Intravenous Infusion Administration Research Articles

Pharmacokinetics and Safety of Spesolimab in Healthy Chinese Subjects: An Open-Label, Phase I Study.

Generalized pustular psoriasis (GPP) is a rare and potentially life-threatening inflammatory skin disease. Interleukin (IL)-36 signalling may play a central role in GPP pathogenesis. Spesolimab is a humanized anti-IL-36 monoclonal antibody inhibiting the IL-36 signalling pathway. Here, we investigated the pharmacokinetics and safety of spesolimab in healthy Chinese subjects. In this Phase 1, single-dose, parallel-group, open-label study, healthy Chinese subjects aged 18-45years received a single spesolimab dose by intravenous infusion (IV; 450mg, 900mg, or 1200mg) or subcutaneous (SC) administration (300mg or 600mg). Primary endpoints were spesolimab exposure (area under the plasma concentration-time curve and maximum plasma concentration); secondary endpoints were treatment-emergent adverse events (TEAEs) and drug-related adverse events (AEs). Fifty subjects received IV (n = 30) or SC (n = 20) spesolimab (n = 10 per dose group); 60.0% were male, mean ± standard deviation age was 31.5 ± 6.6 and 31.0 ± 6.5years in the IV and SC groups, respectively. Spesolimab exposure increased in a dose-proportional manner in both groups. TEAEs were reported in 83.3% and 80.0% of subjects in the IV and SC groups, the most common TEAE was upper respiratory tract infection (20.0% and 25.0%, respectively). One serious AE of hand fracture was reported in the 900mg IV group that was not considered drug-related. Drug-related AEs were reported in 53.3% and 55.0% of subjects in the IV and SC groups. All laboratory-related AEs were mild and resolved. Spesolimab exposure increased in a dose-proportional manner after a single dose by IV and SC administration. Spesolimab was well tolerated in healthy Chinese subjects. Clinicaltrials.gov registration: NCT04390568.

Hybrid treatment of recurrent venous mesenteric thrombosis with small intestinal necrosis

The article presents a clinical case of a 39-year-old patient with thrombosis and postoperative rethrombosis of the superior mesenteric vein. The disease was complicated by the small intestine necrosis and abdominal surgical infection. Successful thrombectomy and bowel resection made it possible to restore mesenteric blood supply, to stabilize the patient’s condition and to perform an enteroenteroanastomosis. Due to antithrombin III deficiency, rethrombosis in the early postoperative period was complicated by anastomotic leak, unformed intestinal fistula and peritonitis. A hybrid treatment (surgical, parasurgical and conservative) was performed, which included selective infusion of a thrombolysis activator at the superior mesenteric artery mouth. The patient recovered.Clinical and laboratory manifestations of superior mesenteric vein thrombosis, in contrast to acute circulatory disorders in the arteriomesenteric system, are nonspecific and do not always allow timely diagnosis of intestinal ischemia. MSCT angiography identifies venous mesenteric thrombosis in most cases. The ineffectiveness of anticoagulant therapy against the background of antithrombin III deficiency caused superior mesenteric vein thrombosis and rethrombosis. The treatment of the small intestine critical postoperative ischemia included an increase in the volume of antithrombin III and frozen plasma intravenous infusion and selective administration of a thrombolysis activator (actilyse) into the superior mesenteric artery, which made it possible to restore the arteriolovenular intramural blood flow of the small intestine and to prevent another stem rethrombosis of the superior mesenteric vein. Laparostomy using a silicone plate made it possible to constantly monitor the course of the abdominal infectious process and to make timely decisions about the next intervention if medically required. The vacuum assisted design provided permanent lavage of the abdominal cavity without trauma to the soft tissues of the abdominal wall and presenting intestinal loops.

The Diagnosis and Treatment of Acute Cholecystitis: A Comprehensive Narrative Review for a Practical Approach.

