Intravenous Bolus Research Articles

Abstract CT246: An open-label, single-center, phase 0, microdose study to demonstrate delivery of TTX-MC138-NODAGA-Cu64 to radiographically confirmed metastases in subjects with advanced solid tumors

Abstract Purpose: Cu-64 labeled TTX-MC138, a microRNA-10b (miR-10b) inhibitor, will be evaluated in a Phase 0 clinical study conducted under an Exploratory IND to evaluate delivery of the molecule to metastatic lesions in subjects with advanced solid tumors by using positron emission tomography-magnetic resonance imaging (PET-MRI). Background: miR10b is a master regulator of the viability of metastatic tumor cells and promotes capacity of tumor cells to migrate and invade surrounding tissue. These findings prompted design of a miR10b-targeted therapeutic consisting of an anti-miR10b antagomir conjugated to ultrasmall iron oxide nanoparticles (MN), termed TTX-MC138. In mouse models of cancer, TTX-MC138 caused durable regressions of established metastases with no systemic toxicity. Clinical development will investigate if TTX-MC138 would accumulate in clinical metastases. TTX-MC138 is radiolabeled with isotope Cu-64 to generate the radiopharmaceutical TTX-MC138-NODAGA-Cu64. PET-MRI will assess pharmacokinetics (PK) of the radiolabeled product in humans and determine uptake in metastatic lesions. Methods: This open-label, single-center, single-arm, phase 0, microdose study in subjects with advanced solid tumors and radiographically confirmed metastases will evaluate delivery of TTX-MC138-NODAGA-Cu64 by using PET-MRI; establish PK of TTX-MC138-NODAGA-Cu64; and assess safety of TTX-MC138-NODAGA-Cu64. Approximately 12 subjects age ≥ 18 years are expected to be enrolled in the study. Eligible subjects will have confirmed diagnosis of at least 1 metastatic solid tumor (that is not amenable to curative therapy unless participation in the study would delay standard therapy), Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, and at least 1 target lesion per Response Evaluation Criteria in Solid Tumors version 1.1 (at least 10 mm per MRI from fludeoxyglucose [FDG] PET-MRI). Study duration is up to 46 days and includes a screening visit, dosing period (2 visits), and a follow-up visit. On Day 1, subjects receive 1 microdose of TTX-MC138-NODAGA-Cu64 by intravenous bolus. Days 1 and 2 include whole body PET-MRI imaging, ECG and blood collection. Safety data are collected at all visits. A Data Review Committee may review specific study data, including safety data. The primary endpoint will measure percent injected dose per cubic centimeter (%ID/cc) tissue of TTX-MC138-NODAGA-Cu64 delivered to metastatic lesions. Secondary endpoints may include evaluation of PK of key components of TTX-MC138-NODAGA-Cu64, metabolite analysis, and target engagement. Safety data, including incidence of adverse events, clinical lab data, ECGs, vital signs and concomitant medications, will be summarized. Enrollment is expected to start in 2023. Citation Format: Andreas Varkaris, Peter Caravan, Neil Robertson, Subrata Ghosh, Michael Warren, Zdravka Medarova, Susan Duggan. An open-label, single-center, phase 0, microdose study to demonstrate delivery of TTX-MC138-NODAGA-Cu64 to radiographically confirmed metastases in subjects with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT246.

The Uses and Advantages of Kirchhoff’s Laws vs. Differential Equations in Pharmacology, Pharmacokinetics, and (Even) Chemistry

