Min Of Infusion Research Articles

Eleclazine Suppresses Ventricular Fibrillation in Failing Rabbit Hearts with Ischemia- Reperfusion Injury Undergoing Therapeutic Hypothermia.

Eleclazine is a highly selective late sodium current inhibitor, possibly effective in reducing ventricular fibrillation (VF) in heart failure (HF) with ischemia-reperfusion (IR) injury. The electrophysiological effects of eleclazine at therapeutic hypothermia (TH) are unknown. We investigated the effects of eleclazine in suppressing VF in failing rabbit hearts with IR injury undergoing TH. HF was induced by right ventricular pacing. An IR model was created using coronary artery ligation for 60 min, followed by reperfusion for 30 min. Hearts were excised and Langendorff-perfused for optical mapping and electrophysiological studies. Electrophysiological studies were repeated after TH (33 oC) for 30 min or eleclazine (1 μM) infusion for 20 min. In failing IR-injured hearts, eleclazine reduced action potential duration (APD) dispersion and accelerated intracellular Ca2+ uptake to suppress arrhythmogenic alternans, but also exacerbated rate-dependent conduction slowing, resulting in neutral effects on VF inducibility at normothermia. TH increased VF severity. Eleclazine after TH ameliorated TH-induced APD dispersion and further depressed conduction to reduce VF inducibility and severity. TH after eleclazine also slowed conduction to a greater extent to reduce VF inducibility and severity by extrastimulus pacing. In control IR-injured hearts, eleclazine increased VF severity by dynamic pacing at normothermia, which was counteracted by TH. Eleclazine does not prevent VF at normothermia, but reduces VF inducibility and severity by extrastimulus pacing at TH in isolated failing hearts with regional IR injury.

Phase I clinical trial evaluating the safety, tolerance, pharmacokinetics and pharmacodynamics of HSK21542 injection in healthy volunteers.

HSK21542 injection is a new peripheral kappa opioid receptor (KOR) agonist. To evaluate its safety, tolerability, pharmacokinetics and pharmacodynamics, this study was conducted in healthy volunteers, consisting of two parts: a single ascending dose (0.2-3.375 μg/kg, 15-min infusion) and different infusion durations (0.2 and 1μg/kg, 2- or 15-min infusion). The area under the plasma concentration-time curve (AUC) and peak concentration (Cmax) of HSK21542 were dose-linear among 0.2-3.375 μg/kg. After intravenous injection, HSK21542 was rapidly eliminated with a half-life (t1/2) of 1.5h, and the majority (48.02%) of the dose was excreted unchanged in urine. Pharmacodynamic results showed that HSK21542 increased prolactin release and reached a peak at 1-2h after administration but had no significant effect on vasopressin levels. There was a brief increase in urine volume within the initial 2h after administration. HSK21542 was well tolerated; most of the adverse effects (AEs) in the trial group were grade 1, and only 2 cases (4.0%) were grade 2. The main AE was paresthesia, which appeared in 42% (21/50) in the trial group. No serious adverse event (SAE) was observed. No subject withdrew early due to AEs. These results suggest that HSK21542 may be a potential treatment for pain and pruritic conditions.

Precision Dosing of Meropenem in Adults with Normal Renal Function: Insights from a Population Pharmacokinetic and Monte Carlo Simulation Study.

This study aimed to develop a population pharmacokinetic (PK) model for meropenem in healthy adults and explore optimal dosing regimens for patients with normal renal function. PK samples were obtained from 12 healthy participants, which were analyzed using noncompartmental analysis and nonlinear mixed-effect modeling. The PK profiles of meropenem were characterized using a two-compartment model, and serum creatinine level was identified as a significant covariate affecting total clearance. Monte Carlo simulations were conducted using this model to inform dosing recommendations. The target index for meropenem efficacy was defined as the cumulative percentage over 24 h during which free (f) drug concentration exceeded the minimum inhibitory concentration (MIC) under steady state conditions (fT>MIC). These simulations indicated that the current dosage regimen of 1 g for 30 min infusions every 8 h achieved a 90% probability of target attainment (PTA) for 40%fT>MIC when the MIC was <2 mg/L. However, to achieve more stringent therapeutic targets, such as a 90%PTA for 100%fT>MIC or a 90%PTA for 100%fT>4MIC, higher doses administered as 3 h extended infusions or as continuous infusions may be necessary. These results highlight the need for model-informed precision dosing to enhance the efficacy of meropenem therapy across various MIC levels and therapeutic targets.

A phase I safety and efficacy clinical trial of plocabulin and gemcitabine in patients with advanced solid tumors.

