Intravenous Infusion Research Articles

The Safety, Tolerability, and Pharmacokinetics of Active Ingredients From Hydroxysafflor Yellow A in Healthy Chinese Volunteers

AbstractHydroxysafflor yellow A (HSYA), an active ingredient extracted from Carthami flos, shows potential for treating ischemic stroke. This phase 1 study assessed the safety, tolerability, and pharmacokinetic (PK) properties of HSYA in healthy Chinese volunteers who received intravenous infusions of pure HSYA powder. The study comprised 2 parts. Part A was a randomized, double‐blind, placebo‐controlled dose‐escalation study that evaluated safety and tolerability. This included a single‐dose study with 7 dose levels of HSYA (6.25, 12.5, 25, 50, 75, 100, and 125 mg) in 52 volunteers, and a multidose study (100 and 125 mg) in 16 volunteers. Part B was an open‐label study where 12 volunteers received 75 mg of HSYA once daily for 14 consecutive days to examine PKs. There were no adverse events (AEs) leading to treatment discontinuation by HSYA throughout the treatment period. All reported AEs were mild and did not require special treatment. PK analysis revealed rapid absorption (median Tmax of 1.1 hours) and elimination (median t1/2 4.0 and 4.7 hours) of HSYA. Total body clearance on the 1st and 14th days was 1.7 and 1.6 L/h, respectively.

Preclinical pharmacology characterization of HX009, a novel PD1 x CD47 Bi-specific antibody.

Certain immune-checkpoint inhibitors have a narrow therapeutic window (TW) as cancer therapeutics, and engineered dual-/multi-targeting agents could potentially widen the TW to bring true clinical benefits. We report a new rationally-designed bispecific-antibody (BsAb), HX009, simultaneously targeting PD1 and CD47 to improve both the efficacy and safety over the respective single-targeting agents by grafting the extracellular domain of SIRPα onto the parental anti-PD1-monoclonal antibody, HX008. This resulted in an IgG4-based "2 × 2" symmetric structure but with an intentionally-reduced CD47-binding affinity, suggesting a novel candidate cancer immunotherapy. Specifically, HX009 has binding affinity constant of 8.951 × 10-9M for human PD1 and 2.557 × 10-8M for human CD47, respectively, where the CD47 binding is significantly weaker as compared to the binding affinity of HX008 to PD1 as well as the binding affinity of SIRPα-Fc to CD47, leading to little binding to RBCs and platelets and is contrasting to many CD47-agents in development. However, HX009 effectively and simultaneously binds to the PD1 and CD47 on PD1+CD47+ T-cells via cis-binding and elicits enhanced T cell activation compared to the parental HX008. HX009 caused little cytokine-release in human peripheral blood mononuclear cells. HX009 cross-species binds to cynomolgus monkey PD1/CD47 but not to rodents, making cynomolgus monkeys the choice of species to investigate the pharmacokinetics (PK) and toxicology of HX009. HX009's anti-tumor activities were confirmed in several humanized preclinical mouse models by determining either its anti-PD1 (humanized hu-CD47-MC38 models) or anti-CD47 (HuT-102 lymphoma CDX and three PDX-AML models) functions, although limited available humanized models have hindered broadly demonstration of enhanced anti-tumor activities contributed from the dual targeting of the BsAb. The expanded DLBCL-PDX trial data suggested that both EBV-status and OX40 expression could potentially be two positive predictors for response to HX009. An intravenous (IV) infusion PK study in cynomolgus monkey revealed its largely vasculature distribution, terminal half-life (T1/2) of ~ 50h, and dose-proportional exposure without accumulation. The anti-drug antibody (ADA) was observed in all monkeys as expected, affecting the PK parameters of repeated administration. The IV single-dose toxicology study with a 14-day observation revealed a maximum tolerated dose of 150mg/kg, while the repeated-dose (once weekly for 4weeks, 5 doses in total) study showed a highest non-severely toxic dose (HNSTD) of 15mg/kg. The desired preclinical PK and safety profiles, along with its antitumor activity, support HX009's candidacy for its clinical development.

Effect of intravenous tranexamic acid on postoperative drainage and elbow joint function after traumatic elbow stiffness release