Acute cholecystitis (AC), generally associated with the presence of gallstones, is a relatively frequent disease that can lead to serious complications. For these reasons, AC warrants prompt clinical diagnosis and management. There is general agreement in terms of considering early laparoscopic cholecystectomy (ELC) to be the best treatment for AC. The optimal timeframe to perform ELC is within 72 h from diagnosis, with a possible extension of up to 7-10 days from symptom onset. In the first hours or days after hospital admission, before an ELC procedure, the patient's medical management comprises fasting, intravenous fluid infusion, antimicrobial therapy, and possible administration of analgesics. Additionally, concomitant conditions such as choledocholithiasis, cholangitis, biliary pancreatitis, or systemic complications must be recognized and adequately treated. The importance of ELC is related to the frequent recurrence of symptoms and complications of gallstone disease in the interval period between the onset of AC and surgical intervention. In patients who are not eligible for ELC, it is suggested to delay surgery at least 6 weeks after the clinical presentation. Critically ill patients, who are unfit for surgery, may require rescue treatments, such as percutaneous or endoscopic gallbladder drainage (GBD). A particular treatment approach should be applied to special populations such as pregnant women, cirrhotic, and elderly patients. In this review, we provide a practical diagnostic and therapeutic approach to AC, even in specific clinical situations, based on evidence from the literature.

STELLATE GANGLION BLOCK REVERSES PHSML-INDUCED VASCULAR HYPOREACTIVITY THROUGH INHIBITING AUTOPHAGY-MEDIATED PHENOTYPIC TRANSFORMATION OF VSMCs.

Posthemorrhagic shock mesenteric lymph (PHSML) return-contributed excessive autophagy of vascular smooth muscle cells (VSMCs) is involved in vascular hyporeactivity, which is inhibited by stellate ganglion block (SGB) treatment. The contractile phenotype of VSMCs transforms into a synthetic phenotype after stimulation with excessive autophagy. Therefore, we hypothesized that SGB ameliorates PHSML-induced vascular hyporeactivity by inhibiting autophagy-mediated phenotypic transformation of VSMCs. To substantiate this hypothesis, a hemorrhagic shock model in conscious rats was used to observe the effects of SGB intervention or intravenous infusion of the autophagy inhibitor 3-methyladenine (3-MA) on intestinal blood flow and the expression of autophagy- and phenotype-defining proteins in mesenteric secondary artery tissues. We also investigated the effects of intraperitoneal administration of PHSML intravenous infusion and the autophagy agonist rapamycin (RAPA) on the beneficial effect of SGB. The results showed that hemorrhagic shock decreased intestinal blood flow and enhanced the expression of LC3 II/I, Beclin 1, and matrix metalloproteinase 2, which were reversed by SGB or 3-MA treatment. In contrast, RAPA and PHSML administration abolished the beneficial effects of SGB. Furthermore, the effects of PHSML or PHSML obtained from rats treated with SGB (PHSML-SGB) on cellular contractility, autophagy, and VSMC phenotype were explored. Meanwhile, the effects of 3-MA on PHSML and RAPA on PHSML-SGB were observed. The results showed that PHSML, but not PHSML-SGB, incubation decreased VSMC contractility and induced autophagy activation and phenotype transformation. Importantly, 3-MA administration reversed the adverse effects of PHSML, and RAPA treatment attenuated the effects of PHSML-SGB incubation on VSMCs. Taken together, the protective effect of SGB on vascular reactivity is achieved by inhibiting excessive autophagy-mediated phenotypic transformation of VSMCs to maintain their contractile phenotype.

Safety and Effectiveness of a Standardized Intravenous Insulin Infusion Order Set for Managing Uncontrolled Hyperglycemia Outside the Intensive Care Unit.

Few studies have evaluated the administration of intravenous (IV) insulin infusions for uncontrolled hyperglycemia in non-intensive care unit (ICU) patients, and there is inadequate data to guide how to appropriately administer IV insulin infusions to this patient population. Determine the effectiveness and safety of our institution's non-critical care IV insulin infusion order set. This retrospective study was conducted at 2 institutions within a health care system. The primary outcome was the number of individuals who achieved a glucose level ≤180 mg/dL. For those meeting this endpoint, the time to achieving this outcome and the percentage of glucose checks within the goal range were determined. The primary safety endpoint was the number of individuals who experienced hypoglycemia (glucose level <70 mg/dL). Patients were included if they were ≥18 years of age and received the non-critical care IV insulin infusion order set outside of the ICU. Twenty-one (84%) patients achieved a glucose level ≤180 mg/dL. The median (inter-quartile range [IQR]) time to achieving the primary outcome was 5.7 h (3.9-8.3). In patients who achieved the primary outcome, 41.8% of the glucose readings obtained after achieving this outcome were within goal range. Two (8%) patients experienced hypoglycemia. Both of these events occurred within 8 hours of therapy initiation and neither patient received prior doses of subcutaneous insulin. Of the 4 patients who did not achieve a glucose level ≤180 mg/dL, 2 received high-dose corticosteroids, and 3 achieved a glucose level between 181 and 200 mg/dL. Our findings support the safe administration of IV insulin infusions to non-ICU patients when targeting a glucose range of 140 to 180 mg/dL and limiting the infusion duration.