In chemistry, rate processes are defined in terms of rate constants, with units of time−1, and are derived by differential equations from amounts. In contrast, when considering drug concentrations in biological systems, particularly in humans, rate processes must be defined in terms of clearance, with units of volume/time, since biological volumes, which are highly dependent on drug partition into biological tissues, cannot be easily determined. In pharmacology, pharmacokinetics, and in making drug dosing decisions, drug clearance and changes in drug clearance are paramount. Clearance is defined as the amount of drug eliminated or moved divided by the exposure driving that elimination or movement. Historically, all clearance derivations in pharmacology and pharmacokinetics have been based on the use of differential equations in terms of rate constants and amounts, which are then converted into clearance equations when multiplied/divided by a hypothesized volume of distribution. Here, we show that except for iv bolus dosing, multiple volumes may be relevant. We have recently shown that clearance relationships, as well as rate constant relationships, may be derived independent of differential equations using Kirchhoff’s Laws from physics. Kirchhoff’s Laws may be simply translated to recognize that when two or more rate-defining processes operate in parallel, the total value of the overall reaction parameter is equal to the sum of those rate-defining processes. In contrast, when two or more rate-defining processes operate in series, the inverse of the total reaction parameter is equal to the sum of the inverse of those rate-defining steps.Graphical

Abstract 4493: Sudocetaxel Zendusortide (TH1902), a peptide-drug conjugate for the treatment of sortilin-positive (SORT1+) TNBC and Her2-positive breast cancers

Abstract Over the last decade, the targeting of specific cell surface receptors such as human epidermal growth factor receptor 2 (Her2) in breast cancer cells has allowed the emergence of innovative strategies for the delivery of anticancer agents. High expression levels of the sortilin receptor (SORT1) have been reported in various tumors of breast cancer patients, including triple-negative breast cancer (TNBC), HR+ and Her2+ breast cancers. Given SORT1 function in ligand internalization, we addressed the sorting and trafficking of the newly designed TH19P01 peptide recognizing SORT1, and of TH1902, an anticancer TH19P01-docetaxel conjugate (PDC), and whether such PDC could target SORT1+ breast cancers. In vitro, high expression of SORT1 was found in several TNBC and Her2+ breast cancer cell lines as well as in in more than 88% of cases (H-score >100) from commercial breast cancer tissue microarrays. SORT1-mediated cell surface binding and internalization of TH19P01 was first investigated in TNBC-derived MDA-MB-231 cells. The binding and uptake of Alexa488-labeled TH19P01, at 4 and 37°C respectively, were found significantly reduced upon siRNA-mediated SORT1 silencing. This demonstrates that functional SORT1 processes are required for both cell surface recognition and internalization of TH19P01. Moreover, the internalization of TH19P01 and TH1902 in MDA-MB-231 cells were monitored by fluorescence microscopy using a polyclonal antibody generated against TH19P01. Both TH19P01 and TH1902 showed a rapid uptake and co-localized in the perinuclear region with the late endosomal marker Rab-7 and with the lysosomal marker Lamp-1 within 30 minutes indicating that both compounds are internalized through a receptor-mediated endocytosis pathway. In addition, TH19P01 internalization after 1 hour appeared significantly associated within intracellular compartments of MDA-MB-231 cells whereas Herceptin remained mostly localized at the cell surface of Her2+ BT-474 cells. In vivo, weekly administration of intravenous bolus of TH1902 (35 mg/kg) at an equivalent docetaxel MTD dose (15 mg/kg) led to complete tumor regression, while docetaxel only inhibited tumor growth by half in a murine MDA-MB-231 xenograft tumor model. Furthermore, in mice bearing Her2+ HCC-1954 breast tumor xenografts, TH1902 induced complete tumor regression in contrast to docetaxel and Herceptin. Taken together, these preclinical data demonstrate the high anticancer properties of TH1902 against SORT1+ TNBC and Herceptin resistant Her2+ breast cancers. These results demonstrate that TH1902 can be a promising avenue for personalized therapy in the treatment of all SORT1+ breast cancers. Citation Format: Cyndia Charfi, Michel Demeule, Jean-Christophe Currie, Alain Zgheib, Bogdan Alexandru Danalache, Richard Béliveau, Christian Marsolais, Borhane Annabi. Sudocetaxel Zendusortide (TH1902), a peptide-drug conjugate for the treatment of sortilin-positive (SORT1+) TNBC and Her2-positive breast cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4493.