To explore the effect of intravenous tranexamic acid on postoperative drainage and elbow joint function after traumatic elbow stiffness release. The clinical data of 44 patients with elbow joint stiffness who were treated with release surgery between March 2022 and December 2023 and met the selection criteria were retrospectively analyzed. Among them, 20 patients were given intravenous infusion of 100 mL (1 g/100 mL, once a day) of tranexamic acid solution for 3 consecutive days after surgery (group A), and 24 patients were not treated with tranexamic acid after surgery (group B). There was no significant difference in baseline data such as gender, age, side, body mass index, initial injury, and preoperative hemoglobin, visual analogue scale (VAS) score, and Mayo elbow function score (MEPS), elbow flexion and extension activity between the two groups ( P>0.05). The drainage volume at 1 day and 3 days after operation, total drainage volume, drainage tube indwelling time, postoperative hospital stay, VAS score before operation and at 1, 2, and 3 days after operation, MEPS score before operation, at 3 months after operation, and at last follow-up, and elbow flexion and extension activity before operation and at last follow-up were recorded and compared between the two groups. Both groups of patients successfully completed the operation, and there was no significant difference in operation time ( P>0.05). The drainage volume at 1 day and 3 days after operation, total drainage volume, drainage tube indwelling time, and postoperative hospital stay in group A were significantly less than those in group B ( P<0.05). Both groups of patients were followed up 6-12 months, with an average of 8.6 months. No complications such as wound infection, elbow joint varus and varus instability or dislocation, and pulmonary embolism or other thromboembolic events occurred in either group. The VAS scores of both groups were significantly higher at 1 day and 2 days after operation than before operation ( P<0.05); the VAS score of group A was significantly lower than that of group B ( P<0.05). The VAS scores of both groups decreased to the preoperative level at 3 months after operation, and there was no significant difference between the two groups ( P>0.05). At 3 months after operation and at last follow-up, the MEPS scores of both groups significantly improved when compared with those before operation ( P<0.05); there was no significant difference between the two groups ( P>0.05). At last follow-up, the postoperative elbow flexion and extension activity of the two groups significantly increased when compared with that before operation ( P<0.05); there was no significant difference in change of elbow flexion and extension activity between the two groups ( P>0.05). Intravenous tranexamic acid for 3 consecutive days after release of traumatic elbow stiffness can significantly reduce postoperative drainage volume, shorten drainage tube indwelling time and hospital stay, and relieve early postoperative pain, but it has no effect on the risk of thrombotic and embolic events and postoperative elbow function.

Proof of concept for a superior therapeutic index of corticosterone compared with hydrocortisone in patients with congenital adrenal hyperplasia.

Outcomes are poor for patients with congenital adrenal hyperplasia (CAH), in part due to the supraphysiological glucocorticoid doses required to control adrenal androgen excess. Hydrocortisone (i.e. cortisol) is the recommended glucocorticoid for treatment of CAH. However, the other endogenous glucocorticoid in humans, corticosterone, is actively transported out of metabolic tissues such as adipose tissue and muscle, so we hypothesized that corticosterone could control adrenal androgens while causing fewer metabolic adverse effects than hydrocortisone. Thirteen patients (8 female, 5 male) with CAH due to 21-hydroxylase deficiency completed a randomised placebo-controlled crossover study comparing 5h intravenous infusions of either hydrocortisone, corticosterone or placebo. 6-6[2H]2-glucose and 1,1,2,3,3-[2H]5-glycerol were infused to measure glucose and glycerol kinetics, and blood samples were collected throughout. Subcutaneous abdominal adipose tissue biopsies were obtained at the end of each infusion. During the infusion, corticosterone and hydrocortisone similarly reduced ACTH, 17α-hydroxyprogesterone, androstenedione, and testosterone (in females only) compared with placebo. Despite achieving circulating corticosterone concentrations ∼2.5-fold higher than hydrocortisone, by T+300 minutes hydrocortisone but not corticosterone increased glucose and insulin concentrations and reduced 6-6-[2H]2-glucose clearance compared with placebo. Hydrocortisone increased mRNA levels of the glucocorticoid regulated transcript PER1 in adipose to a greater extent than corticosterone. Corticosterone acutely controls biochemical markers of androgen excess similarly to hydrocortisone but without inducing markers of glucocorticoid 'toxicity' in CAH. These data demonstrate proof of concept that corticosterone may be a safer glucocorticoid replacement than current medications, although further research is required to assess the longer-term effects of corticosterone replacement.

Inebilizumab for Treatment of IgG4-Related Disease.