Systemic Anti-Inflammatory Effects of Intravenous Lidocaine in Surgical Patients: A Systematic Review and Meta-Analysis.

There has recently been increasing evidence that the use of perioperative intravenous lidocaine infusion possesses analgesic, opioid-sparing and anti-inflammatory effects in surgical patients. Although opioid-sparing and analgesic properties have been strongly supported, the anti-inflammatory features are not well established in elective surgery. Therefore, the aim of this systematic review is to examine the effect of perioperative intravenous lidocaine infusion on postoperative anti-inflammatory status in patients undergoing elective surgery. A search strategy was created to identify suitable randomised clinical trials (RCTs) in PubMed, Scopus, Web of Science and Clinicaltrials.gov databases until January 2023. RCTs that evaluated the effect of intravenous lidocaine infusion, compared with placebo, on adult patients who underwent elective surgery, in inflammatory markers response were included. Exclusion criteria consisted of paediatric patients, animal studies, non-RCT methodology, intervention without intravenous lidocaine, inadequate control group, duplicated samples, ongoing studies and lack of any relevant clinical outcome measures. The following inflammatory markers-interleukin (IL)-6, tumour necrosis factor (TNF)-α, IL-1RA, IL-8, IL-10, C-reactive protein (CRP), IL-1, IL-1β, interferon (IFN)-γ, cortisol, IL-4, IL-17, high-mobility group protein B1 (HMGB1) and transforming growth factor (TGF)-β-were evaluated as outcomes in this review. A total of 21 studies, including 1254 patients, were identified. Intravenous lidocaine infusion significantly reduced the change from IL-6 baseline levels at the end of surgery compared to a placebo (standardised mean difference [SMD]: -0.647, 95% confidence interval [CI]: -1.034 to -0.260). Usage of lidocaine was associated with a significant reduction in other postoperative pro-inflammatory markers, such as TNF-α, IL-1RA, IL-8, IL-17, HMGB-1 and CRP. There was no significant difference in other markers, such as IL-10, IL-1β, IL-1, IFN-γ, IL-4, TGF-β and cortisol. This systematic review and meta-analysis provide support for the administration of perioperative intravenous lidocaine infusion as an anti-inflammatory strategy in elective surgery.

Genetic Studies in Infants with Congenital Nephrotic Syndrome: A Case Series.

Information on the genetic profile of congenital nephrotic syndrome (CNS) from India is scarce. The management of CNS is largely supportive of the setting of developing countries, mainly via the administration of intravenous albumin infusions, angiotensin-converting enzyme inhibitors, and levothyroxine. Inadequate infrastructure and management facilities, including genetic analyses, further hamper the outcome. These infants may progress to end-stage renal disease, and mortality is high in infancy. Here, we report a case series of four infants (aged 14-60 days) with CNS from our center with genetic mutations (including mutations in the NPHS1 and LAMB2 genes) that were not described in previous reports from India. Although responsiveness to enalapril has been documented in anecdotal reports of NPHS1 mutations, our case series of four infants did not exhibit any response to enalapril. Our case series adds to the existing literature regarding the genetic profile of CNS in India.

Management of insulinoma in a dog with subcutaneous diluted glucagon and a continuous glucose monitoring system

Glucagon has been shown effective for the treatment of insulinoma-associated hypoglycemia. However, its use has been limited to preoperative supportive care and emergency treatment of hypoglycemic crisis because of the need of constant intravenous infusion administration. Here, we report a case of insulinoma in a dog managed with subcutaneous saline-diluted glucagon and a continuous glucose monitoring system (CGMS), which were effective in glycemic control allowing long-term home treatment.

