Multiple Infusions Research Articles

Effect of human umbilical cord mesenchymal stem cells on ovarian function in lupus mice

AbstractBackgroundPatients with systemic lupus erythematosus (SLE) suffer from a high incidence of premature ovarian failure, which might be due to cyclophosphamide gonadal toxicity, immune abnormalities, or other reasons. This study aimed to investigate whether the transplantation of human umbilical cord mesenchymal stem cells (HUC‐MSCs) can improve ovarian reserve function in lupus mice.MethodsWe used MRL/lpr mice to observe changes in ovarian structure and secretory function in SLE. Lupus mice and controls were injected with HUC‐MSCs at Weeks 12 and 16. We detected serum concentrations of the sex hormones estradiol (E2), follicle‐stimulating hormone (FSH), and anti‐Müllerian hormone (AMH), using enzyme‐linked immunosorbent assays. Hematoxylin and eosin staining showed ovarian tissue structure and enabled the counting of follicles. Hepatocyte growth factor (HGF) and insulin‐like growth factor 1 (IGF‐1) expression in ovarian tissue was observed by immunohistochemistry.ResultsOvarian function in lupus mice was abnormal, as indicated by decreased serum E2 and AMH concentrations, and increased FSH concentrations. HUC‐MSC transplantation caused significant upregulation of serum E2 and AMH and downregulation of FSH (all p < 0.05). Ovarian structure improved and the follicle number increased after HUC‐MSC transplantation. Multiple infusions of HUC‐MSCs at Weeks 12 and 16 resulted in a significantly higher number of primordial follicles than infusions of HUC‐MSCs at only Week 12 (p < 0.05). Immunohistochemistry showed that IGF‐1 and HGF expression increased after HUC‐MSC transplantation, but this was not significant.ConclusionsHUC‐MSCs transplantation restores disturbed hormone secretion and folliculogenesis in lupus mice. HUC‐MSC transplantation should be repeated for the best treatment effect.

Compatibility of calcium chloride with milrinone, epinephrine, vasopressin, and heparin via in vitro testing and simulated Y-site administration.

The purpose of this study is to evaluate calcium chloride (CaCl) compatibility with commercially available and extemporaneously compounded milrinone, vasopressin, epinephrine, and heparin. This report describes 2 clinical scenarios in which patients experienced intravenous catheter precipitation when receiving multiple continuous infusions, including CaCl, and the results of an in vitro simulation of those scenarios. The hypothesis was that one or a combination of the medications would precipitate with CaCl. CaCl compatibility was tested in 3 stages to simulate clinical situations where line precipitation occurred. Multiple tests were conducted in each stage to determine if precipitation had occurred, including visual assessment, absorbance measurement at 650 nm, and pH measurement. First, milrinone, vasopressin, epinephrine, and heparin were mixed pairwise with CaCl in a test tube. Second, the medications were mixed in different combinations deemed likely to precipitate. Finally, 5 medications were infused via simulated Y-site administration. Incompatibility was defined as observed crystals, haziness, or turbidity upon visual inspection or absorbance of greater than 0.01 absorbance unit (AU). All solutions were tested at time 0 and at 20, 60, 240, and 1,440 minutes. Across all tests, only a commercially available formulation of heparin 2 units/mL in 0.9% sodium chloride injection precipitated with CaCl, alone or in combination with other medications. Upon further review, it was found that this specific formulation of heparin contained a monohydrate and dibasic sodium phosphate buffer. CaCl only precipitated with a commercially available heparin formulation that contained a phosphate buffer. CaCl was deemed to be compatible with all other medications and formulations tested.

Trace elements in successive tea infusions made via a brewing method widespread in China: Implications for human exposure

Tea is a globally popular drink with many associated health benefits, although tea plants can also accumulate potentially toxic metals from industrial and agricultural contamination of soil and water. This study determined 10 trace elements present in tea leaves and successive tea infusions made using a brewing method widespread in southern China. The levels of aluminium in tea infusions were the highest (range: 32.0–6130 μg/mL), followed by zinc (5.76–92.6 μg/mL), nickel (1.97–17.7 μg/mL), copper (1.49–14.9 μg/mL), cobalt (0.11–1.97 μg/mL), lead (0.02–1.22 μg/mL), chromium (0.10–1.01 μg/mL), selenium (0.04–0.47 μg/mL), arsenic (0.01–0.23 μg/mL), and cadmium (0.001–0.03 μg/mL). Average aluminium concentrations in tea infusions exceeded the Chinese maximum allowance level (MAL) established for drinking water (20 μg/mL). In pairwise comparisons of trace element levels in eight sequential infusions, greater concentrations were found in the 2nd infusion than the last six infusions (p < 0.05). Notably, the analysis showed considerable health risks associated with trace element exposure from drinking all of the first eight infusions of Tieguanyin tea, Hazard Index (HI) = 1.08, and Rock tea (HI=0.94). In addition, potential increases in cancer risks (2.5×10-5) associated with total arsenic intake were found among Tieguanyin or Rock tea consumers. Based on these findings, a tea brewing method is recommended which involves multiple successive infusions of 10 s each, discarding the first and second infusions. To the best of our knowledge, this is the first scientific verification of a traditional tea-making method to reduce trace element exposure.