Plocabulin (Plo) induces depolymerization of tubulin fibers with disorganization and fragmentation of the microtubule network leading to mitosis. Plo combined with gemcitabine (Gem) showed synergistic anti-tumor activity in preclinical studies.This phase I trial evaluated the safety, pharmacokinetics (PK) and efficacy of Plo 10-min infusion plus Gem on Day 1 and 8 every 3-week in patients with advanced solid tumors.Fifty-seven patients were enrolled into 8 dose levels (DLs); 74%: females; 74%: ECOG performance status 1; median age: 62years; median number of prior lines of therapy:3. Dose-limiting toxicities (DLT) in Cycle 1 were grade (G) 3 intestinal obstruction at the maximum tolerated dose (MTD), G3 peripheral sensory neuropathy (PSN), G3 abdominal pain, and G4 thrombocytopenia (1 patient each). The highest DL (DL8: Plo 10.5mg/m2/Gem 1000mg/m2) was the MTD. Accrual into DL7 (Plo 10.0mg/m2/Gem 1000mg/m2) was stopped before it was formally defined as the recommended dose (RD). Most common treatment-related adverse events (AEs) were fatigue (56%), nausea (55%), diarrhea (31%); G3/4 hematologic toxicities comprised anemia (35%), neutropenia (27%) and thrombocytopenia (17%). No treatment-related deaths occurred. PK parameters for Gem or dFdU at all DLs were in line with reference values from the literature. Six of 46 evaluable pts were responders (overall response rate:13%). Of note, 2 partial responses (PR) and 2 stable disease (SD) ≥ 4months occurred among 13 pts with ovarian cancer.The combination of Plo and Gem is well tolerated. The MTD was Plo 10.5mg/m2/Gem 1000mg/m2. No PK drug-drug interaction was found. The most encouraging outcome occurred in ovarian cancer patients.

Identifying optimal dosing strategies for meropenem in the paediatric intensive care unit through modelling and simulation.

Meropenem, a β-lactam antibiotic commonly prescribed for severe infections, poses dosing challenges in critically ill patients due to highly variable pharmacokinetics. We sought to develop a population pharmacokinetic model of meropenem for critically ill paediatric and young adult patients. Paediatric intensive care unit patients receiving meropenem 20-40 mg/kg every 8 h as a 30 min infusion were prospectively followed for clinical data collection and scavenged opportunistic plasma sampling. Nonlinear mixed effects modelling was conducted using Monolix®. Monte Carlo simulations were performed to provide dosing recommendations against susceptible pathogens (MIC ≤ 2 mg/L). Data from 48 patients, aged 1 month to 30 years, with 296 samples, were described using a two-compartment model with first-order elimination. Allometric body weight scaling accounted for body size differences. Creatinine clearance and percentage of fluid balance were identified as covariates on clearance and central volume of distribution, respectively. A maturation function for renal clearance was included. Monte Carlo simulations suggested that for a target of 40% fT > MIC, the most effective dosing regimen is 20 mg/kg every 8 h with a 3 h infusion. If higher PD targets are considered, only continuous infusion regimens ensure target attainment against susceptible pathogens, ranging from 60 mg/kg/day to 120 mg/kg/day. We successfully developed a population pharmacokinetic model of meropenem using real-world data from critically ill paediatric and young adult patients with an opportunistic sampling strategy and provided dosing recommendations based on the patients' renal function and fluid status.

Sotrovimab in the treatment of coronavirus disease-2019 (COVID-19): a systematic review and meta-analysis of randomized clinical trials.

This study was carried out to verify the evidence regarding the effectiveness and safety of sotrovimab in patients with COVID-19. This is a systematic review of randomized clinical trials retrieved from the PubMed, Embase, Scopus, Lilacs, and Cochrane Library databases. The risk of bias was measured using the Cochrane Risk and Bias Checklist (RoB 2). For the meta-analysis, RStudio Version 2024.04.2 software was used. The certainty of evidence was assessed using GRADE. The study protocol was registered in PROSPERO (CRD42022355786). A total of 1893 studies were identified and four were included in the study. The total population consisted of 5470 patients with COVID-19, 1921 (35%) in the sotrovimab group and 3549 (65%) in the control group (placebo or BRII-196 + BRII-198 or casirivimab + imdevimab or bamlanivimab + etesevimab, administered in a similar way to sotrovimab, in a single dose with a 60-min intravenous infusion). For the effectiveness outcome, three studies presented low risk and one high risk of bias, while for safety all presented high risk of bias. The meta-analysis showed no significant difference between the sotrovimab and control groups in terms of hospitalization rates (95% confidence interval (CI) - 2.10-0.51; p = 0 > 0.05), use of invasive mechanical ventilation (95% CI - 2.78-0.65; p = 0.35) and mortality (95% CI - 0.92-0.59; p = 0.39). However, sensitivity analysis showed that sotrovimab may be effective in reducing hospitalization rates compared to the control (IV = - 1.57; 95% CI - 2.41-0.73; p = 0.99). The use of sotrovimab in the treatment of patients with COVID-19 had no significant impact on mortality and need for mechanical ventilation and did not appear to be safer compared to controls. However, there was evidence of effectiveness in reducing the rate of hospitalization, although the certainty of the evidence is moderate and the risk of bias is high.