Renal Dysfunction and Arrhythmia Association in Patients Receiving Milrinone After Cardiac Surgery

The altered pharmacokinetics of milrinone in renal impairment could result in an increased risk of cardiac arrhythmias. This study aimed to determine if there is an association between new-onset arrhythmias and renal impairment after cardiac surgery following milrinone administration. A retrospective cohort study. A single-center tertiary care hospital. Adult patients whoreceived a milrinone infusion in the intensive care unit (ICU) setting after coronary artery bypass graft, valvuloplasty, annuloplasty, or a combination of these surgeries from July 1,2014to July 1, 2021. Renal impairment was defined using a creatinine clearance <60 mL/min, calculated using the Cockcroft-Gault equation. Patients received a weight-based continuous intravenous infusion of milrinone. The primary outcome was the presence of new arrhythmias after the initial administration of a weight-based continuous intravenous infusion of milrinone postcardiac surgery. Of the 197 patients who met inclusion, there was no difference in the presence of new arrhythmias (42.9% v 40.3%, p=0.76) or in the time to first new arrhythmia from milrinone initiation in those with renal impairment compared to those without renal impairment (29.1 hours v 33.3 hours, p=0.54). Patients with renal impairment had a longer hospital stay than patients without renal impairment (17.5 days v 13.9 days, p=0.016). Arrhythmia type, length of ICU stay, ICU mortality, and hospital mortality were not different between the cohorts. There was no association between new arrhythmias, milrinone, and renal impairment in patients postcardiac surgery.

Teclistamab Population Pharmacokinetics and Exposure-Response Relationship Support 1.5 Mg/Kg Dose Regimen in Relapsed/Refractory Multiple Myeloma

Background: Teclistamab (JNJ-64007957) is a B-cell maturation antigen (BCMA) × CD3 bispecific antibody that redirects CD3+ T cells to induce cytotoxicity of BCMA-expressing multiple myeloma (MM) cells. The objectives of this work were to develop a population pharmacokinetics (PK) model for serum teclistamab concentrations after intravenous (IV) infusion and subcutaneous (SC) administration, evaluate the effects of patients' demographic characteristics and other covariates (such as soluble BCMA [sBCMA]) on PK, and explore the exposure-efficacy/safety relationships in patients with relapsed/refractory MM (RRMM). Methods: Analyses were conducted using data from the phase 1/2 study MajesTEC-1 (NCT03145181/NCT04557098) in eligible patients with RRMM. A population PK model was developed using serum teclistamab concentrations from 338 patients who received IV (range, 0.0003-0.0192 mg/kg every 2 weeks and 0.0192-0.72 mg/kg weekly; n=83) or SC doses (range, 0.08 mg/kg weekly to 6 mg/kg [weekly in cycles 1-2, biweekly in cycles 3-6, monthly in cycle 7+]; n=255). Exposure-response (E-R) analyses for efficacy were evaluated based on the predicted exposure metrics (average concentration of the first treatment dose and trough concentration after the first 4 weekly treatment doses) on overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS) at the recommended phase 2 dose (RP2D; 1.5 mg/kg teclistamab SC administered weekly with the first treatment dose preceded by step-up doses of 0.06 and 0.3 mg/kg) as well as 0.08 to 6 mg/kg SC doses in Phase 1. Safety E-R analyses were conducted based on the predicted maximum concentrations (after the first treatment dose and the first 4 weekly treatment doses) on Grade ≥3 treatment-emergent adverse events of anemia, neutropenia, lymphopenia, thrombocytopenia, and infection. Results: The PK of teclistamab was adequately described by a 2-compartment model with first-order absorption (associated with SC administration) and parallel time-independent (CL1) and time-dependent (CL2; decreased over time to reflect the change in tumor burden) elimination pathways. The covariate effects in the final model included the effect of body weight on CL1, volume of distribution in the central compartment (V1), and volume of distribution in the peripheral compartment (V2); the effects of International Staging System stage on CL1; and the effect of type of myeloma (IgG vs non-IgG) on CL1 and CL2. A rapid decrease in sBCMA was observed in the majority of responders within the first month of treatment. At 1.5 mg/kg, E-R for ORR was near flat, and DOR, PFS, and OS were not significantly correlated with teclistamab exposures. For 0.08 to 6 mg/kg SC doses in phase 1, a positive E-R relationship was observed for ORR and the response rate at the concentration range associated with 1.5 mg/kg weekly was approaching the plateau (or maximum response). No apparent positive E-R trend was observed in the incidence of grade ≥3 anemia, neutropenia, lymphopenia, thrombocytopenia, and infections across the predicted exposure quartiles in patients who received teclistamab SC. Conclusions: Teclistamab population PK following IV and SC dosing has been well characterized. The E-R analyses for ORR showed positive trend with a plateau at the RP2D, while there was no apparent E-R trend between teclistamab exposure and the grade ≥3 hematologic and infection treatment-emergent adverse events. These results support 1.5 mg/kg teclistamab SC weekly as the recommended dose regimen for the treatment of RRMM.