Pre-Antibiotic Treatment Followed by Prolonged Repeated Faecal Microbiota Transplantation Improves Symptoms and Quality of Life in Patients with Irritable Bowel Syndrome: An Observational Australian Clinical Experience.

Background The use of faecal microbiota transplantation (FMT) in irritable bowel syndrome (IBS) has frequently failed to induce long-term symptomatic improvement. The use of multiple FMT infusions is one proposed mechanism through which the efficacy of FMT can be amplified. Aims To evaluate the safety and efficacy of a novel six-month FMT treatment protocol in IBS. Methods Patients diagnosed with IBS confirmed by Rome IV Criteria were recruited for single-centre, single-arm, prospective clinical observational study. Participants received one colonoscopically delivered FMT followed by 36 rectal enemas across a six-month period. Validated abdominal symptoms and Short-Form (SF-36) Quality of Life (QOL) questionnaires were collected at baseline, week-12, week-24, and week-56, respectively. Wilcoxon matched-pairs signed-rank tests were conducted to compare differences in abdominal symptom and SF-36 QOL scores over the follow-up timepoints. Statistical significance was set at 5%. Results Sixty participants diagnosed with IBS [IBS-constipation (n = 27), IBS-diarrhoea (n = 18), and IBS-mixed (n = 15)] received the six-month FMT treatment. IBS symptom severity reduction was achieved in up to 61% of respondents at week-12, 64% of respondents at week-24, and maintained in up to 75% of respondents at week-52. Long-term reduction in symptom severity was associated with an increase in QOL, achieved in up to 64% of respondents at week-52 when compared to baseline. Adverse events were experienced in 28% of participants, though they were both transient and mild in nature. Conclusions Six-month sustained FMT appears to be both safe and effective in the short- and long-term alleviation of IBS associated symptoms as well as improving participant QOL.

Safety and outcomes of short-term use of peripheral vasoactive infusions in critically ill paediatric population in the emergency department

Early restoration of oxygen delivery to end organs in paediatric patients experiencing shock states is critical to optimizing outcomes. However, obtaining central access in paediatric patients may be challenging in non-intensive care settings. There is limited literature on the use of peripheral vasoactive infusions in the initial resuscitation of paediatric patients in the emergency department. The aims of this study were to report the associated complications of peripheral vasoactive infusions and describe our local experience on its use. This was a single-centre, retrospective study on all paediatric patients who received peripheral vasoactive infusions at our paediatric emergency department from 2009 to 2016. 65 patients were included in this study. No patients had any local or regional complications. The mean patient age was 8.29 years old (± 5.99). The most frequent diagnosis was septic shock (45, 69.2%). Dopamine was the most used peripheral vasoactive agent (71.2%). The median time to central agents was 2 h (IQR 1–4). 16(24.2%) received multiple peripheral infusions. We reported no complications of peripheral vasoactive infusions. Its use could serve as a bridge till central access is obtained. Considerations on the use of multiple peripheral vasoactive infusions in the emergency department setting needs further research.

Gender differences in the antianhedonic effects of repeated ketamine infusions in patients with depression.