Pharmacokinetics and Safety of Oliceridine Fumarate Injection in Chinese Patients with Chronic Non-Cancer Pain: A Phase I, Single-Ascending-Dose, Open-Label Clinical Trial.

Oliceridine is a novel G protein-biased ligand μ-opioid receptor agonist. This study aimed to assess the pharmacokinetics and safety profile of single-ascending doses of oliceridine fumarate injection in Chinese patients with chronic non-cancer pain. Conducted as a single-center, open-label trial, this study administered single doses of 0.75, 1.5, and 3.0 mg to 32 adult participants. The trial was conducted in two parts. First, we conducted a preliminary test comprising the administration of a single dose of 0.75mg to 2 participants. Then, we conducted the main trial involving intravenous administration of escalating doses of oliceridine fumarate (0.75 to 3 mg) to 30 participants. Pharmacokinetic (PK) parameters were derived using non-compartmental analysis. Additionally, the safety evaluation encompassed the monitoring of adverse events (AEs). 32 participants were included in the PK and safety analyses. Following a 2-min intravenous infusion of oliceridine fumarate injection (0.75, 1.5, or 3 mg), Cmax and Tmax ranged from 51.293 to 81.914 ng/mL and 0.034 to 0.083 h, respectively. AUC0-t and half-life (t1/2) increased more than proportionally with dosage (1.85-2.084 h). Treatment emergent adverse events (TEAEs) were found to be consistent with the commonly reported adverse effects of opioids, both post-administration and as documented in the original trials conducted in the United States. Critically, no serious adverse events were observed. Oliceridine demonstrated comparable PK parameters and a consistent PK profile in the Chinese population, in line with the PK results observed in the original trials conducted in the United States. Oliceridine was safe and well tolerated in Chinese patients with chronic non-cancer pain at doses ranging from 0.75 mg to 3.0 mg. The trial is registered at chictr.org.cn (ChiCTR2100047180).

Malonate given at reperfusion prevents post-myocardial infarction heart failure by decreasing ischemia/reperfusion injury

The mitochondrial metabolite succinate is a key driver of ischemia/reperfusion injury (IRI). Targeting succinate metabolism by inhibiting succinate dehydrogenase (SDH) upon reperfusion using malonate is an effective therapeutic strategy to achieve cardioprotection in the short term (< 24 h reperfusion) in mouse and pig in vivo myocardial infarction (MI) models. We aimed to assess whether inhibiting IRI with malonate given upon reperfusion could prevent post-MI heart failure (HF) assessed after 28 days. Male C57BL/6 J mice were subjected to 30 min left anterior coronary artery (LAD) occlusion, before reperfusion for 28 days. Malonate or without-malonate control was infused as a single dose upon reperfusion. Cardiac function was assessed by echocardiography and fibrosis by Masson’s trichrome staining. Reperfusion without malonate significantly reduced ejection fraction (~ 47%), fractional shortening (~ 23%) and elevated collagen deposition 28 days post-MI. Malonate, administered as a single infusion (16 mg/kg/min for 10 min) upon reperfusion, gave a significant cardioprotective effect, with ejection fraction (~ 60%) and fractional shortening (~ 30%) preserved and less collagen deposition. Using an acidified malonate formulation, to enhance its uptake into cardiomyocytes via the monocarboxylate transporter 1, both 1.6 and 16 mg/kg/min 10 min infusion led to robust long-term cardioprotection with preserved ejection fraction (> 60%) and fractional shortening (~ 30%), as well as significantly less collagen deposition than control hearts. Malonate administration upon reperfusion prevents post-MI HF. Acidification of malonate enables lower doses of malonate to also achieve long-term cardioprotection post-MI. Therefore, the administration of acidified malonate upon reperfusion is a promising therapeutic strategy to prevent IRI and post-MI HF.

Safety and feasibility analysis of rapid daratumumab infusion in Chinese patients with multiple myeloma.