The Improved Brain-Targeted Drug Delivery of Edaravone Temperature-Sensitive Gels by Ultrasound for γ-ray Radiation-Induced Brain Injury.

Radiation-induced brain injury (RBI) is a common neurological disease caused by ionizing radiation (IR). Edaravone (EDA) is a free radical scavenger, has the potential to treat RBI. EDA loaded temperature-sensitive gels (TSGs) were prepared for subcutaneous injection to improve inconvenient administration of intravenous infusion. RBI mice model was established by irradiation of 60Co γ-ray on head. EDA TSGs could improve spontaneous behavior, learning and memory and anxiety of RBI mice by behavior tests, including the open field test, the novel object recognition test, the elevated plus maze test and the fear conditioning test. The therapeutic effects were enhanced with the assistance of ultrasound. Alleviative pathological changes, decreased the expression of Molondialdehyde (MDA) and Interleukin-6 (IL-6) in the hippocampus of brain, indicated reduced oxidative stress and inflammatory response with the treatment of EDA TSGs and ultrasound. Moreover, ultrasound was superior to the use of EDA TSGs. Safe and effective EDA TSGs were prepared for RBI, and the feasibility of brain-targeted drug delivery enhanced by ultrasound was preliminarily demonstrated in this study.

Population-based cellular kinetic characterization of ciltacabtagene autoleucel in subjects with relapsed or refractory multiple myeloma.

The aims of this work were to develop a population pharmacokinetic (PK) model for chimeric antigen receptor (CAR) transgene after single intravenous infusion administration of ciltacabtagene autoleucel in adult patients with relapsed or refractory multiple myeloma. CAR transgene level in blood were measured by quantitative polymerase chain reaction (qPCR) from 97 subjects in a phase Ib/II CARTITUDE-1 study (NCT03548207), with a targeted cilta-cel dose of 0.75 × 106 (range 0.5-1.0 × 106 ) CAR positive viable T-cells per kg body weight. The population PK model development was primarily guided by the current mechanistic understanding of CAR-T kinetics and the principles of building a parsimonious model. Cilta-cel PK was adequately described by a two-compartment model (with a fast and a slow apparent decline rate from each compartment, respectively) and a chain of four transit compartments with a lag time empirically representing the process from infused CAR-T cell to measurable CAR transgene. No apparent relationship was observed between cilta-cel dose (i.e., the actual number of CAR positive viable T-cells infused), given the narrow dose range, and the observed transgene level. Based on covariate search and subgroup analysis of maximum systemic CAR transgene level (Cmax ) and area under curve from the first dose to day 28 (AUC0-28d ), none of the investigated subjects' demographics, baseline characteristics, and manufactured product characteristics had significant effects on cilta-cel PK. The developed model is deemed robust and adequate for enabling subsequent exposure-safety and exposure-efficacy analyses.

Anti-factor X activity levels with continuous intravenous infusion and subcutaneous administration of enoxaparin after coronary artery bypass grafting: A randomized clinical trial.