ObjectivesSubanaesthetic ketamine (0. 5 mg/kg/40 min intravenous infusion) produces rapid and robust antianhedonic effects in subjects with mood disorders, independent of other depressive symptoms. The objective of this study was to examine potential differences in rate of antianhedonic response to ketamine in males and females, which has not been previously examined.MethodsA total of 135 patients with depression (68 males, 67 females) who received six intravenous infusions of ketamine (0.5 mg/kg/40 min) during 2 weeks were enrolled. The anhedonia subscale of the Montgomery–Åsberg Depression Rating Scale (MADRS) was utilized to measure anhedonic symptoms. Antianhedonic remission and response were defined as ≥75 and ≥50% improvement of anhedonic symptoms at 24 h after the sixth ketamine infusion (day 13).ResultsAntianhedonic response (50 vs. 47.8%, p > 0.05) and remission (26.5 vs. 14.9%, p > 0.05) rates did not differ significantly between males and females. A linear mixed model revealed a nonsignificant between-group difference in MADRS anhedonia subscale scores [F(1, 132.5) = 1.1, p = 0.30]. Females reported a significantly larger reduction in anhedonic symptoms than males at the 2-week follow-up (p < 0.05).ConclusionThe rates of antianhedonic response and remission to multiple ketamine infusions for the treatment of depression were similar between males and females. These findings should be verified by future studies, preferably randomized controlled trials (RCTs).

Comparison of three insulin bolus calculators to increase time in range of glycemia in a group of poorly controlled adults Type 1 diabetes in a Brazilian public health service

BackgroundA main factor contributing to insufficient glycemic control, during basal/bolus insulin therapy, is poor self-management bolus. Insulin bolus administration frequency is strongly associated with glycated hemoglobin (A1c) in Type 1 Diabetes (T1D). In the present study, we analyzed the performance of two-bolus calculator’s software that could be accessible to T1D patients from a Public Health Service to improve glycemic time in range (TIR) and A1c.MethodsThis prospective, controlled, randomized, parallel intervention clinical trial was carried out with 111 T1D participants on basal/bolus therapy [multiple daily insulin injections (MDI) or subcutaneous infusion pump (CSII)] with basal A1c ≥ 8.5% for 24 weeks. Patients were divided into 3 groups: 2 interventions: COMBO® (bolus calculator) and GLIC (mobile application) and 1 control (CSII group). Anthropometrics and metabolic variables were assessed on basal, 3 and 6 months of follow-up.ResultsTIR was increased in 9.42% in COMBO group (29 ± 12% to 38.9 ± 12.7%; p < 0.001) in 8.39% in the GLIC® group (28 ± 15% to 36.6 ± 15.1%; p < 0.001) while remained stable in CSII group (40 ± 11% to 39.3 ± 10.3%). A1c decrease in 1.08% (p < 0.001), 0.64% (p < 0.001) and 0.38% (p = 0.01) at 6 months in relation to basal in the COMBO, GLIC and CSII respectively. Daily basal insulin dose was reduced by 8.8% (p = 0.01) in the COMBO group.ConclusionThe COMBO and a mobile applicative (GLIC) bolus calculator had a similar and a good performance to optimize the intensive insulin treatment of T1D in the public health system with increase in the TIR and reduction in A1C without increase hypoglycemia prevalence.

Pharmacokinetics and Biochemical Efficacy of an α1-Proteinase Inhibitor (Aralast NP) in α1-Antitrypsin Deficiency: a Cross-Product Retrospective Comparability Analysis.

IntroductionAugmentation therapy with plasma-derived α1-proteinase inhibitor (A1PI) products is currently the only approved disease-specific therapy for α1-antitrypsin deficiency (AATD), a genetic disorder associated with decreased levels of A1PI. Systemic trough levels of A1PI in plasma or serum are widely accepted as a biochemical efficacy endpoint in clinical trials for A1PI products.MethodsRetrospective analyses utilizing data from three clinical studies in patients with AATD were conducted to evaluate the pharmacokinetic(s) (PK) and biochemical efficacy comparability of Aralast NP and two other A1PI augmentation therapies, Aralast and Prolastin. All three A1PI products were administered as either single or multiple 60 mg/kg intravenous infusions. PK and biochemical efficacy comparability analyses were conducted by evaluating antigenic and functional A1PI serum or plasma concentration data from each of the three studies.ResultsComparable PK parameters were demonstrated between the three products for antigenic A1PI levels following a single infusion, with baseline-corrected and uncorrected geometric mean ratios for peak and systemic exposure ranging from 89.0% to 99.6%, with 90% confidence intervals within the 80–125% reference interval for bioequivalence. Biochemical efficacy comparability analyses of Aralast and Prolastin after multiple infusions at steady state showed geometric mean ratios for uncorrected and baseline-corrected antigenic and functional A1PI trough concentrations over weeks 8–11, and for individual weeks, that ranged from 75.8% to 106.6%, with the majority of the 90% confidence intervals falling either within the 80–125% interval or in proximity to it. Nonparametric superpositioning at steady state suggested that predicted trough concentrations for Aralast NP were comparable to the observed concentrations for Aralast and Prolastin.ConclusionThese retrospective analyses provide robust evidence that Aralast NP has biochemical efficacy and PK comparable to that of Aralast and Prolastin, supporting the use of any of these A1PI products for the treatment of patients with AATD.Trial Registration NumbersClinicalTrials.gov identifiers, NCT00242385 and NCT00396006.