With the increasing use of daratumumab (DARA)-containing regimens for multiple myeloma (MM) patients in China, the standard infusion time of DARA is long, with the potential for infusion-related reactions (IRRs) and increased hospitalization and use of resources. Shortening the duration of DARA infusion helps to optimize the hospital stay and enhance the patient treatment experience. The current, commonly used 90-min rapid DARA infusion regimen may not be applicable to Chinese MM patients, and therefore, we explored a new 110-min rapid DARA infusion regimen aimed at reducing the treatment burden on patients to guarantee therapeutic safety. MM inpatients treated with the DARA regimen were divided into two groups according to the number of times the DARA regimen was used: a standard infusion regimen for patients treated with the first two doses of DARA and a 110-min rapid infusion regimen for patients treated with more than two doses of DARA. Anti-allergy medications were routinely administered prior to the start of DARA infusion, patient consent, and authorization was obtained for all treatments, and statistical evaluation of the results was conducted via descriptive analyses, one-way ANOVA and chi-square tests. A total of 129 patients were included in this study: 68 in the standard infusion group, with 121 DARA infusions, and 129 in the rapid infusion group (patients who participated in the standard infusion subsequently participated in the rapid infusion), with 738 DARA infusions. The incidence of IRRs was 27.27% (36/121) in the standard infusion group and 1.35% (10/738) in the rapid infusion group, which were significantly different (p < 0.001). The incidence of IRRs after rapid infusion in other studies was <6%. The incidence of grade 1 IRRs in the rapid infusion group was 0.81% (6/738), the incidence of grade 2 IRRs was 0.54% (4/738), and there were no IRRs above grade 3; age, sex, and underlying disease had no effect on the choice of infusion method (p > 0.05). The mean infusion time after the occurrence of IRRs was also shorter in the rapid infusion group than in the standard infusion group (F = 24.781, p < 0.001). The 110-min rapid infusion DARA regimen is feasible and safe for use in Chinese MM patients.

The FIPO23 trial: First-in-human phase I/II study of XON7 in advanced solids tumors.

TPS2673 Background: XON7 is a first-in-class glyco-humanized polyclonal antibody (GH-pAb) targeting selectively multiple tumor-associated antigens. XON7 induces tumor cell apoptosis and promotes the elimination of tumor cells by immune effector cells through CDC (Complement Dependent Cytotoxicity) and ADCP (Antibody-Dependent Cell Phagocytosis). XON7 demonstrated anti-tumor efficacy in mice xenograft models with human solid tumors such as colon, prostate, lung and triple negative breast cancers. Safety pharmacology and toxicology studies in non-human primates demonstrated an acceptable safety profile for XON7. Taken together, these preclinical data support the initiation of human trials in patients with advanced solid tumors. Methods: First-in-patient, multicenter, open-label, two phases (dose-escalation (ESC) followed by dose expansion (EXP)) study of XON7 single agent, in patients with relapsed refractory, locally advanced or metastatic solid tumors without standard available treatments ( NCT06154291). Key eligibility criteria include disease progression after ≤ 4 lines of therapy; age &gt; 18 years; ECOG performance status ≤2; adequate organ functions; no known CNS involvement. All advanced or metastatic tumor types except glioblastoma, can be included during ESC. Primary endpoints: safety, tolerability and determination of MTD/RP2D. Secondary endpoints: pharmacokinetics (PK), pharmacodynamics, immunogenicity and preliminary anti-tumor activity (RECIST 1.1). AEs graded according to CTCAE 5.0. In the ESC part, XON7 is administered as 60-min intravenous infusion every 2 weeks according to an escalating schedule of doses from 1.5 to 20 mg/kg for up to 12, 28-day cycles. Dose escalation/de-escalation is based on the Bayesian Optimal Interval (BOIN) design, up to 45 pts are planned. At the recommended dose, up to 7 EXP cohorts (30 pts each) defined according to the primary tumor site are planned. Bayesian sequential monitoring will be used. Patient recruitment is planned or ongoing at 25 sites worldwide. Results: As of Feb 3rd, 2024, 3 pts are enrolled in the first dose cohort and have received XON7 at dose 1,5 mg/kg Q2W for the first 28-days cycle. Conclusions Accrual is ongoing in this first-in-human trial of XON7. Clinical trial information: NCT06154291 .

Hypersensitivity to CGRP as a predictive biomarker of migraine prevention with erenumab.

The present study aimed to investigate the predictive value of calcitonin gene-related peptide (CGRP)-induced migraine attacks for effectiveness to erenumab treatment in people with migraine. In total, 139 participants with migraine underwent a single experimental day involving a 20-min infusion with CGRP. Following this, the participants entered a 24-week treatment period with erenumab. The primary endpoints were the predictive value of CGRP-induced migraine attacks on the effectiveness of erenumab, defined as ≥50% reduction in monthly migraine days, or ≥ 50% reduction in either monthly migraine or monthly headache days of moderate to severe intensity. Among participants with CGRP-induced migraine attacks, 60 of 99 (61%) achieved ≥50% reduction in monthly migraine days during weeks 13-24 with erenumab. Conversely, 13 of 25 (52%) where CGRP infusion did not induce a migraine achieved the same endpoint (p = 0.498). There were no significant differences between the ≥50% reduction in either monthly migraine or monthly headache days of moderate to severe intensity between CGRP-sensitive and non-sensitive participants (p = 0.625). Our findings suggest that the CGRP-provocation model cannot be used to predict erenumab's effectiveness. It remains uncertain whether this finding extends to other monoclonal antibodies targeting the CGRP ligand or to gepants.Trial Registration: The study was registered at ClinicalTrials.gov (NCT04592952).