Low-molecular-weight heparin enoxaparin is widely used in pharmacological thromboprophylaxis after coronary artery bypass grafting (CABG). The aim of this study was to compare anti-factor X activity (anti-Xa) levels when the thromboprophylactic dose of enoxaparin was provided after CABG, with two different administration routes: continuous intravenous infusion (CIV) and subcutaneous bolus (SCB) injection. We hypothesized that the current standard method of SCB administration might lead to lower anti-Xa levels than recommended in other patient groups, due to reduced bioavailability. In this prospective, randomized, controlled clinical trial, 40 patients scheduled for elective CABG were randomized to receive 40 mg of enoxaparin per day either as CIV or SCB for 72 h. Enoxaparin was initiated 6-10h after CABG. Anti-Xa levels were measured 12-14 times during the study period. The primary outcome, that is, the maximum anti-Xa concentration over 0-24 h (Cmax0-24h ), was calculated from these measured values. Secondary outcomes were Cmax25-72h and the trough concentration of anti-Xa after 72 h of enoxaparin initiation (C72h ). Twenty patients were randomized to the CIV-group and 19 to the SCB-group. The median anti-Xa Cmax0-24h was significantly lower in the CIV-group than in the SCB-group: 0.15 [interquartile range (IQR) 0.13-0.19] IU/ml versus 0.25 (IQR 0.18-0.32) IU/ml, p < .005. The median anti-Xa Cmax25-72h was 0.12 (IQR, 0.1-0.17) IU/ml versus 0.23 (IQR 0.19-0.31) IU/ml, respectively, p < .005. At 72 h, there was no difference between the groups in their anti-Xa levels. In this low-risk CABG patient population, SCB administration of a thromboprophylactic dose of enoxaparin provided anti-Xa levels that are considered sufficient for thromboprophylaxis in other patient groups. CIV administration resulted in lower anti-Xa levels compared to the SCB route.

Quantification of pharmacokinetic profiles of a recombinant canine PD-1 fusion protein by validated sandwich ELISA method.

Tumors are becoming a serious threat to the quality of life of human and dogs. Studies have shown that tumors have caused more than half of the deaths in older dogs. Similar to human, dogs will develop various and highly heterogeneous tumors, but there are currently no viable therapies for them. In human, immunotherapy has been used widely and considered as an effective treatment for tumors by immune checkpoint targets, which are also expressed on canine tumors, suggesting that immunotherapy may be a potential treatment for canine tumors. In this work, we developed a sandwich ELISA method to detect the concentration of recombinant canine PD-1 fusion protein in canine serum and investigated pharmacokinetics in canines after intravenous infusion administration. After being validated, the ELISA method showed an excellent linear relationship in 25.00–3,200.00 ng/ml in serum, and the R2 was more than 0.99 with four-parameter fitting. The precision and accuracy of intra-assay and inter-assay at the five different concentrations met the requirements of quantitative analysis. At the same time, no hook effect was observed at the concentration above ULOQ, and the stability was good under different predicted conditions with accuracy > 80%. The pharmacokinetic study in dogs has shown that the recombinant canine PD-1 fusion protein exhibited a typical biphasic PK profile after intravenous infusion administration, and the linear pharmacokinetic properties were observed between 1.00 and 12.00 mg/kg. Meanwhile, the T1/2 after intravenous infusion administration with non-compartmental analysis was about 5.79 days.

Use of dexmedetomidine repeated subcutaneous administration for balanced anaesthesia in horses

BackgroundA balanced anaesthetic protocol is a common concept in modern veterinary anaesthesia and aims to maintain good intraoperative cardiopulmonary function. In horses, alpha-2-agonists produce sedation and analgesia and have been shown to reduce inhalational anaesthetic requirements when administered intravenously. Furthermore, these drugs can improve recovery quality. Preliminary investigations of subcutaneous dexmedetomidine administration in humans demonstrated a reduced haemodynamic impact if compared with the intravenous route suggesting that dexmedetomidine is adequately absorbed with both administration routes. The aim of the study was to compare two different dexmedetomidine (DEX) administration routes: intravenous constant rate infusion (CRI) versus repeated subcutaneous (SC) injections on cardiopulmonary function and recovery in anaesthetized horses.ResultsNo significant differences between groups in heart rate and systolic arterial pressure were detected. A significantly higher mean and diastolic arterial pressure were detected in the SC group at T25 (p = 0.04; p = 0.02), T75 (p = 0.02; p = 0.009), and T85 (p = 0.001; p = 0.005). In SC group there was a significantly lower dobutamine infusion rate (p = 0.03) and a significantly higher urinary output (p = 0.02). Moreover, recovery quality was higher (p = 0.01).ConclusionsCardiopulmonary effects in both groups were comparable and within clinical ranges with less dobutamine requirement in the subcutaneous group. Recovery was of better quality with fewer attempts in horses receiving subcutaneous dexmedetomidine. The present study suggests that intravenous constant rate infusion and subcutaneous repeated administration of dexmedetomidine at indicated dosage can be useful in balanced anaesthesia without any systemic or local adverse effects; moreover, in healthy horses undergoing general anaesthesia, repeated subcutaneous dexmedetomidine administration may be a suitable alternative if constant rate infusion is not feasible.