IgG4-related disease is a multiorgan, relapsing, fibroinflammatory, immune-mediated disorder with no approved therapy. Inebilizumab targets and depletes CD19+ B cells and may be effective for treating patients with IgG4-related disease. In this phase 3, multicenter, double-blind, randomized, placebo-controlled trial, adults with active IgG4-related disease underwent randomization in a 1:1 ratio to receive inebilizumab (300-mg intravenous infusions on days 1 and 15 and week 26) or placebo for a 52-week treatment period. Participants in both groups received identical glucocorticoid tapers. Glucocorticoids were allowed to treat disease flares, but background immunosuppressants were not permitted. The primary end point was the first treated, adjudicated disease flare during the treatment period, assessed in a time-to-event analysis. Key secondary end points were the annualized flare rate and treatment-free and glucocorticoid-free complete remission. A total of 135 participants with IgG4-related disease underwent randomization: 68 participants were assigned to receive inebilizumab and 67 were assigned to receive placebo. Treatment with inebilizumab reduced flare risk; 7 participants (10%) in the inebilizumab group had at least one flare, as compared with 40 participants (60%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.06 to 0.28; P<0.001). The annualized flare rate was lower with inebilizumab than with placebo (rate ratio, 0.14; 95% CI, 0.06 to 0.31; P<0.001). More participants in the inebilizumab group than in the placebo group had flare-free, treatment-free complete remission (odds ratio, 4.68; 95% CI, 2.21 to 9.91; P<0.001) and flare-free, glucocorticoid-free complete remission (odds ratio, 4.96; 95% CI, 2.34 to 10.52; P<0.001). Serious adverse events occurred during the treatment period in 12 of the participants (18%) who received inebilizumab and 6 of the participants (9%) who received placebo. Inebilizumab reduced the risk of flares of IgG4-related disease and increased the likelihood of flare-free complete remission at 1 year, confirming the role of CD19-targeted B-cell depletion as a potential treatment for IgG4-related disease. (Funded by Amgen; MITIGATE ClinicalTrials.gov number, NCT04540497.).

A time trade-off study in the UK, Canada and the US to estimate utilities associated with the treatment of haemophilia.

Haemophilia is a rare bleeding disorder caused by a deficient or absent clotting factor, leading to frequent bleeding. Multiple intravenous (IV) infusions have been the standard prophylactic treatment; however, newer treatment options involve less frequent subcutaneous (SC) injections. To inform future health economic evaluations, this study applied the time trade-off (TTO) method for estimation of utilities associated with haemophilia treatment for both people with the disease and potential caregivers. Using the TTO method, utilities were estimated through two online surveys distributed in the UK, Canada and the US. In survey 1 (S1), adults from the general population aged 18years and above evaluated health states as if they were living with haemophilia themselves and were receiving treatment for the condition. In survey 2 (S2), adults from the general population with a child under the age of 15years evaluated health states as if they were treating their child for haemophilia. The surveys assessed the following treatment aspects: frequency of treatment, treatment device and injection site reactions. In total, 812, 739 and 703 respondents completed S1 and 712, 594 and 527 completed S2 in the UK, Canada and the US, respectively. In both surveys, the treatment device was associated with the largest impact on utilities for both people with haemophilia and caregivers. Monthly SC injections with a prefilled pen-device were associated with a significant utility gain compared with SC injections with a syringe and IV infusions. In S1, a lower treatment frequency was preferred in all three countries, while in S2, a lower treatment frequency was preferred only in the UK. Avoiding injection site reactions was associated with a significant utility gain in both surveys, but only in the UK and Canada. The study suggests that the administration of haemophilia treatment in particular has an impact on utilities for both people and caregivers living with the disease. Thus, less complex and time-consuming treatment devices are expected to improve health-related quality of life. This can be further modified additively by less frequent administration. These results can inform future health economic analyses of haemophilia and haemophilia treatment.

The effect of intravenous lidocaine infusion on subarachnoid anesthesia in patients undergoing total knee replacement: a randomised controlled trial.

Intravenous lidocaine is a non-opioid analgesic adjunct for perioperative pain relief. The aim of our study was to explore whether concurrent administration of intravenous lidocaine prolongs the duration of sensory block during total knee replacement (TKR) under spinal anaesthesia. This prospective randomized double blind controlled trial was conducted on 28 patients (14 in lidocaine group and 14 in the control group) undergoing unilateral TKR under spinal anesthesia. In the lidocaine group, intravenous lidocaine 1.5mg·kg-1 followed by an infusion of 1.5mg·kg-1·h-1 was administered intraoperatively after spinal anesthesia. The primary outcome was the duration of sensory block of spinal anesthesia. Secondary outcomes included onset time of sensory and motor block, duration of motor block, time to first postoperative analgesic, postoperative visual analog scale (VAS) scores and postoperative analgesia requirement in 24h after surgery. The duration of sensory and motor block was longer in the lidocaine group (Mean ± SD; 112.50 ± 5.80min versus 78.21 ± 9.12min;p < 0.001 and 237.14 ± 9.14min versus 215.00 ± 10.12min;p < 0.001, respectively). Time to requirement of first rescue analgesia was 184.29 ± 9.38min in the lidocaine group and 127.14 ± 23.35min in the control group (p < 0.001). VAS scores were lower in the lidocaine group at 4, 8, 12 and 24h after surgery (p < 0.00001, p < 0.00001, p < 0.00006, p = 0.032, respectively). Requirement of additional analgesia in the first 24h was higher in the control group. There were no clinical signs to suggest lidocaine toxicity in any patient. During unilateral TKR under spinal anaesthesia, concurrent use of intravenous lidocaine prolonged sensory block and reduced postoperative analgesic requirements.