Brief Repetitive Pressure Overload Elicits a Fibrosis-Independent Reduction in Left Ventricular Diastolic Compliance in Swine

Objective: We have previously shown that swine subjected to repetitive pressure overload (RPO) via daily 2-hr infusions of phenylephrine (PE) develop a reduction in left ventricular (LV) diastolic compliance that coincides with increased interstitial myocardial fibrosis. The objective of the present study was to determine if brief episodes of RPO produce a similar cardiac phenotype. Methods: Swine (n=6) were subjected to a single 30-min PE infusion (300 μg/min) to determine if brief pressure overload causes myocardial injury (circulating cardiac troponin I; cTnI), inflammation (IL-6), and cardiac dysfunction (echocardiography). A separate group of swine (n=5) were subsequently instrumented with an indwelling venous catheter to enable daily 30-min PE infusions for 2 weeks (“Brief RPO”). LV diastolic compliance (ΔLVEDV/ΔLVEDP during PE) and interstitial fibrosis (picrosirius red staining) were compared to values derived from swine subjected to prolonged RPO (2-hr PE/day; n=8) and age-matched controls (n=8). Results: A single episode of brief pressure overload led to an increase in circulating cTnI (from 22±6 ng/L at baseline to 365±12 ng/L 3-hours post-PE) and IL-6 (from 10±2 to 34±4 pg/mL), along with a transient reduction in LV ejection fraction (from 65±2 to 45±5 %, all p&lt;0.05). Brief RPO led to a significant reduction in LV diastolic compliance (ΔLVEDV/ΔLVEDP: 0.59±0.13 mL/mmHg vs. 1.87±0.12 mL/mmHg in controls; p&lt;0.01) that was nearly identical to that observed after prolonged RPO (0.58±0.17 mL/mmHg, p=0.95). Surprisingly, in contrast to prolonged RPO (10.0±1.4% collagen) the brief RPO-induced reduction in LV compliance was not accompanied by an increase in interstitial fibrosis (5.0±0.3 % collagen vs. 5.0±0.3 % collagen in controls, p=0.95). Conclusion: Brief pressure overload initially causes myocardial injury and inflammation, with repetitive exposure leading to a reduction in LV compliance that is similar to that observed following prolonged RPO. However, the brief RPO-induced reduction in LV compliance occurs in the absence of fibrosis, suggesting that mechanisms of repetitive stretch-induced myocardial stiffening may depend on the duration of episodic pressure overload. Supported by funding from the U.S. Department of Veterans Affairs and National Institutes of Health. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Ketamine Sedation Decreases Survival after Extremity Trauma and Moderate Hemorrhage in Rats

Objective: Traumatic hemorrhage (HEM) is often associated with pain. The use of ketamine (KET) has increased both on the battlefield and in civilian emergency care for analgesia and sedation. We have reported that an analgesic dose of KET does not impact cardiorespiratory responses or survival after HEM (JAP 130: 1583-1593, 2021). In this study, we measured the effects of a larger, sedative, dose of KET on cardiovascular responses and survival to moderate (37% blood volume) HEM combined with extremity trauma (ET), and whether midazolam (MDZ), a drug often given in combination with KET alters these responses. Hypothesis: We hypothesized that either KET (50 mg/kg) or KET+MDZ (5 mg/kg) would compromise cardiovascular responses to HEM and thereby decrease survival. Methods: Male rats were implanted with a telemetry transmitter to measure mean arterial pressure (MAP) and heart rate (HR); buprenorphine SR was used to relieve pain associated with surgical procedures. Following 2 weeks recovery, rats were anesthetized using isoflurane, and a carotid catheter was implanted. The next day, rats were briefly anesthetized using isoflurane to perform ET (fibular fracture + hindlimb soft tissue crush injury) and were allowed to recover 90 min before starting conscious HEM (time = 0-25 min). Rats received either 1) saline vehicle (VEH, n=8); 2) KET (n=8); or 3) KET followed by MDZ (KET+MDZ; n=9) during a 15 min infusion (t = 25-40 min). The study continued for 200 minutes (time = 40-240 min). Data are mean ± SD. Results: There were no differences between groups in MAP or HR at either baseline (t = 0 min) or at end of HEM (t = 25 min). However, during the 20 min after treatment (t = 40-60 min), MAP and HR were significantly lower (P≤0.05) in KET (46 ± 3 mmHg; 220 ± 11 bpm) and KET+MDZ (45 ± 10 mmHg; 212 ± 24 bpm) compared to VEH (68 ± 20 mmHg; 297 ± 37 bpm). During this time, only 3 of 8 rats in the KET group survived HEM, while all rats survived in VEH and KET+MDZ groups. At the end of the study (t = 240 min), survival rate was significantly lower (P=0.003) in KET (37.5%) compared to VEH (87.5%) or KET+MDZ (100%). Similarly, survival time was significantly lower (P=0.004) in KET (115 ± 103 min) compared to VEH (227 ± 37 min) or KET+MDZ (240 ± 0 min). Summary of Results: A sedative dose of KET decreased survival following HEM, but the same dose of KET followed by MDZ was protective. The MDZ effect was not due to improvements in cardiovascular responses to the HEM. Conclusion: Sedation with ketamine alone after trauma and moderate HEM decreased survival. Further studies of the effects of sedation with KET alone or KET+MDZ on respiration and metabolic responses to HEM may provide insight on the overall effect on survival. Congressionally Directed Medical Research Program (CDMRP). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Intrinsic mechanisms of right ventricular autoregulation