Comparison Between Lignocaine Intravenous Lignocaine Infusion and Ketorolac in Reducing Postoperative Opioid Requirement in Upper Limb Surgeries

Objective: To compare the frequency of opioid requirement, after intravenous lignocaine infusion and ketorolac tromethamine in the upper limb surgeries.&#x0D; Study Design: Quasi-experimental study.&#x0D; Place and Duration of Study: Combined Military Hospital, Lahore Pakistan, from Oct 2017 to Apr 2018.&#x0D; Methodology: ASA I/II patients of either gender undergoing upper limb surgery were included. Patients were randomly divided into two equal groups, “L” (Lignocaine) and “K” (Ketorolac). In L-group, patients were given intravenous 1.5 mg/kg lignocaine bolus, followed by 2.0 mg/kg/hr infusion during entire procedure; while in K-group, patients were given intravenous 0.5 mg/kg (maximum 30 mg) ketorolac, at induction. The patients were monitored for 12 hours postoperatively and in case of severe postoperative pain (Visual Analogue Scale score &gt;5), rescue analgesia (intravenous Nalbuphine 0.1 mg/kg) was provided.&#x0D; Results: Total eighty patients were included in the study. There was no statistical difference between the two groups with age (p-value 0.823), gender (p-value 0.808) and ASA status (p-value 0.184). There was statistically significant difference between the two groups in terms of opioid requirement at 1-hour (p-value 0.035), 6-hours (p-value 0.032) and 12-hours (p-value 0.035), with K-group showing more requirement as compared to the L-group.&#x0D; Conclusion: Intraoperative administration of intravenous lignocaine infusion is superior to ketorolac in effective postoperative pain management in patients undergoing upper limb surgeries.

Abstract 5182: Population pharmacokinetic modeling of ciltacabtagene autoleucel in subjects with relapsed or refractory multiple myeloma

Abstract Objectives: Ciltacabtagene autoleucel (cilta-cel, CARVYKTI, previously JNJ-68284528) is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T-cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory multiple myeloma. Due to the restricted expression of BCMA in normal tissue and expression primarily on late-stage B-cells, plasma cells and malignant B-lineage cells, BCMA is an attractive target for cell therapy for multiple myeloma. The chimeric antigen receptor (CAR) consists of two BCMA-targeting single domain antibodies designed to confer avidity, a CD3ζ signaling domain and a 4-1BB costimulatory domain. The aims of this work were to develop a population pharmacokinetic (PK) model for CAR transgene after single intravenous infusion administration of cilta-cel and to evaluate the effects of subjects’ demographic characteristics and other covariates on CAR transgene PK. Methods: Subjects CAR transgene level in blood, as measured by quantitative polymerase chain reaction (qPCR) were available from 97 subjects in a Phase 1b/2 CARTITUDE-1 study (NCT03548207). A targeted cilta-cel dose of 0.75x106 (range 0.5-1.0x106) CAR-positive viable T-cells/kg body weight was given 5-7 days after lymphodepletion (300 mg/m2 cyclophosphamide, 30 mg/m2 fludarabine daily for 3 d). The data were analyzed by a non-linear mixed effects modeling approach implemented in NONMEM V7.4.3. The population PK model development was based on existing information on CAR T-cell (CAR-T) PK with some modifications. Model qualification was guided by the objective function value, diagnostic plots, standard error of parameters, evaluation of condition number, shrinkage, and visual predictive checks. Results: The PK of cilta-cel following IV infusion was adequately described by a 2-compartment model (with a fast and a slow apparent decline rate from each compartment, respectively) and a chain of 4 transit compartments with a lag time empirically representing the process from infused CAR-T cell to measurable CAR transgene. The model diagram is shown in Figure 1, consisting of 5 parameters and their respective inter-individual variability (lognormal distribution). The dose was defined as the number of CAR-positive viable T cells infused, and the fitted CAR transgene level (units of copies/μg genomic DNA) observation was the sum of the 2 CAR-T cell compartments. Conclusion: A population PK model has been developed to characterize CAR transgene level of cilta-cel in blood following IV infusion of 0.75x106 (range 0.5-1.0x106) CAR-positive viable T-cells/kg body weight. The developed model is robust and adequate for investigating the covariate effects on CAR transgene level of cilta-cel and enabling subsequent exposure-safety and exposure-efficacy analyses. Citation Format: Liviawati S. Wu, Yaming Su, Claire Li, Wangda Zhou, Carolyn Jackson, Yu-Nien Sun, Honghui Zhou. Population pharmacokinetic modeling of ciltacabtagene autoleucel in subjects with relapsed or refractory multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5182.