Multiple Asparaginase Infusions Cause Increasingly Severe Acute Hyperammonemia.

Adverse reactions during and shortly after infusing asparaginase for the treatment of acute lymphoblastic leukemia can increase in severity with later doses, limiting further use and increasing relapse risk. Although asparaginase is associated with hyperammonemia, the magnitude of the increase in serum ammonia immediately after the infusion and in response to multiple infusions has not been examined. The concurrence of hyperammonemia and infusion reactions was studied using weaned juvenile pigs that received 12 infusions of Erwinia asparaginase (Erwinase; 1250 U/kg) over 28 days, with two 5-day recovery periods without asparaginase after the eighth and eleventh doses. Infusion reactions and prolonged hyperammonemia (>50 µM ammonia 48 h after the infusion) began after the fourth dose and increased with later doses. Dense sampling for 60 min revealed an acute phase of hyperammonemia that peaked within 20 min after starting the first infusion (298 + 62 µM) and lasted less than 1 h, without apparent symptoms. A pronounced acute hyperammonemia after the final infusion (1260 + 250 µM) coincided with severe symptoms and one mortality during the infusion. The previously unrecognized acute phase of hyperammonemia associated with asparaginase infusion coincides with infusion reactions. The juvenile pig is a translational animal model for understanding the causes of acute and chronic hyperammonemia, differentiating from hypersensitivity reactions, and for improving infusion protocols to reduce acute hyperammonemia and to allow the continued use of asparaginase.

Clinical Safety of NK Cell in the Prevention of Leukemia Relapse Post-transplantation and in Treatment of the Elderly Leukemia Patients

To observe the safety of donor NK cell infusions in the settings of hematopoietic stem cell transplantation and after consolidation chemotherapy in elderly patients with acute myeloid leukemia (AML). Forty patients with AML were included, in which 21 patients aged over 60 years were at the stage of complete remission (CR) and 19 patients that received allogeneic hematopoietic stem cell transplantation (allo-HSCT). Mononucleated cells were isolated from peripheral blood from the donors (for allo-HSCT) or healthy immediate family members (elderly AML). The cells were seeded into the flasks pre-coated with NK cell specific activators, and expanded in media containing recombinant human IL-15 and IL-2 for 14 days. The cells were transfused intravenously after the identification of quality control. Trypan blue exclusion test was used for the determination of cell viability and counting. Flow cytometry analysis was performed to assess the surface antigenic profile. Seventy-eight infusions of the cell products were received by the elderly patients with AML after consolidation chemotherapy, 11 infusions were received by the patients during allo-HSCT and 32 infusions 3 moths after transplantation. The safety of cell therapy, body temperature, blood pressure and other indexes were observe during and 48 hours after cell transfusion. Meanwhile, the occurrence and severity of acute graft-versus-host disease (GVHD) were documented. Flow cytometry analysis showed that the proportion of NK cells (CD3-CD56+) in the mononucleated cells before culture was (14.10±4.22)% (n=121), and the proportion increased dramatically up to (87.29±8.75)% (n=121) after culture for 14 days, the number of NK cells increased to 753.47±140.13 times (n=121). The doses of the infused NK cells was (7.58±2.50)×107/kg per infusion. Moderate fever occurred in three cases after multiple infusions, and the temperature restored to normal on the same day after treatment. Fever was observed in one patient after every infusion of four times in total. The temperature reached to 38.5-39.0 ℃ and returned to normal within 1-2 hours after adequate antipyretic treatment, and then there was no discomfort. No GVHD was observed in the elderly AML patients, while 6 cases that received allo-HSCT developed moderate acute GVHD, among them grade I in 5 cases and grade II in 1 case. No other severe toxicities were observed. NK cell products with a high-purity could be obtained by ex vivo expansion with this protocol. The transfusion of these expanded cells is generally safe in the elderly patients with AML that have received chemotherapy or patients that received hematopoietic stem cell transplantation.