To elucidate the adaptation of the right ventricle to acute and intermittently sustained afterload elevation, targeted preload reductions and afterload increases were implemented in a porcine model involving 12 pigs. Preload reduction was achieved via balloon occlusion of the inferior vena cava before, immediately and 5 min after acute afterload elevation induced by pulmonary artery occlusion or thromboxane A2 analog (U46619) infusion. Ventricular response was monitored by registration of pressure–volume (PV) loops using a conductance catheter. The end-systolic pressure–volume relationship (ESPVR) during pure preload reduction was adequately described by linear regression (mean and SEM slope of ESPVR (Ees) 0.414 ± 0.064 mmHg/ml), reflecting the classical Frank-Starling mechanism (FSM). The ESPVR during acute afterload elevation exhibited a biphasic trajectory with significantly distinct slopes (mean and SEM Ees bilin1: 1.256 ± 0.066 mmHg ml; Ees bilin2: 0.733 ± 0.063 mmHg ml, p < 0.001). The higher slope during the first phase in the absence of ventricular dilation could be explained by a reduced amount of shortening deactivation (SDA). The changes in PV-loops during the second phase were similar to those observed with a preload intervention. The persistent increase in afterload resulted in an increase in the slopes of ESPVR and preload recruitable stroke work (PRSW) with a slight decrease in filling state, indicating a relevant Anrep effect. This effect became more pronounced after 5 min or TXA infusion. This study demonstrates, for the first time, the relevance of intrinsic mechanisms of cardiac autoregulation in the right ventricle during the adaptation to load. The SDA, FSM, and Anrep effect could be differentiated and occurred successively, potentially with some overlap. Notably, the Anrep effect serves to prevent ventricular dilation.

Abstract 15483: Mitoquinone Pretreatment Mitigates Dox-induced Systolic Dysfunction in Isolated Rat Hearts

Background: Doxorubicin (DOX) is a common and effective chemotherapeutic agent that can exert cardiotoxicity by inducing oxidative stress in mitochondria, compromising mitochondrial function, and inducing apoptosis. Currently, there is no treatment that targets this mechanism. We previously found that pretreatment with higher concentrations of mitoquinone (MQ), a mitochondrial antioxidant, exerts cardioprotection against DOX in myoblast H9C2 cells. Hypothesis: We hypothesize that MQ pretreatment would preserve cardiac function against DOX in isolated rat hearts. Methods: Cardiac parameters (heart rate (HR) and left ventricular end systolic pressure (LVESP)) were monitored before and after 60 min infusion of DOX, MQ, or DOX with MQ pretreatment (10-15 min) in a Langendorff preparation of male SD rat hearts. TUNEL assay was conducted on heart tissue slides to evaluate apoptosis. The ratio between the final and initial cardiac parameters was calculated and compared among experimental groups. Results: Higher dose DOX (25 μM, n=5) induced a higher reduction in the ratios of LVESP, to 39±5% than lower dose DOX infusion (20 μM, n=3; 74±3%). DOX had no effects on HR. A 60-minute perfusion of higher doses of MQ (1-5 μM, n=7) unexpectedly reduced the ratios of LVESP and HR to 73±12% and 66±5%, respectively. Higher dose MQ (1-2.5 μM, n=6) pretreatment showed similar improvement of LVESP ratio (68±9%) to lower dose MQ (0.25-0.5 μM, n=6; 71±11%). TUNEL assay showed that higher dose DOX caused a higher rate of apoptosis (number of TUNEL-positive nuclei) (326.3±6.4. n=3) than lower dose (214±29.5, n=3). Pretreatment with higher dose MQ prior to DOX 25 μM infusion resulted in a notable reduction of apoptosis (60.3±5, n=6) compared to DOX alone, while lower dose pretreatment reduced apoptosis to 70.5± 0.5 (n=4). Conclusion: This study suggests that infusion of DOX into the heart acutely attenuated cardiac systolic function accompanied with higher apoptotic cell damage. Although prolonged administration of higher doses of MQ suppressed cardiac function, MQ pretreatment for 10-15 minutes mitigated DOX-induced systolic dysfunction and reduced cardiomyocyte apoptosis. In summary, MQ pretreatment may mitigate DOX-induced cardiac damage.