A 68-Year-Old Man Presenting to the ER with Sudden Dyspnea, A Rare Case of Snowstorm View in the Right Ventricle during Echocardiography

Pulmonary Thromboembolism (PTE) is a fatal condition and the third leading cause of hospital-related deaths. We present a case of acute PTE in a 68 year-old man with dyspnea. Patient had a history of bone malignancy. Bedside echocardiography revealed snowstorm view in the right ventricle. Patient was treated with 10 units reteplase intravenous bolus. Echocardiography was repeated and no signs of snowstorm view were detected. Finally, patient died of cardiogenic shock and massive PTE. In this case we report snowstorm view during echocardiography which is rare and should be considered in clinical assessment of PTE.

Antithrombotic Effects of the Novel Small-Molecule Factor XIa Inhibitor Milvexian in a Rabbit Arteriovenous Shunt Model of Venous Thrombosis

Background Factor XIa (FXIa) is an emerging therapeutic target, and FXIa inhibition is a promising mechanism to improve therapeutic index over current anticoagulants. Milvexian (BMS-986177/JNJ-70033093) is an oral small-molecule FXIa inhibitor. Objective Milvexian's antithrombotic efficacy was characterized in a rabbit arteriovenous (AV) shunt model of venous thrombosis and compared with the factor Xa inhibitor apixaban and the direct thrombin inhibitor dabigatran. Methods The AV shunt model of thrombosis was conducted in anesthetized rabbits. Vehicle or drugs were administered as intravenous bolus plus a continuous infusion. Thrombus weight was the primary efficacy endpoint. Ex vivo activated partial thromboplastin time (aPTT), prothrombin time (PT), and thrombin time (TT) were measured as the pharmacodynamic responses. Results Milvexian dose dependently reduced thrombus weights by 34.3 ± 7.9, 51.6 ± 6.8 ( p < 0.01; n = 5), and 66.9 ± 4.8% ( p < 0.001; n = 6) versus vehicle at 0.25 + 0.17, 1.0 + 0.67, and 4.0 ± 2.68 mg/kg bolus + mg/kg/h infusion, respectively. Ex vivo clotting data supported a dose-dependent prolongation of aPTT (with 1.54-, 2.23-, and 3.12-fold increases from baseline upon the AV shunt start), but no changes in PT and TT. Dose-dependent inhibition in thrombus weight and clotting assays was also demonstrated for both apixaban and dabigatran as the references for the model validation. Conclusion Results demonstrate that milvexian is an effective anticoagulant for prevention of venous thrombosis in the rabbit model, which supports the utility of milvexian in venous thrombosis, as seen in the phase 2 clinical study.

Development of a primate model to evaluate the effects of ketamine and surgical stress on the neonatal brain.

With advances in pediatric and obstetric surgery, pediatric patients are subject to complex procedures under general anesthesia. The effects of anesthetic exposure on the developing brain may be confounded by several factors including pre-existing disorders and surgery-induced stress. Ketamine, a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, is routinely used as a pediatric general anesthetic. However, controversy remains about whether ketamine exposure may be neuroprotective or induce neuronal degeneration in the developing brain. Here, we report the effects of ketamine exposure on the neonatal nonhuman primate brain under surgical stress. Eight neonatal rhesus monkeys (postnatal days 5-7) were randomly assigned to each of two groups: Group A (n = 4) received 2 mg/kg ketamine via intravenous bolus prior to surgery and a 0.5 mg/kg/h ketamine infusion during surgery in the presence of a standardized pediatric anesthetic regimen; Group B (n = 4) received volumes of normal saline equivalent to those of ketamine given to Group A animals prior to and during surgery, also in the presence of a standardized pediatric anesthetic regimen. Under anesthesia, the surgery consisted of a thoracotomy followed by closing the pleural space and tissue in layers using standard surgical techniques. Vital signs were monitored to be within normal ranges throughout anesthesia. Elevated levels of cytokines interleukin (IL)-8, IL-15, monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein (MIP)-1β at 6 and 24 h after surgery were detected in ketamine-exposed animals. Fluoro-Jade C staining revealed significantly higher neuronal degeneration in the frontal cortex of ketamine-exposed animals, compared with control animals. Intravenous ketamine administration prior to and throughout surgery in a clinically relevant neonatal primate model appears to elevate cytokine levels and increase neuronal degeneration. Consistent with previous data on the effects of ketamine on the developing brain, the results from the current randomized controlled study in neonatal monkeys undergoing simulated surgery show that ketamine does not provide neuroprotective or anti-inflammatory effects.