High carbon yielding and melt processable bis-ortho-diynylarene (BODA)-derived resins for rapid processing of dense carbon/carbon composites

Bis-ortho-diynylarene (BODA)-derived resins undergo thermal, radical-mediated Bergman cyclization to predominately naphthalene diradicals which propagate in a stepwise fashion to highly branched processable intermediates that are amenable to current composite fabrication techniques prior to network cure and subsequent carbonization. Post-carbonization analysis reveals significantly higher density and consolidation in the BODA-derived carbon/carbon (C/C) over existing phenolic-based C/Cs without the need for arduous, multiple infusion and carbonization steps. The modular BODA approach combines and controls: (1) variable melt processability dictated by terminal or spacer group substitution, (2) mild cure kinetics via a non-autocatalytic reaction, (3) high carbon yield (>80%) to provide relatively dense (∼1.55 g/cm3) C/C substrates after a single carbonization at 1000 °C, and (4) remarkable efficiencies that allow fast carbonization ramp rates (10 °C/min) while maintaining high density. Isothermal DSC kinetics, monomer melt stability in air, order/disorder characterization by Raman and WAXS, resin processing under selected air environments, and fractured cross-section analyses of C/C composites by SEM is discussed.

Surveillance and attribution of ambulatory central line-associated bloodstream infections in a pediatric healthcare system

Central line-associated bloodstream infections (CLABSI) in ambulatory pediatric populations are difficult to track at an institutional level, especially for complex patients seen by multiple divisions and home health infusion agencies. A multidisciplinary team comprised of key stakeholders from divisions with the most patients discharged with a central line utilized Lean Six Sigma methodology of Define-Measure-Analyze-Design-Verify (DMADV) to create a standardized data collection process for all ambulatory CLABSIs and infection event reviews. A surveillance workflow was created to track, identify, and confirm ambulatory CLABSIs in all patients with an indwelling central line. Defined surveillance criteria included scope of patients eligible for ambulatory CLABSI surveillance, numerator definitions, and denominator calculations. Additionally, a novel attribution method was created for ambulatory CLABSIs in complex patient populations shared among multiple divisions and home care infusion services. This report is a novel institutional approach to accurately surveil, attribute, and calculate ambulatory CLABSI data in a pediatric healthcare system.

95-LB: Interim Data from a Prospective Study Measuring User Satisfaction and Metabolic Outcome while Using a Novel Modular Patch Pump System

Background and aims: Intensified insulin therapy for type 1 diabetes (T1D) can be administered by multiple daily injection therapy (MDI) or continuous subcutaneous insulin infusion therapy (CSII) . Despite the clinical benefits of CSII, its therapeutic implementation rate remains low. Thus, this study aims to evaluate the change in treatment satisfaction and metabolic changes of people with T1D switching from MDI to CSII therapy using a novel modular patch pump system. Materials and Methods: A total of 50 adults from Argentina with T1D, naïve to CSII, were enrolled in a multi - center, prospective, single - armed study for the Accu-Chek® Solo micropump system (ACS) . Change in diabetes treatment satisfaction after 13 weeks (mean 106, min 83, max 176 days) was assessed by the “Impact and Satisfaction” section of the Diabetes Technology Questionnaire (DTQ) as the primary outcome. In addition, changes in the HbA1c were reported by the investigator as a secondary outcome. Results: The mean DTQ “now” score improved from 92.96 ± 14.98 to 103.15 ± 19.47 (p = 0.0166) and the “change” score, as the primary outcome, was 113.24 ± 17.50 (p &amp;lt; 0.0001) . Based on pre - defined sub - categories, the following mean DTQ scores were measured: 3.83 ± 0.62 for “diabetes distress and burden,” 3.98 ± 0.70 for “hypoglycemia fear, worry and behavior,” 3.59 ± 0.70 for “device acceptance and satisfaction,” 3.92 ± 0.61 for “other.” In addition, the mean HbA1c, as a secondary outcome, decreased from 8.19 % ± 1.36 to 7.83 % ± 1.23 (- 0.37 %pt, p = 0.0148) . Thereby, the HbA1c reduction was not associated with any reported incidents of hypoglycemia. Conclusion: The switch from MDI to the Accu-Chek® Solo micropump system led to a significant improvement of subjects’ treatment satisfaction after 13 weeks, which was linked to a significant reduction of the outcome HbA1c without any reported incidents of hypoglycemia. Disclosure A. Dain: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk, Roche Diabetes Care, Speaker’s Bureau; Abbott Diabetes, AstraZeneca, Lilly Diabetes, Novo Nordisk. S. Moceri: Employee; Roche Diabetes Care. N. Dagenbach: Employee; Roche Diabetes Care. C. Rees: Employee; Roche Diabetes Care. C. Vulcano: Employee; Roche Diabetes Care. G. Vogt: Employee; Roche Diabetes Care. T. J. Etter: Employee; Roche Diabetes Care. Funding Roche Diabetes Care Gmbh, Mannheim, Germany

Phase I study of drug-resistant immunotherapy (DRI) with gene-modified autologous γδ T cells in patients with newly diagnosed glioblastoma multiforme (GBM) receiving maintenance temozolomide (TMZ).