Hemispheric divergence of interoceptive processing across psychiatric disorders

Interactions between top-down attention and bottom-up visceral inputs are assumed to produce conscious perceptions of interoceptive states, and while each process has been independently associated with aberrant interoceptive symptomatology in psychiatric disorders, the neural substrates of this interface are unknown. We conducted a preregistered functional neuroimaging study of 46 individuals with anxiety, depression, and/or eating disorders (ADE) and 46 propensity-matched healthy comparisons (HC), comparing their neural activity across two interoceptive tasks differentially recruiting top-down or bottom-up processing within the same scan session. During an interoceptive attention task, top-down attention was voluntarily directed towards cardiorespiratory or visual signals. In contrast, during an interoceptive perturbation task, intravenous infusions of isoproterenol (a peripherally-acting beta-adrenergic receptor agonist) were administered in a double-blinded and placebo-controlled fashion to drive bottom-up cardiorespiratory sensations. Across both tasks, neural activation converged upon the insular cortex, localizing within the granular and ventral dysgranular subregions bilaterally. However, contrasting hemispheric differences emerged, with the ADE group exhibiting (relative to HCs) an asymmetric pattern of overlap in the left insula, with increased or decreased proportions of co-activated voxels within the left or right dysgranular insula, respectively. The ADE group also showed less agranular anterior insula activation during periods of bodily uncertainty (i.e. when anticipating possible isoproterenol-induced changes that never arrived). Finally, post-task changes in insula functional connectivity were associated with anxiety and depression severity. These findings confirm the dysgranular mid-insula as a key cortical interface where attention and prediction meet real-time bodily inputs, especially during heightened awareness of interoceptive states. Furthermore, the dysgranular mid-insula may indeed be a ‘locus of disruption’ for psychiatric disorders.

Which is the safer option for adult patients between peripherally inserted central catheters and midline catheters: a meta-analysis.

Peripherally inserted central catheters (PICC) and midline catheters (MC) are widely used for intravenous infusions in oncology and critically ill patients. However, controversy remains regarding which method is superior. This meta-analysis systematically compares the safety differences between these 2 methods of intravenous catheterization. Eligible studies comparing PICC and MC were identified through searches in 6 databases. Thrombosis is the primary endpoint, while secondary endpoints include other complications, cost, and satisfaction rate. Fourteen studies with 20,675 patients were analyzed. Based on patient data, the MC group exhibited higher rates of catheter-related superficial vein thrombosis (SVT) (risk ratio [RR]: 0.42 [0.28, 0.64]), infiltrations (RR: 0.27 [0.12, 0.62]), and leaks (RR: 0.16 [0.05, 0.53]). In contrast, the PICC group had more catheter-related bloodstream infections (RR: 1.95 [1.15, 3.32]). Considering catheter days, the MC group showed increased total complications (RR: 0.51 [0.26, 0.99]), catheter-related thrombosis (deep vein thrombosis [DVT]+SVT) (RR: 0.41 [0.18, 0.95]), and leaks (RR: 0.17 [0.05, 0.64]). In the PICC group, the top 3 complications were catheter occlusions (20 per 1,000 catheter days [CDs]), pain (15 per 1,000 CDs), and phlebitis (11 per 1,000 CDs); for the MC group, they were leaks (33 per 1,000 CDs), premature removals (22 per 1,000 CDs), and catheter-related DVT (22 per 1,000 CDs). Additionally, the PICC group had higher dissatisfaction rates (RR: 4.77 [2.33, 9.77]) and increased costs. Compared to MC, PICC appears to be a safer intravenous catheterization option for adult patients, exhibiting fewer complications. However, the higher associated costs and lower satisfaction rates of PICC warrant serious attention.

Hemispheric divergence of interoceptive processing across psychiatric disorders.

Interactions between top-down attention and bottom-up visceral inputs are assumed to produce conscious perceptions of interoceptive states, and while each process has been independently associated with aberrant interoceptive symptomatology in psychiatric disorders, the neural substrates of this interface are unknown. We conducted a preregistered functional neuroimaging study of 46 individuals with anxiety, depression, and/or eating disorders (ADE) and 46 propensity-matched healthy comparisons (HC), comparing their neural activity across two interoceptive tasks differentially recruiting top-down or bottom-up processing within the same scan session. During an interoceptive attention task, top-down attention was voluntarily directed towards cardiorespiratory or visual signals. In contrast, during an interoceptive perturbation task, intravenous infusions of isoproterenol (a peripherally-acting beta-adrenergic receptor agonist) were administered in a double-blinded and placebo-controlled fashion to drive bottom-up cardiorespiratory sensations. Across both tasks, neural activation converged upon the insular cortex, localizing within the granular and ventral dysgranular subregions bilaterally. However, contrasting hemispheric differences emerged, with the ADE group exhibiting (relative to HCs) an asymmetric pattern of overlap in the left insula, with increased or decreased proportions of co-activated voxels within the left or right dysgranular insula, respectively. The ADE group also showed less agranular anterior insula activation during periods of bodily uncertainty (i.e. when anticipating possible isoproterenol-induced changes that never arrived). Finally, post-task changes in insula functional connectivity were associated with anxiety and depression severity. These findings confirm the dysgranular mid-insula as a key cortical interface where attention and prediction meet real-time bodily inputs, especially during heightened awareness of interoceptive states. Furthermore, the dysgranular mid-insula may indeed be a 'locus of disruption' for psychiatric disorders.