378 Regulation of renal function by the peroxisome proliferator-activated receptor-alpha: A novel target for treating hypertension

OBJECTIVES/GOALS: Approximately 37 million people in the U.S. have chronic kidney disease, which is a major risk factor for cardiovascular and end stage renal diseases. PPAR-αknockout (KO) mice exhibit increased renal inflammation and blood pressure. In this study, we investigated the role of PPAR-αin renal function in a mouse model of hypertension. METHODS/STUDY POPULATION: Male 4-month-old wild type (WT) and PPAR-αKO mice were instrumented with radio transmitters by artery canulation (Data Science Intl). This method minimizes stress and artifacts by avoiding the use of tethering, restraining, or anesthetizing the mice during data sampling. After recovery from surgery, we continuously measured mean arterial pressure (MAP) via radio telemetry in conscious ambulatory mice. After baseline MAP was established, vehicle (Veh; saline) or angiotensin II (Ang II) were infused using an osmotic minipump at a slow pressor dose (400 ng/kg/min) for 12 days. On day 12, we injected an intravenous bolus of fluorescin-sinistrin (3.74µl/g body weight) and collected 8 blood samples (20µl/sample) over 75 minutes to enable calculation of the glomerular filtration rate (GFR) using [GFR = I/(A/α+ B/ß)]. RESULTS/ANTICIPATED RESULTS: Similar to our prior observations, no significant (ns) differences in baseline MAP were observed between WT and PPAR-αKO mice [(mmHg): WT (n=6), 111 ± 20 vs. PPAR-αKO (n=6), 113 ± 10; ns] whereas after 12 days of the slow pressor effect of Ang II, MAP was increased in both strains [(mmHg): WT (n=8), 138 ± 11# vs. PPAR-αKO (n=8) , 156 ± 16#; #p DISCUSSION/SIGNIFICANCE: PPAR-αprotects mice from worsening hypertension and is critical to preserving GFR during normotensive conditions. Ongoing studies are further investigating how PPAR-αregulates renal function. These finding suggest therapeutics designed to increase PPAR-αactivity could have clinical benefit in chronic kidney disease.

Serotonin alters the response to a glucose challenge in lactating cows.

Energy partitioning in lactating cows affects milk production, feed efficiency, and body reserves, with the latter having health implications for the transition into the following lactation. One molecule likely involved in the regulation of energy partitioning is serotonin. The objective of this experiment was to explore how increasing circulating serotonin, by intravenous infusion of the serotonin precursor 5-hydroxytryptophan (5-HTP), affects metabolic responses to a glucose challenge in midlactation cows as a means to manipulate energy partitioning. We intravenously infused Holstein cows with 5-HTP (1 mg/kg bodyweight dissolved in saline, n = 11) or saline alone as control (n = 9) over 1 h/day for 3 days. Cows were fasted overnight on day 2. On day 3, fasted cows were given an intravenous bolus of glucose (0.092 g/kg bodyweight). Blood samples were collected for the following 120 min for metabolic and hormonal analysis. Infusion of 5-HTP elevated circulating concentrations of serotonin and free fatty acids, reduced the concentration of insulin and amino acids, and did not affect the concentration of glucose and glucagon before the glucose challenge. Surrogate insulin sensitivity indices indicated improved insulin sensitivity in 5-HTP cows, but due to the unique metabolism of lactating ruminants, these index changes may instead reflect effects in insulin-independent glucose disposal, like milk synthesis. Challenging 5-HTP-treated cows with a glucose bolus reduced the insulin spike and blunted the decrease in free fatty acids, compared to saline cows, without changing glucose dynamics. Overall, these results suggest that serotonin stimulates insulin-independent glucose disposal, requiring less insulin to maintain normoglycemia.