30-Minute Infusion of Isatuximab in Newly Diagnosed Multiple Myeloma (NDMM) Patients: Results of a Phase 1b Study

Introduction: The anti-CD38 antibody isatuximab (Isa) is approved in various countries with pomalidomide-dexamethasone for relapsed/refractory multiple myeloma (RRMM) patients (pts) with ≥2 prior therapies including lenalidomide and a proteasome inhibitor, based on the ICARIA-MM study, and with carfilzomib-dexamethasone for RRMM pts with ≥1 prior therapy, based on the IKEMA study. To enhance convenience of intravenous (IV) Isa administration, a shorter IV infusion over 30 minutes (30-min) was assessed in pts with NDMM not eligible/with no immediate intent for autologous stem cell transplantation (ASCT) still on maintenance therapy in a Phase 1b trial (NCT02513186). Results previously reported from this study showed efficacy of treatment with Isa in combination with bortezomib-cyclophosphamide-dexamethasone (VCd) or bortezomib-lenalidomide-dexamethasone (VRd), with manageable safety profiles. The rates of very good partial response or better and of minimal residual disease negativity (at 10 -5 sensitivity) were 80% and 53.3% with Isa-VCd, and 92.9% and 50.7%, respectively, with Isa-VRd [Ocio EM et al. HemaSphere 2023;7(2):e829; Ocio EM et al. Leukemia 2023;37(7):1521-1529]. Preliminary results with the new 30-min Isa administration method are presented here. Methods: Pts still receiving maintenance treatment were to be switched to the 30-min infusion with Isa at 10 mg/kg diluted in a 250 mL infusion bag of 0.9% sodium chloride. The infusion rate of the first infusion was 250 mL/hr; in the absence of infusion reactions (IRs), subsequent infusions were to be administered at an infusion rate of 500 mL/hr. The objective was to evaluate safety in terms of incidence and severity of IRs during the first 2 full 30-min infusions. The initial, recommended premedication to be given at the time of the switch consisted of dexamethasone 20 mg orally (PO) (or equivalent [eq.]), acetaminophen (paracetamol) 650 to 1000 mg PO; ranitidine 50 mg IV (or eq.), diphenhydramine 25 to 50 mg IV (or eq.), and montelukast 10 mg PO (or eq.). Prior to switching, pts received weight-based Isa infusion in the VCd cohorts and initially in the VRd Part A cohort, followed by fixed-volume Isa infusion in both VRd Parts A and B (in Part B, at 200 mL/hr from 3 rd infusion, ~75 min with no IRs/interruptions). Results: As of 19 May 2023, 29.4% of pts in Isa-VCd, 48.1% in Isa-VRd Part A, and 60.9% in Isa-VRd Part B were still on treatment. The median follow-up for all pts was 71.1, 55.1, and 38.1 months for the Isa-VCd, Isa-VRd Part A, and Isa-VRd Part B cohorts, with a median duration of exposure of 63.5, 54.1, and 40.8 months, respectively. A total of 45 pts received 142 infusions between Jan 2023 and May 2023: 45 first infusions with intermediate rate and 97 30-min infusions across cohorts, with a median of 3 cycles started by pts (range, 1-5) (44 pts received at least 2 infusions) and a median relative Isa dose intensity of 99.4% (range, 73.7-105.5%). Switching occurred at a median of 46 cycles (range, 38-88) for all treated pts. The median duration of Isa infusion in all treated pts was 32 min, 33 min, and 33 min at the 2 nd, 3 rd, and subsequent infusions, respectively ( Table). 30-min infusion of Isa was well tolerated, with no IRs and no infusion interruptions across cohorts. Conclusions: These preliminary results show that 30-min infusion of Isa is a feasible, well-tolerated, and convenient administration method for pts with multiple myeloma on Isa treatment for several months. The 30-min Isa infusion is currently being assessed from day 1 of cycle 2 in the ongoing Phase 1-2 UMBRELLA trial of Isa with or without dexamethasone in combination with novel agents, conducted in pts with RRMM (NCT04643002). Clinical trial registration: NCT02513186. Funding: Sanofi.

Quality and antioxidant activity of dandelion root infusions as affected by cold plasma pretreatment.