Effect of crystalloidsolution co-loading infusion rate on the dose requirements of prophylactic phenylephrine for preventing hypotension following combined spinal-epidural anesthesia for cesarean delivery.

Intravenous fluid administration and prophylactic vasopressor infusion are the primary methods for preventing spinal anesthesia-induced hypotension during cesarean delivery. However, evidence regarding the impact of different volumes of crystalloid solution on the phenylephrine infusion dosage for preventing this hypotension remains inconclusive. This study aimed to determine the effect of two IV fluid infusion rates (10 or 20 mL/kg/h) on phenylephrine requirement for preventing spinal anesthesia-induced hypotension. Eighty healthy parturients undergoing elective cesarean delivery under combined spinal-epidural anesthesia were enrolled. Participants were randomly assigned to receive either 10 mL/kg/h (group 10) or 20 mL/kg/h (group 20) of lactated Ringer's solution. The first patient in each group received 0.5µg/kg/min of phenylephrine infusion immediately after intrathecal injection. The phenylephrine dose in subsequent patients was adjusted by increments or decrements of 0.05µg/kg/min based on the previous patient's response. The ED50 of phenylephrine infusion for preventing spinal-induced hypotension for cesarean delivery was estimated using a modified up-down sequential analysis, with probit analysis applied as a backup sensitivity analysis. The ED50 values for preventing spinal anesthesia-induced hypotension were 0.30µg/kg/min (95% CI, 0.29-0.32µg/kg/min) for group 10, and 0.19µg/kg/min (95% CI, 0.16-0.22µg/kg/min) for group 20, respectively. The estimated relative potency for phenylephrine in group 10 compared to group 20 was 1.52 (95%CI, 1.24-1.97), showing a significant difference in the ED50 values between the two groups. This study found that a higher crystalloid co-loading rate significantly reduces prophylactic phenylephrine requirement for preventing spinal anesthesia induced hypotension. https://www.chictr.org.cn/showproj.html?proj=125918 (Trial number: ChiCTR2100048002).

Plain language summary: tarlatamab for patients with previously treated small cell lung cancer.

This is a summary of a phase 2 clinical study called DeLLphi-301. The study looked at how effective and safe a medicine called tarlatamab was in participants with small cell lung cancer (SCLC). Participants previously received at least two other treatments for their SCLC. Tarlatamab is a new medicine that locates a protein called DLL3 on the cancer, which allows T cells to attack the cancer. T cells belong to the body's natural defense system known as the immune system. The DeLLphi-301 study separated participants into two groups to receive tarlatamab 10mg or 100mg to determine which dose best shrank SCLC with minimal side effects. All participants received a small first dose (1mg tarlatamab) to decrease the risk of an immune system reaction called cytokine release syndrome (CRS). Tarlatamab was given through the participant's vein once every 2weeks. This method of administration is known as intravenous (IV) infusion. In the group given 10mg tarlatamab, 40% of participants responded to treatment (cancer shrank). In the group given 100mg tarlatamab, 32% of participants responded to treatment (cancer shrank). After taking tarlatamab at either dose, 59% of participants lived for at least 6months without their cancer growing or getting worse.The most common side effect was CRS, which occurred in 51% of participants in the group given 10mg tarlatamab and 61% of participants in the group given 100mg tarlatamab. Other common side effects were decreased appetite, fever, constipation, and anemia. Some participants had a type of immune reaction called immune effector cell-associated neurotoxicity syndrome (ICANS). A small number of participants (3%) stopped taking tarlatamab because of side effects related to tarlatamab. The study found that tarlatamab given every 2weeks shrank SCLC in participants with SCLC who received previous treatments. Participants given the 10mg tarlatamab dose had fewer side effects than those given the 100mg tarlatamab dose.Clinical Trial Registration: NCT05740566 (DeLLphi-304) (ClinicalTrials.gov).