Preliminary study on fluid bolus administration for prevention of spinal hypotension in dogs undergoing elective cesarean section.

This study aimed to investigate the effect of fluid bolus administration during epidural anesthesia (coload) in female dogs scheduled for elective cesarean section (CS). Hypotension is one of the most common complications of epidural (EA) and spinal (SA) analgesia, and in the case of cesarean section, it may pose a significant risk for placental perfusion and subsequent fetal vitality and puppy survival. Pregnant bitches scheduled for elective CS underwent EA with (treatment group) or without (control group) intravenous fluid bolus administration. The following parameters were measured and compared between both groups: HR, RR, etCO2, SpO2, systolic, diastolic and mean arterial blood pressure were measured at three time points (T1: before surgery, T2: after the last puppy removal, and T3: end of surgery) in dams; vitality (Apgar score at 0, 5, and 20 min) and umbilical cord blood parameters (pH, pCO2, HCO3, base excess, lactate and glucose) in newborns. The results indicated that crystalloid coloading increased maternal systolic, diastolic, and mean blood pressure (treatment vs. control group, 101.46 ± 9.18, 48.01 ± 13.47, and 67.07 ± 13.15 mmHg vs. 80.68 ± 7.29, 36.52 ± 8.75, and 180 52.30 ± 7.77, p < 0.05) with significantly fewer episodes of hypotension. Additionally, puppies in the treatment group received higher scores in the 5-min (7.91 ± 1.67 vs. 6.74 ± 2.20) and 20-min (9.38 ± 0.87 vs. 8.39 ± 2.50) assessments without the favorable effect on umbilical blood gas parameters. Based on the obtained results, it can be stated that crystalloid coload offers an effective option in cases of hypotension during cesarean section, with clear benefits for both mothers and newborns.

Steady-State Piperacillin Concentrations in the Proximity of an Orthopedic Implant: A Microdialysis Porcine Study

Implant-associated osteomyelitis is one of the most feared complications following orthopedic surgery. Although the risk is low, sufficient antibiotic protection of the implant surface is important. The aim of this study was to assess steady-state piperacillin concentrations in the proximity of an orthopedic implant. Time above the minimal inhibitory concentration (fT>MIC) was evaluated for MIC of 8 (low target) and 16 μg/mL (high target). Six female pigs received an intravenous bolus infusion of 4 g/0.5 g piperacillin/tazobactam over 30 min every 6 h. Steady state was assumed achieved in the third dosing interval (12-18 h). Microdialysis catheters were placed in a cannulated screw in the proximal tibial cancellous bone, in cancellous bone next to the screw, and in cancellous bone on the contralateral tibia. Dialysates were collected from time 12 to 18 h and plasma samples were collected as reference. For the low piperacillin target (8 µg/mL), comparable mean fT>MIC across all the investigated compartments (mean range: 54-74%) was found. For the high target (16 µg/mL), fT>MIC was shorter inside the cannulated screw (mean: 16%) than in the cancellous bone next to the screw and plasma (mean range: 49-54%), and similar between the two cancellous bone compartments. To reach more aggressive piperacillin fT>MIC targets in relation to the implant, alternative dosing regimens such as continuous infusion may be considered.