2044 Background: γδ T cells, MHC unrestricted immune cells, target NKG2D ligands differentially expressed on tumor cells. DeltEx drug resistant immunotherapy (DRI), a novel ex vivo expanded, activated γδ T cell expresses MGMT, conveying TMZ resistance. NCT04165941 , a phase 1 trial assessing the safety of single and multiple infusions of autologous DeltEx DRI cells presents updated safety and efficacy data. Methods: Adult newly diagnosed GBM patients with adequate organ function and KPS≥70% are enrolled. Cells engineered from apheresis after tumor resection were infused through a Rickham catheter placed during surgery. Cohort (C) 1, 2 and 3 receive 1, 3 and 6 doses of cells respectively on day (D) 1 of each 28-day maintenance cycle. Patients receive 1 x 107 γδ T cells intratumorally on D1 with 150 mg/m2 of TMZ intravenously with the Stupp regimen. Primary endpoint is safety; secondary endpoints include progression free and overall survival. Immunologic and genomic correlative analyses are being conducted. Dose limiting toxicities (DLTs) are defined as treatment related ≥ grade 3 cardiopulmonary or hepatic toxicity, grade 4 toxicity exceeding 72 hours or neurologic deterioration that exceeds 2 weeks. Results: 12 patients (58% male; median age 66.5 (range: 21-76); 66.7% IDH-WT, 66.7% MGMT unmethylated) were enrolled with 6 dosed (3 in C1, 3 in C2). No patients had DLTs, cytokine release syndrome (CRS), or neurotoxicity. The most common adverse events (AEs) were Grade 1/2 events including fever, leukopenia, nausea, and vomiting attributable to TMZ or radiotherapy. One subject had Grade 3 treatment related AEs of UTI, dehydration, and thrombocytopenia. Three evaluable C1 patients have PFS of 8.3, 11.9, 7.4 months and OS of 15.6, 17.7 and 9.6 months respectively. In C2, three patients have been dosed, with one patient with stable disease at 8.2 months after receiving all three doses and no DLTs. Patient recruitment continues with anticipated completion in 2022. Conclusions: Data demonstrates that single, repeat doses of DRI T cells have manageable toxicity with encouraging trend in PFS.

Excretion of Pu-238 during Long-term Chelation Therapy by Repeated DTPA Inhalation.

An individual underwent an extensive diethylenetriaminepentaacetate (DTPA) chelation therapy that started several months after plutonium incorporation, most likely by inhalation of a soluble compound. After receiving multiple intravenous infusions of DTPA, the patient continued the treatment by pulmonary delivery of aerosolized DTPA. The purpose of the present work is to provide and discuss the bioassay data obtained during the DTPA aerosol therapy and compare them with those under the DTPA infusion therapy that have been largely interpreted elsewhere. As with DTPA given intravenously, each delayed DTPA inhalation increased the clearance of plutonium not only in urine but also in feces, thus demonstrating the ability to remove plutonium retained by extrapulmonary tissues. Also, the slow decline of increased plutonium urinary elimination together with enhanced fecal excretion are two features coherent with the contribution of intracellular chelation to overall decorporation. The therapeutic benefit of DTPA inhalation appeared lower than with DTPA infusion, most likely due to a lower amount of DTPA reaching the systemic compartments where plutonium chelation predominates. The results suggest that DTPA administration through aerosol could be an alternative to the invasive procedure using a needle, i.e., intravenous injection/infusion, when protracted decorporation therapy is needed following transuranic internalization. Indeed, the patient may be more inclined to undergo a chelation treatment for a longer period because taking DTPA by inhalation may make it less cumbersome and painful.

A feeder cell-free activation and expansion strategy to generate memory-like NK cells sufficient for off-the-shelf multi-dose adoptive cell therapy.