Abstract 4119680: First-in-Man Treatment of Heart Failure by Repeated Intravenous Infusions of a Cardiovascular Cell-Derived Extracellular Vesicle-Enriched Secretome

Background: Most of the effects of intramyocardially transplanted stem cells can be duplicated by the sole administration of their secretome but this approach has not yet been tested in heart failure (HF). Methods: The SECRET-HF phase I trial (NCT05774509) was designed according to a Bayesian optimal interval scheme to assess the effects of repeated intravenous infusions of a cellular secretome in 12 patients with a non-ischemic dilated cardiomyopathy. The main inclusion criteria are severe symptoms (NYHA Class III despite an optimal guideline-directed medical therapy), a reduced left ventricular (LV) ejection fraction (EF ≤40%) and ineligibility for a heart transplant. The Investigational Medicinal Product was derived from human induced pluripotent stem cells reprogrammed from a healthy donor and differentiated in cardiovascular progenitor cells (CPC). Following CPC culture in a dedicated "vesiculation" medium, the conditioned media were collected, filtered, enriched for extracellular vesicles, concentrated by tangential flow filtration and scaled out into glass vials stored at -80°C. Quality controls were implemented throughout the whole process which was conducted according to current Good Manufacturing Practices. Results: Three patients, out of the 4 of the initial low-dose cohort, have now been treated. All had been previously fitted with an automatic internal cardioverter defibrillator (AICD). The secretome was delivered intravenously 3 times, 3 weeks apart, at a dose of 20 x10 9 particles/kg for each infusion. By November, 2024, the follow-up will be 16, 9, 6 and 2 months for each of them (mean: 8 months). So far, none of the treated patients has experienced a dose-limiting toxicity; in particular, there have been no post-treatments ventricular arrhythmia detected by the AICD, no allo-immunization and no inflammation based on the enumeration of lymphocyte subpopulations by flow cytometry. At 6 months, the first patient improved to NYHA Class II with a decrease in echographic LVEDV and LVESV (from 108 mL/m 2 to 87 mL/m 2 and from 80 mL/m 2 to 60 mL/m 2 , respectively) and a concomitant increase in LVEF from 25% to 32%. At 1 month post-treatment, the second patient also reports a symptomatic improvement (NYHA Class II) with an increase in EF from 21% to 28%. Conclusions: This initial experience supports the safety of repeated intravenous administrations of a cardiovascular cellular secretome as a potential noninvasive and user-friendly treatment of severe HF.

The Effects of Intra-Operative Lidocaine Infusion on Post Operative Pain and Morphine Consumption Following Major Gynaecological Surgeries Under General Anaesthesia

&amp;lt;i&amp;gt;Introduction&amp;lt;/i&amp;gt;: Major gynaecological surgeries are associated with considerable postoperative pain, which remains a challenge for many practitioners. Multimodal forms of analgesia significantly reduce the requirement of opioids for pain management. Despite its local anaesthetic effects, lidocaine infusion improves postoperative pain and morphine consumption following gynaecological surgeries. &amp;lt;i&amp;gt;Materials and methods&amp;lt;/i&amp;gt;: Sixty patients were assigned randomly into 2 groups (A and B) with 30 patients per group. Group A received intravenous lidocaine 1.5 mg/kg at induction via a bolus injection and 1.5 mg/kg/hr in normal saline infusion from onset of surgery to the end of surgery, while the control group (Group B) received equal volume of normal saline at the same timelines. Pain scores were assessed postoperatively using the numerical rating scale and the cumulative morphine consumed postoperatively were also measured. &amp;lt;i&amp;gt;Results&amp;lt;/i&amp;gt;: The mean pain scores were significantly higher in the Saline Group than in the Lidocaine group. The cumulative morphine consumption after 48 hours was significantly reduced in the study group 4.87 ± 1.80 mg vs 14.13 ± 4.10 mg (P&amp;lt;0.0001). Conclusion: The administration of a bolus dose (1.5 mg/kg) of intravenous lidocaine at induction and a continuous intravenous infusion of 1.5 mg/kg/hr from onset of surgery till skin closure reduced the postoperative pain intensity and morphine consumption in patients undergoing major gynaecological surgeries under general anaesthesia.

Multi-year enzyme expression in patients with mucopolysaccharidosis type VI after liver-directed gene therapy.

Mucopolysaccharidosis type VI (MPS VI) is due to a deficiency of the lysosomal enzyme arylsulfatase B (ARSB) that results in multi-organ accumulation of glycosaminoglycans (GAGs). Limitations of current treatments prompted the development of a liver-directed gene therapy clinical trial for MPS VI. We report the long-term follow-up of patients with MPS VI who discontinued enzyme replacement therapy (ERT) and received a single intravenous infusion of high-dose (6×1012 genome copies/kg) recombinant adeno-associated virus serotype 8 (AAV8) vector expressing ARSB under the control of a liver-specific promoter (ClinicalTrials.gov: NCT03173521). Primary outcomes were safety and urinary GAG excretion. Secondary outcomes were endurance and respiratory function. Median follow-up time was 45months (n= 4, three females and one male; age range: 5-10 years). No late-emergent safety events were observed. Patients showed sustained serum ARSB activity (38%-67% of mean healthy reference values), a modest increase in urinary GAG concentrations, and no relevant changes in endurance, cardiac, or pulmonary function. In one of the four patients, ERT was restarted because of elevated urinary GAGs without decreased serum ARSB activity up to about 2.5 years after gene transfer. Liver and spleen size remained within the reference ranges. A single intravenous administration of AAV8.TBG.hARSB was safe and resulted in sustained ARSB expression and a modest increase in urinary GAGs in most patients, thus supporting liver-directed gene therapy for MPS VI. This study was sponsored by the Telethon Foundation ETS, the European Union, the Isaac Foundation, and the Italian Ministry of University and Research.