Hypoglycaemia associated with variable rate intravenous insulin infusion and concurrent administration of balanced electrolyte solution: A single hospital experience

Hypoglycaemia associated with variable rate intravenous insulin infusion and concurrent administration of balanced electrolyte solution: A single hospital experience

Comparison of Epigastric Pain Between Intravenous Infusion and Intravenous Bolus Administration in C-Section

Objective: The purpose of this study is to assess the frequency of epigastric pain following intravenous infusion versus intravenous bolus administration of oxytocin in caesarean section. Study Design: Case control/Prospective Place and Duration: M. Islam Medical College, Gujranwala from 1st January 2018 to 30th June 2018. Methods: A total of 100 patients were enrolled in this research. After obtaining written agreement, detailed demographic information such as the patient's age, BMI, and parity were collected. Those who took part in the study ranged in age from 18 to 45. Patients were separated into two equal groups, designated as I and II, respectively. Group I received an intravenous infusion, while group II received an intravenous bolus of medication. There was a significant difference in the frequency of epigastric pain between the groups. The SPSS 25.0 version was used to examine the entire set of data. Results: In group I mean age was 26.11± 7.64 years and mean BMI was 25.12±3.19 kg/m2 while in group II mean age was 27.07 ±4.37 years with mean BMI 25.01±4.55 kg/m2. Mean diastolic blood pressure was 80.88± 3.55 and 81.34 ±7.78 among both groups. We found that most of the patients were multigravida in both groups 33 (66%) and 34 (68%) while frequency of primigravida in group I was 17 (34%) and in group II was 16 (32%).We found that prevalence of epigastric pain was observed higher 25 (50%) in bolus group II as compared to infusion 14 (28%) group I with p value &lt; 0.05. Conclusion: We found from this study that the frequency of epigastric discomfort was higher in the intravenous bolus group as compared to the infusion of an equivalent dose of oxytocin in the control group. Keywords: Intravenous bolus, Intravenous infusion, Epigastric pain, Pregnancy, C-section

Population pharmacokinetics of ciclosporin in allogeneic hematopoietic stem cell transplant recipients: C-reactive protein as a novel covariate for clearance.

Ciclosporin (CsA), a potent immunosuppressive agent used to prevent graft-versus-host disease in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients, is characterized by large inter-individual variability and a narrow therapeutic range. The aim of this study was to develop a population pharmacokinetic model for CsA in Chinese allo-HSCT recipients and to identify covariates influencing CsA pharmacokinetics. A total of 758 retrospective drug monitoring data points were collected after intravenous infusion or oral administration of CsA from 59 patients. Population pharmacokinetic analysis was performed using nonlinear mixed effects modelling expressed by differential equations. Monte Carlo simulation was applied to optimize dosage regimens. The final model was validated using bootstrap and normalized prediction distribution errors. The results showed that the daily CsA dose, haematocrit, total bile acid, C-reactive protein (CRP) and co-administration of triazole antifungal agent were identified as significant covariates for clearance (CL) of CsA. The typical value of CL was 19.8L/h with an inter-individual variability of 13.1%. The volume of distribution was 1340L. Bioavailability was 67.2% with an inter-individual variability of 8.5%. Dosing simulation based on the developed model indicated that patients with high CRP concentration required a higher daily dose to attain the therapeutic trough concentration. The influence of CRP ultimately on the therapy outcome of CsA is not clear, which needs further study. CRP concentration was identified as a novel marker associated with CsA pharmacokinetics, which should be considered when determining the appropriate dosage of CsA in allo-HSCT recipients.