Understanding fluorescence time curves during ileal pouch-anal anastomosis with or without vascular ligation

BackgroundIntraoperative indocyanine green fluorescence angiography (ICG-FA) may be of added value during pouch surgery, in particular after vascular ligations as lengthening maneuver. The aim was to determine quantitative perfusion parameters within the efferent/afferent loop and explore the impact of vascular ligation. Perfusion parameters were also compared in patients with and without anastomotic leakage (AL).MethodsAll consenting patients that underwent FA-guided ileal pouch-anal anastomosis (IPAA) between July 2020 and December 2021 were included. After intravenous bolus injection of 0.1 mg/kg ICG, the near-infrared camera (Stryker Aim 1688) registered the fluorescence intensity over time. Quantitative analysis of ICG-FA from standardized regions of interests on the pouch was performed using software. Fluorescence parameters were extracted for inflow (T0, Tmax, Fmax, slope, Time-to-peak) and outflow (T90% and T80%). Change of management related to FA findings and AL rates were recorded.ResultsTwenty-one patients were included, three patients (14%) required vascular ligation to obtain additional length, by ligating terminal ileal branches in two and the ileocolic artery (ICA) in one patient. In nine patients the ICA was already ligated during subtotal colectomy. ICG-FA triggered a change of management in 19% of patients (n = 4/21), all of them had impaired vascular supply (ligated ileocolic/ terminal ileal branches). Overall, patients with intact vascular supply had similar perfusion patterns for the afferent and efferent loop. Pouches with ICA ligation had longer Tmax in both afferent as efferent loop than pouches with intact ICA (afferent 51 and efferent 53 versus 41 and 43 s respectively). Mean slope of the efferent loop diminished in ICA ligated patients 1.5(IQR 0.8–4.4) versus 2.2 (1.3–3.6) in ICA intact patients.ConclusionQuantitative analysis of ICG-FA perfusion during IPAA is feasible and reflects the ligation of the supplying vessels.

The effect of nicorandil on cardiac function and clinical outcomes in ST-segment elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: a randomised trial

Background We investigated the effect of nicorandil on infarct size, cardiac function assessed by cardiac magnetic resonance imaging (CMR) and outcomes in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI). Methods In a prospective, randomised, controlled trial, 83 patients with STEMI receiving primary PCI were randomised into the nicorandil (n = 40) or placebo (n = 43) groups. Nicorandil was administered in the emergency room before primary PCI as an intravenous bolus of 4 mg followed by a continuous infusion of 6 mg/h for 24 h and as 2-mg intracoronary injections prior to balloon dilatation and coronary stenting. Nicorandil was continued orally at 10–20 mg/d for 6 months. Infarct size and cardiac function were measured by CMR at 5 d and 6 months after primary PCI. Furthermore, major adverse cardiac events (MACEs) including all-cause death, nonfatal myocardial infarction (MI), any revascularisation, stroke, and definite/probable stent thrombosis (ST) were compared. Results There were no significant differences in baseline clinical characteristics between the groups. Infarct size at baseline and 6 months as well as infarct size changes during 6 months as measured by CMR were similar between the groups. Similarly, other CMR parameters were comparable at baseline and 6 months between the groups. MACEs occurred in four patients (4.8%) during 6 months. No significant difference in the risk of MACEs was observed between the groups. Conclusions Treatment with nicorandil for 6 months after primary PCI was not associated with any improvement in infarct size, CMR-determined cardiac function, and outcomes in STEMI patients.

FDY-5301: An Innovative Approach to The Treatment of Revascularization Coronary Injury.