Co-administration of dexmedetomidine with total intravenous anaesthesia in carotid endarterectomy reduces requirements for propofol and improves haemodynamic stability: A single-centre, prospective, randomised controlled trial.

Total intravenous anaesthesia guided by electroencephalography and neurophysiological monitoring may be used for carotid endarterectomy. Reduction of brain metabolic demand during cross-clamping of the internal carotid artery with propofol titrated to burst suppression requires effect-site concentrations that may delay emergence and interfere with intraoperative neurophysiological monitoring. To test the hypothesis that dexmedetomidine decreases the effect-site concentration of propofol required for burst-suppression in patients undergoing carotid endarterectomy. Randomised controlled trial. Patients undergoing carotid endarterectomy. University Hospital of Berne, Switzerland, from October 2018 to September 2024. Patients were randomised into a control (n = 23) and a dexmedetomidine groups (n = 22). Total intravenous anaesthesia was administered to both groups. Patients in the dexmedetomidine group received an intravenous bolus of dexmedetomidine (0.4 μg kg-1 over 10 min) before induction, followed by a continuous intravenous infusion (0.4 μg kg-1 h-1). The effect-site concentrations of propofol were titrated against frontal electroencephalography parameters. Burst suppression was induced with propofol during cross-clamping of the internal carotid artery. The primary outcome was the effect-site concentration of propofol required for burst-suppression. The secondary outcomes were the requirement for vasoactive substances, neurophysiological monitoring parameters, and postoperative delirium. The effect-site concentration of propofol required for burst suppression was 4.0 μg ml-1 [3.50 to 4.90] (median [interquartile range]) in the dexmedetomidine group compared with 6.0 μg ml-1 [5.5 to 7.3] in the control group (P < 0.001). Less norepinephrine was required in the dexmedetomidine group (total 454 μg [246 to 818] compared with 1000 μg [444 to 1326] (P = 0.015) in the control group). Dexmedetomidine did not affect intraoperative neurophysiological monitoring. Co-administration of dexmedetomidine to total intravenous anaesthesia for carotid endarterectomy decreased the effect-site concentrations of propofol required for burst suppression by 33%. The propofol-sparing effect and peripheral alpha-agonism of dexmedetomidine may explain the reduced requirement for vasopressors. Clinicaltrials.gov identifier: NCT04662177.

Optimizing the Smart Pump Drug Library Update Process: An Ongoing Effort at an Academic Medical Center

Smart infusion pumps with dose-error reduction software and customizable drug libraries have increased the safety of intravenous infusion delivery; however, maintaining the most updated drug library is a multistep process for most infusion pumps, which requires effort and engagement by the end user to activate the latest drug library. Delays in updating the drug library have been shown to impact patient safety. This article reviews steps taken at an academic medical center to improve the drug library update process. Multidisciplinary efforts resulted in improved drug library activation rates; however, despite workflow optimizations and improvements, achieving complete pump fleet library activation in a timely manner after scheduled updates remains challenging.

SURG-35. NEURONAVIGATED INTRAOPERATIVE ULTRASSOUND X SODIUM FLUORESCEIN FOR BRAIN METASTASIS: WHICH IS BETTER?

Abstract BACKGROUND Improve quality of life with a maximum surgical resection is the main goal of neurosurgeons. Brain metastasis are even more prevalent because of patients are living more. The grade of resection and the maintenance of a good performance are fundamental for these patients perform adjuvant radiotherapy. There are several technologies that may help. Considering two of them that have an easier access and are cheaper, we compared a high definition ultrasound (BK 3000) coupled to neuronavigation system (Brainlab) and sodium fluorescein (SF). METHODS Adult patients with main radiological hypothesis of brain metastasis were included in a PhD study previously approved by ethics committee. 3-5mg/kg of SF was administered by intravenous infusion during anesthetic induction. An specific craniotomy transducer was used in all cases with shift correction in real time by neuronavigator. All procedures were guided by the same neurosurgeon. RESULTS High definition ultrasound allows an excellent tumor delimitation. SF helped to increase grade of resection however made confusion about what is infiltration and what is tumor and for this ultrasound were superior. Increased fluorescence is easily detected when compared to ultrasound information’s.. For both technologies, when the surgical site had blood, the evaluation about grade of resection is not accurate because in ultrasound appears a posterior shadow and considering SF it seems that there are not further tumor because blood does not have increased fluorescence. CONCLUSIONS US and SF are different tools which improve brain metastasis resection. In each moment of surgery one technology was superior or not. We used an specific probe for neurosurgery that has high quality and allowed detailed evaluations. These technologies helps surgeons take quick decision and optimized brain tumor removal. The neurosurgeon should be more familiar to US images because provide a real time evaluation with low cost.

