DB766 decreased ketoconazole exposure. In L. donovani-infected BALB/c mice, DB766-posaconazole combinations given orally for 5 days were more effective than DB766 or posaconazole alone. For example, 81% ± 1% (means ± standard errors) inhibition of liver parasite burden was observed for 37.5 mg/kg of body weight DB766 plus 15 mg/kg posaconazole, while 37.5 mg/kg DB766 and 15 mg/kg posaconazole administered as monotherapy gave 40% ± 5% and 21% ± 3% inhibition, respectively. Combination index (CI) analysis indicated that synergy or moderate synergy was observed in six of nine combined dose groups, while the other three were nearly additive. Liver concentrations of DB766 and posaconazole increased in almost all combination groups compared to monotherapy groups, although many increases were not statistically significant. For DB766-ketoconazole combinations evaluated in this model, two were antagonistic, one displayed synergy, and one was nearly additive. These data indicate that the efficacy of DB766-posaconazole and DB766-ketoconazole combinations in vivo is influenced in part by the pharmacokinetics of the combination, and that the former combination deserves further consideration in developing new treatment strategies against visceral leishmaniasis.

P032 - Consistent reduction in the annualized rate of brain volume loss across phase 3 core and extension trials of fingolimod in relapsing multiple sclerosis

Background/objective In phase 3 trials, fingolimod 0.5 mg or 1.25 mg daily reduced brain atrophy versus placebo over 2 years (FREEDOMS and FREEDOMS II), and versus interferon beta-1a IM (IFNβ-1a) over 1 year (TRANSFORMS). Rates of brain atrophy on continuous fingolimod treatment were sustained in extension studies, but diminished number of completers might limit interpretability. We estimated the continuous effect of fingolimod treatment on brain volume (BV) loss, using all data from phase 3 and extension trials. Design/methods We determined annualized percentage BV change (PBVC) for all patients individually, to account for variable treatment-time exposures. During phase 3 studies and extensions, annualized PBVC was calculated for each patient from fingolimod treatment initiation until last available scan. Descriptive analyses included cohorts of patients receiving fingolimod 0.5 mg continuously, and all patients receiving fingolimod (combined-dose group) continuously, for up to 60 months from phase 3 baseline. Further analyses, using these dose-group definitions, were also conducted for up to 24 months from extension baseline to compare annualized PBVC among patients after switching to fingolimod from placebo or IFNβ-1a, with that determined on long-term fingolimod treatment. Results Respectively, mean annualized PBVC in the long-term continuous fingolimod 0.5 mg and combined-dose groups was FREEDOMS, ?0.45% ( n =372), ?0.42% ( n =718); FREEDOMS II, ?0.41% ( n =279), ?0.38% ( n =553); TRANSFORMS, ?0.31% ( n =379), ?0.31% ( n =728); and after switching was FREEDOMS, ?0.49% ( n =135), ?0.44% ( n =259); FREEDOMS II, ?0.47% ( n =47), ?0.43% ( n =103); TRANSFORMS, ?0.25% ( n =130), ?0.19% ( n =267). Conclusion Annualized PBVC during fingolimod phase 3 and extension studies demonstrate a consistent low rate of brain atrophy, supporting previous observations from individual studies. After switching to fingolimod from the comparator, patients exhibited similar atrophy rates to those initially randomized to fingolimod. Annualized PBVC calculation incorporates all available PBVC data, despite varying treatment-time exposures, and partly addresses discontinuation bias that may occur in long-term analyses.

Long-Term Ambrisentan Therapy for the Treatment of Pulmonary Arterial Hypertension

This study evaluated the safety and efficacy of ambrisentan for a period of 2 years in patients with pulmonary arterial hypertension (PAH). Ambrisentan is an oral, once-daily endothelin receptor antagonist that is selective for the endothelin type A receptor. The ARIES-1 (Ambrisentan in Pulmonary Arterial Hypertension, Randomized, Double-Blind, Placebo-Controlled, Multicenter, Efficacy Studies) and ARIES-2 trials were the pivotal 12-week, placebo-controlled studies that led to the regulatory approval of ambrisentan (5 and 10 mg) for the treatment of PAH. In the ARIES-1 and -2 studies, and the subsequent long-term extension protocol, the ARIES-E study, 383 patients received ambrisentan (2.5, 5, or 10 mg). Efficacy and safety assessments are presented from the time of the first dose of ambrisentan for all patients with post-baseline data. After 2 years of ambrisentan exposure, the mean change from baseline in 6-min walk distance was improved for the 5-mg (+23 m; 95% confidence interval: 9 to 38 m) and 10-mg (+28 m; 95% confidence interval: 11 to 45 m) groups. Estimates of survival and freedom from clinical worsening for the combined dose group were 94% and 83%, respectively, at 1 year and 88% and 72%, respectively, at 2 years. The annualized risk of aminotransferase abnormalities >3x the upper limit of normal was approximately 2% per year; most of these events were mild and did not lead to discontinuation of drug. Two years of ambrisentan treatment was associated with sustained improvements in exercise capacity and a low risk of clinical worsening and death in patients with PAH. Ambrisentan was generally well tolerated and had a low risk of aminotransferase abnormalities over the 2-year study period. (A Long Term Study of Ambrisentan in Pulmonary Arterial Hypertension Subjects Having Completed AMB-320 or AMB-321; NCT00578786).