After experiencing an acute ST-segment elevation myocardial infarction (STEMI), percutaneous coronary intervention (PCI) is a preferred method of restoring blood flow to the heart. While this reperfusion has long-term benefits, it can result in reperfusion injury in the short term, which involves the formation of reactive oxygen species (ROS) and neutrophil recruitment. FDY-5301 is a sodium iodide-based drug that acts as a catalyst in the conversion of hydrogen peroxide to water and oxygen. FDY-5301 is designed to be administered as an intravenous bolus following a STEMI, before reperfusion with PCI, to reduce the damage associated with reperfusion injury. Clinical trials have shown FDY-5301 administration to be safe, feasible, and fast-acting in its ability to increase plasma iodide concentration, and the results are favorable in demonstrating potential efficacy. FDY-5301 shows potential in its use to reduce the effects of reperfusion injury, and ongoing Phase 3 trials will allow for continued evaluation of its performance.

Adjunctive Hydrocortisone Improves Hemodynamics in Critically Ill Patients with Septic Shock: An Observational Study Using Transpulmonary Thermodilution.

Introduction: Septic shock is associated with high mortality and hemodynamic impairment. The use of corticoids is a common therapeutic tool in critically ill patients. However, data on the mechanisms and prognostic ability of hemodynamic improvement by adjunctive steroids are rare. This study primarily aimed to evaluate short-term effects of hydrocortisone therapy on catecholamine requirement and hemodynamics derived from transpulmonary thermodilution (TPTD) in 30 critically ill patients with septic shock and a 28 days mortality rate of 50%. Methods: Hydrocortisone was administered with an intravenous bolus of 200 mg, followed by a continuous infusion of 200 mg per 24 h. Hemodynamic assessment was performed immediately before as well as 2, 8, 16, and 24 h after the initiation of corticoids. For primary endpoint analysis, we evaluated the impact of hydrocortisone on vasopressor dependency index (VDI) and cardiac power index (CPI). Results: Adjunctive hydrocortisone induced significant decreases of VDI from 0.41 (0.29-0.49) mmHg-1 at baseline to 0.35 (0.25-0.46) after 2 h (P < .001), 0.24 (0.12-0.35) after 8 h (P < .001), 0.18 (0.09-0.24) after 16 h (P < .001) and 0.11 (0.06-0.20) mmHg-1 after 24 h (P < .001). In parallel, we found an improvement in CPI from 0.63 (0.50-0.83) W/m2 at baseline to 0.68 (0.54-0.85) after 2 h (P = .208), 0.71 (0.60-0.90) after 8 h (P = .033), 0.82 (0.6-0.98) after 16 h (P = .004) and 0.90 (0.67-1.07) W/m2 after 24 h (P < .001). Our analyses revealed a significant reduction in noradrenaline requirement in parallel with a moderate increase in mean arterial pressure, systemic vascular resistance index, and cardiac index. As a secondary endpoint, our results showed a significant decrease in lung water parameters. Moreover, changes in CPI (ΔCPI) and VDI (ΔVDI) after 24 h of hydrocortisone therapy revealed accurate prognostic ability to predict 28 days mortality (AUC = 0.802 vs 0.769). Conclusion: Adjunctive hydrocortisone leads to a rapid decrease in catecholamine requirement and a substantial circulatory improvement in critically ill patients with septic shock.

EFFECT OF TWO DRUG COMBINATIONS PROPOFOL-KETAMINE AND PROPOFOL-FENTANYL ON HEMODYNAMIC PARAMETERS AND RECOVERY FROM ANAESTHESIA IN TIVA-A COMPARATIVE STUDY