Abstract Adoptive cell therapy (ACT) using NK cells is a promising armament in the fight against cancer. Cytokine induced memory like (CIML) NK cells have been shown in clinical studies to have potent antitumor activity with superior in vivo persistence. Currently, the expansion of NK cells for clinical development is mainly based on feeder cells, which imposes significant regulatory hurdles and increases the costs for manufacturing. We have developed fusion proteins, HCW9201 and HCW9206 comprising of IL-15/IL-18/IL-12 and IL15/IL-7/IL-21, respectively, capable of priming memory-like differentiation and expanding CIML NK cell products without using feeder cells. This “Kick and Expand” strategy allows greater than 100x expansion of CIML NK cells from donor PBMCs in as little as 14 days without the use of exogenous feeder cells. Continued expansion can yield sufficient CIML NK cells for cryopreservation and multiple ACT infusions. The NK cells generated have bona fide memory-like properties: enhanced antitumor activity across multiple cancer cell lines, higher metabolic capacity, stable epigenetic demethylation of the IFN-γ promoter and increased persistence in NSG mice, when compared to conventional NK cells. In conclusion, this “Kick and Expand” process supports generation of abundant CIML NK cells for multiple ACT infusions and provides simpler, more regulatory friendly, off-the-shelf platform for generating NK cell products, including those with chimeric antigen receptor (CAR) constructs.

Human Growth Factor/Immunoglobulin Complexes for Treatment of Myocardial Ischemia-Reperfusion Injury.

Hepatocyte Growth Factor (HGF) and Fibroblast Growth Factor 2 (FGF2) are receptor tyrosine kinase agonists that promote cell survival after tissue injury and angiogenesis, cell proliferation and migration during tissue repair and regeneration. Both ligands have potential as systemic treatments for ischemia-reperfusion injury, however clinical use of HGF and FGF2 has been limited by poor pharmacokinetic profiles, i.e., their susceptibility to serum proteases, rapid clearance and short half-lives. Previously, we reported vaso- and cardioprotective protein complexes formed between HGF and polyclonal, non-specific immunoglobulin (IgG) with therapeutic efficacy in a rat model of myocardial ischemia with reperfusion (MI/R). Here, using a pre-clinical porcine MI/R model, we demonstrate human HGF/IgG complexes provide significant myocardial salvage, reduce infarct size, and are detectable in myocardial tissue 24 h after intracoronary injection. Furthermore, we show that multiple daily infusions of HGF/IgG complexes after MI do not lead to production of HGF-specific auto-antibodies, an important concern for administered biologic drugs. In experiments to identify other growth factors that non-covalently interact with IgG, we found that human FGF2 associates with IgG. Similar to human HGF/IgG complexes, FGF2/IgG complexes protected primary human cardiac endothelial cells under simulated ischemia (1% oxygen and nutrient deprivation) for 48–72 h. Molecular modeling studies suggested that FGF2 and HGF both interact with the Fc domain of IgG. Also, we tested whether an Fc-fusion protein would bind FGF2 to form complexes. By native gel electrophoretic assays and biochemical pulldowns, we found that Jagged1, a Notch1 ligand that controls stem cell self-renewal and tissue regeneration, bound FGF2 when presented as a Jagged1- Fc fusion protein. Our results suggest that human growth factor/IgG and FGF2/Fc- fusion complexes have potential to provide a biologics platform to treat myocardial ischemia-reperfusion and other forms of tissue injury.

A154 COMPARING RESPONSE TO INTRAVENOUS IRON INFUSION IN CROHN’S DISEASE AND ULCERATIVE COLITIS

BackgroundIron deficiency anemia (IDA) is common in persons with inflammatory bowel disease (IBD). Current evidence-based guidelines suggest iron replacement therapy in IBD patients with IDA. Intravenous (IV) iron has been demonstrated to be more effective than oral iron replacement in the IBD population, and this is thought to be related to oral iron being poorly tolerated, absorbed, and possibly having an adverse impact on the gut microbiome. Studies have not directly compared the response of IV iron between persons with ulcerative colitis (UC) and Crohn’s disease (CD).Aims(1) To compare the increase in serum hemoglobin and ferritin following IV iron therapy between persons with UC and CD. (2) To determine factors associated with response to IV iron (other than disease type), including age, sex, IBD therapies, abdominal surgeries, and IBD phenotype.MethodsIn a retrospective chart review, we evaluated 536 IV iron infusions (iron sucrose) prescribed to 117 IBD patients by a single gastroenterologist between 2012–2020, and collected data on IBD type, age, sex, medications (IBD therapies, NSAIDs, ASA, oral iron), abdominal surgeries, and IBD phenotype. Statistical analysis was performed using SPSS version 26.ResultsMost IV iron infusions were given to patients with CD (77% of infusions, 68% of persons). The majority of infusions were given as a series of multiple iron infusions (84%) over a mean of 27 weeks, rather than a single infusion. Persons with UC had a greater increase in serum ferritin than those with CD (mean difference ± SE of 13.2 ± 5.6 µg/L, p = 0.02). There was no significant difference in the increase in serum hemoglobin between UC and CD (UC= 6.5 ± 1.0 g/L; CD 4.9 ± 2.1 g/L; p = 0.62).ConclusionsPersons with UC had a better ferritin response to IV iron therapy than persons with CD. Patients with UC were prescribed less IV iron than those with CD. In summary, persons with CD may require greater dosing of IV iron therapy than patients with UC. Further studies are needed to discern if this difference is secondary to CD being associated with a greater extent of mucosal disease burden, impaired iron absorption, or a greater intolerance to oral iron.Funding AgenciesFellowship Funding from Pfizer Canada