NIMG-32. ORAL ADMINISTRATION OF DEUTERATED CHOLINE AS A NEW APPROACH TO PROVIDE HIGH TUMOR-TO-BRAIN IMAGE CONTRAST IN DEUTERIUM METABOLIC IMAGING (DMI)

Abstract BACKGROUND Metabolic imaging using FDG-PET is a key component of disease management in many cancers outside of the brain, but in brain tumors it often shows low tumor-to-brain contrast because of high background signal from normal brain. We explore generating cancer-specific metabolic image contrast using Deuterium Metabolic Imaging (DMI), which is a novel 2H magnetic resonance spectroscopic imaging-based technique. DMI was applied after oral administration of deuterated choline, an essential nutrient needed for membrane synthesis whose uptake is often increased in tumors. METHODS Total choline (tCho) DMI was performed in an orthotopic model of glioblastoma, F344 rats (n=11) implanted with RG2 cells, on an 11.7 tesla MRI scanner, with isotropic spatial resolution of 2.5 mm. tCho-DMI data were collected for 36 min during intravenous infusion (IV, n=6) or after 3 days of oral administration (PO, n=5) of [2H9]-choline chloride dissolved in sterile water. At a dose of 285 mg/kg body weight, bolus-continuous IV infusion via the tail vein required 1.57 ml for a 250-gram rat. PO administration via gavage on 3 consecutive days used the max daily dose recommended for human adults, 50 mg/kg. Results - In the PO group, average tumor tCho concentration was 0.78±0.14 mM and 0.20±0.05 mM in contralateral normal brain. In the IV group, the tCho concentration was 0.88±0.18 mM in the tumor, and 0.18±0.03 mM in normal brain (PO vs. IV: p=0.52). Tumor-to-brain contrast was 5.9±1.2 in PO-administered animals, and 7.1±3.3 for animals receiving IV 2H-choline, (p=0.54). CONCLUSIONS - In a preclinical GBM model oral administration of [2H9]-choline resulted in comparably high tumor-to-brain image contrast on tCho-DMI-based maps as during IV infusion. Work is ongoing to identify the different choline metabolites that contribute to the tCho signal. Because oral administration of choline is very safe, this approach could facilitate the translation of tCho-DMI to human subjects.

CTNI-29. A PHASE 1B STUDY TO EVALUATE THE SAFETY, PHARMACOKINETICS, AND OBJECTIVE RESPONSE OF LP-184 ALONE AND IN COMBINATION WITH SPIRONOLACTONE IN IDH WILD TYPE GLIOBLASTOMA AT FIRST PROGRESSION

Abstract LP-184 is a fully synthetic small molecule alkylator of the acylfulvene therapeutics class that induces DNA double-strand breaks and improves survival in orthotopic GBM xenograft models. In preclinical studies, LP-184 is brain penetrant with a brain tumor/plasma concentration ratio of 0.2. DNA damage induced by acylfulvenes is repaired via transcription-coupled nucleotide excision repair (TC-NER) mediated by ERCC complexes. GBM with intrinsic or pharmacologically induced DNA Damage Repair deficiency (dDDR) may preferentially respond to LP-184, independent of MGMT status. LP-184 is currently under investigation in a first-in-human Phase 1a dose-escalation safety study (NCT05933265) in adult patients with advanced solid tumors including GBM, with no dose-limiting toxicities to date at dose level 6. Following determination of the Maximum Tolerated Dose and/or Recommended Phase 2 Dose from Phase 1a, the selected expansion dose will be assessed in a Phase 1b study to evaluate the safety, pharmacokinetics, and objective response of LP-184 alone and in combination with spironolactone in IDH wild type glioblastoma at first progression. Spironolactone is a brain penetrant FDA approved agent that proteolytically degrades the TC-NER component ERCC3, thereby creating dDDR. Two rGBM cohorts will be enrolled according to a Simon’s 2-stage optimal design: (i) LP-184 alone (days 1 and 8 in a 21-day cycle, as intravenous infusion over 30 minutes) and (ii) combination of LP-184 and spironolactone (200 mg orally daily in conjunction and before the LP-184 infusion). In the first stage, 10 response evaluable subjects will be enrolled. If 1 or more of the first 10 response evaluable subjects achieve an objective response, 19 further subjects may be accrued in the second stage. In each cohort, at least 5 subjects will undergo planned tumor resection and will be treated with LP-184 or the combination the day prior to surgery to evaluate PK/PD.