Ground and unground dandelion roots were subjected to dielectric barrier discharge cold plasma (DBDCP) at 40 kV for 0 (control), 10, or 20 min. Then, infusions of the pretreated dandelion roots in water were prepared, and the changes in color, total phenolic content (TPC), antioxidant activity, and sensory properties were investigated. The 20-min pretreatment increased the b* value, TPC, antioxidant activity, and sage odor of the ground dandelion root infusions compared with the control, whereas decreases in the TPC, antioxidant activity, and sage odor were noted in the 10-min pretreated infusions of the unground roots. DBDCP pretreatment did not affect the overall likeliness of infusions of ground and unground roots. In addition, the TPC, antioxidant activity, and overall likeliness of infusions of the ground dandelion roots were higher than those of the unground samples. In conclusion, it can be said that the DBDCP pretreatment can be utilized to improve the TPC and antioxidant activity of ground dandelion roots.

Neprilysin activity is increased in metabolic dysfunction-associated steatotic liver disease and normalizes after bariatric surgery or GLP-1 therapy

Inhibitors of neprilysin improve glycemia in patients with heart failure and type 2 diabetes (T2D). The effect of weight loss by diet, surgery, or pharmacotherapy on neprilysin activity (NEPa) is unknown. We investigated circulating NEPa and neprilysin protein concentrations in obesity, T2D, metabolic dysfunction-associated steatotic liver disease (MASLD), and following bariatric surgery, or GLP-1-receptor-agonist therapy. NEPa, but not neprilysin protein, was enhanced in obesity, T2D, and MASLD. Notably, MASLD associated with NEPa independently of BMI and HbA1c. NEPa decreased after bariatric surgery with a concurrent increase in OGTT-stimulated GLP-1. Diet-induced weight loss did not affect NEPa, but individuals randomized to 52-week weight maintenance with liraglutide (1.2mg/day) decreased NEPa, consistent with another study following 6-week liraglutide (3mg/day). A 90-min GLP-1 infusion did not alter NEPa. Thus, MASLD may drive exaggerated NEPa, and lowered NEPa following bariatric surgery or liraglutide therapy may contribute to the reported improved cardiometabolic effects.

Cardioprotective effect of St. Thomas’ Hospital No. 2 solution against age-related changes in aquaporin-7-deficient mice

ObjectiveThis study aimed to investigate whether St. Thomas’ Hospital No. 2 solution (STH2) is equally effective in both young and aged aquaporin-7-knockout (AQP7-KO) mice and the mechanisms by which the intra-myocardial adenosine triphosphate (ATP) content is altered during ischemia without aquaporin-7.MethodsIn study 1, isolated hearts of male wild-type (WT) and AQP7-KO mice (< 12 weeks old) were Langendorff perfused with 5-min STH2 prior to a 20-min global ischemia (GI) or 25-min GI without STH2. Similarly, in Study 2, hearts from WT and AQP7-KO mice (≥ 24 weeks old) were subjected to 2-min STH2 infusion prior to GI. In study 3, intra-myocardial ATP content was compared before (sham) and after (control or STH2) ischemia in mature WT and AQP7-KO mice.ResultsIn study 1, troponin T levels (ng/g wet weight) of WT and AQP7-KO hearts were significantly lower in the STH2 groups (75.6 ± 45.9 and 80.2 ± 52.2, respectively) than in the GI groups (934.0 ± 341.1 and 1089.3 ± 182.5, respectively). In Study 2, troponin T levels in aged WT and AQP7-KO mice were 566.5 ± 550.0 and 547.8 ± 594.3, respectively (p = 0.9561). In Study 3, ATP levels (μmol/g protein) in the sham, control, and STH2 AQP7-KO mice groups were 4.45, 2.57, and 3.37, respectively(p = 0.0005).ConclusionsThe present study revealed the cardio-protective efficacy of STH2 in an experimental model of isolated AQP7-KO young and aged murine hearts. Further, STH2 preserved intra-myocardial ATP during ischemia with Krebs–Henseleit buffer perfusion in the Langendorff setting.

Pharmacokinetics, pharmacodynamics, and safety of LPM3480392 in two phase I clinical trials in healthy Chinese male subjects.

Drugs for acute postoperative pain and breakthrough cancer pain are still urgent on clinical. LPM3480392 is a G-protein-biased ligand at the μ-opioid receptor and showed potent analgesia in nonclinical studies. Two phase I studies of LPM3480392 were conducted in healthy Chinese male volunteers to explore its tolerability, pharmacokinetics, and pharmacodynamics under single ascending doses (Study I 0.1-3.0 mg, 30 min) and different infusion time (Study II, 0.6-1.0 mg, 2-15 min). There was one serious adverse event (AE) observed in Study II, and the rest AEs were mild or moderate in severity and resolved by the end of the study. Plasma LPM3480392 maximum concentration (Cmax ) (under lower infusion rate) and area under the plasma concentration-time curve (AUCs) were generally increased with dose. Moreover, LPM3480392 at dose of 0.6 mg under 2 min infusion rate elicited effective analgesia as the peak effect within 10-30 min, which measured by cold pain test and pupillometry. These findings suggest that LPM3480392 could be a potential treatment for acute pain management.