Ketamine and Lamotrigine Combination in Psychopharmacology: Systematic Review.

Background and Objectives: Ketamine is a rapid-acting antidepressant with proven efficacy as an add-on agent in unipolar and bipolar treatment-resistant depression. Although many studies have been published, there is still not enough data on the effect of ketamine in combination with other medications. Particularly interesting is the combination of ketamine and lamotrigine, and its potential role in bipolar depression. The aim of this review was to identify animal and human studies in which ketamine and lamotrigine were used together in order to find out if there is scientific ground for combining ketamine and lamotrigine in the treatment of mood disorders. Directions for future studies are presented. Materials and Methods: PubMed and Web of Science were searched. Preferred Reporting Items for Systematic Reviews and Meta-Analyses PRISMA 2020 methodology was applied. Results: Seventeen studies were included for review. Animal studies using models of depression suggested a synergistic effect of ketamine and lamotrigine in combination. Studies on healthy humans showed a reduction in ketamine-induced dissociative symptoms with lamotrigine pretreatment. In a study on patients with depression, ketamine and lamotrigine did not have a stronger antidepressant effect than ketamine alone, but in this study only one ketamine infusion was administered. One case series described the antidepressant and anti-suicidal effect of the combination in two bipolar patients. Available clinical studies on patients with mood disorders did not support the hypothesis that lamotrigine reduces ketamine-induced dissociative symptoms. Conclusions: The results of the analyzed studies were not sufficient to answer any of the stated questions; however, they allowed us to delineate future research directions. The identified animal studies suggested a possible synergistic antidepressant effect of ketamine and lamotrigine. The available clinical studies were not conclusive. No controlled studies on large groups of bipolar patients with multiple ketamine infusions combined with lamotrigine treatment have been published so far. There is some evidence for the reduction of ketamine’s side effects by lamotrigine, and there are reports suggesting that lamotrigine can reduce ketamine craving. More studies with follow-up are needed in order to investigate the ketamine–lamotrigine combination in bipolar patients.

Systemic Administration of Allogeneic Cord Blood Mononuclear Cells in Adults with Severe Acute Contusion Spinal Cord Injury: Phase 1/2a Pilot Clinical Study–Safety and Primary Efficacy Evaluation

Phase 1 of the SUBSCI I/IIa (Systemic Umbilical Cord Blood Administration in Patients with Acute Severe Contusion Spinal Cord Injury) study focused on safety and primary efficacy of multiple systemic infusions of allogeneic unrelated human umbilical cord blood mononuclear cells in patients with severe acute spinal cord contusion having severe neurologic deficit. The primary end point was safety. The secondary end point was the restoration of motor and sensory function in lower limbs within a 1-year period. Ten patients with acute contusion spinal cord injury (SCI) and American Spinal Injury Association (ASIA) level A/B deficit were enrolled into phase 1. Patients were treated with 4 infusions of group-matched and rhesus-matched cord blood samples after primary surgery within 3 days after SCI. All patients were followed up for 12 months after SCI. Safety was assessed using adverse events classification depending on severity and relation to cell therapy. Primary efficacy was assessed using dynamics of deficit (ASIA scale). The overall number of adverse events reached 419 in 10 patients. Only 2 were estimated as possibly related to cell therapy, and the remaining 417 were definitely unrelated. Both adverse events were mild and clinically insignificant. No signs of immunization were found in participants. Analysis of clinical outcomes also showed that cell therapy promotes significant functional restoration of motor function. The data obtained suggest that systemic administration of allogeneic, non-human leukocyte antigen-matched human umbilical cord blood is safe and shows primary efficacy in adults with severe acute contusion SCI and ASIA level A/B deficit.