Introduction- Total Intravenous anaesthesia(TIVA) is widely used procedure. We compared the effect of propofol-ketamine combination with propofol-fentanyl combination on hemodynamic parameters and recovery of patients undergoing TIVA. T Aims and Objective- o compare the effect of combination of propofol and ketamine and combination of propofol and fentanyl for TIVA, on hemodynamic parameters and recovery from anaesthesia. Patients aged 20- to 60-year-old, ASA-PS I and II, undergoing elect Material and Method- ive surgeries were selected for the study and were divided into two groups (1 and 2) of 90 each. TIVA was administered in the two groups as- Group-1 Induction- Propofol 1.0mg/kg+Ketamine 1.0mg/kg, iv boluses. Maintenance- Propofol 2.0 mg/kg/h and Ketamine 2.0 mg/kg/h, iv infusion. Group-2 InductionPropofol 1.0mg/kg+Fentanyl 2.0µg/kg, iv boluses. Maintenance- Propofol 2.0mg/kg/h and Ketamine 2.0µg/kg/h, iv infusion. All the patients were mechanically ventilated with 100% oxygen. Neuromuscular blockade achieved with Vecuronium-bromide. Vital-parameters were recorded at regular intervals and DJ Steward recovery score was calculated. Following i Result- nduction, heart rate (HR) increased in Group-1 and decreased in Group-2 and mean blood pressure (systolic and diastolic) increased in Group-1 while it decreased in Group-2. HR and blood pressure(BP) returned towards baseline during maintenance in both the groups. HR and BP increased in both the groups following extubation but gradually returned to baseline. Group-1 scored higher on ventilation, whereas Group-2 scored higher on wakefulness and movement. Though the difference became insignicant post 10 minutes. Both propofol-ketamine and propofol-fentanyl combinations Summary- can be utilized in TIVA for short elective procedures because they offer effective surgical anaesthesia with little strain on hemodynamic parameters, which helps to preserve stability and speed up recovery

Is Sedation of Choice in Thyroplasty Surgery? A Study on the Effects of Sedatives on Voice Quality

In order to establish the ideal anesthetic protocol in thyroplasty type I surgery, where the intraoperative voice test is used to guide the medialization of the paralyzed fold, we have studied the effects of a sedation with midazolam premedication and adjusted intravenous doses of propofol and remifentanil on voice quality in patients without vocal fold pathology undergoing otorhinolaryngology surgery other than thyroplasty. Prospective cross-sectional study included 40 adult patients. A voice recording was performed when the patient was fully awake and when an appropriate level of conscious sedation was reached. Following premedication with midazolam at anxiolytic doses, remifentanil and propofol were administrated by target controlled infusion pumps (TCI). These results were compared with those obtained in a previous study carried out by the same team using intravenous bolus (IV) according to weight. The recorded voice analysis was performed using the computer program Praat (v.5.3.39) for a sustained vowel. All the parameters obtained from the acoustic analysis of the voice were altered after sedation with target controlled infusion in a statistically significant way. Comparing with bolus intravenous, harmonic and noise ratio (HNR) was the only parameter that decreased less in the TCI group. The state of sedation obtained using midazolam premedication, propofol and remifentanil adjusted intravenous doses alters significantly all the voice parameters, although this alteration is considerably less than the changes produced by the medication administered in bolus IV. According to these results, the sedation and the voice test during thyroplasty surgery would present a series of limitations when it comes to guiding the medialization of the paralyzed vocal fold and therefore it could not be considered as the ideal anesthetic protocol in thyroplasty surgery.

The effect of two dose phenylephrin for preventing hypotension during spinal anesthesia for cesarean delivery

Background: Spinal anesthesia-induced hypotension is one of the most complications which can cause many severe maternal and fetal complications. Therefore, the prevention and treatment of spinal anesthesia-induced hypotension in pregnant women undergoing cesarean delivery play an important role. The use of vasopressors is the most effective method of hypotensive prophylaxis and phenylephrine is currently the first-line vasopressor of choice to prevent this complication. The aim of this study is to evaluate the effectiveness and safety of two-dose phenylephrine for prevention of spinal anesthesia-induced hypotension during cesarean delivery. Materials and methods: In a randommized controlled clinical trial, 150 pregnants undregoing cesarean delivery with spinal anesthesia were randomly divided into three groups: Group I: as a control group without phenylephrine prophylaxis (n = 50), Group II: 50µg intravenously bolus phenylephrine (n = 50), and Group III: 75µg intravenously bolus phenylephrine (n = 50) immediately after induction of spinal anesthesia. Hypotension, defined decreasing systolic blood pressure &gt; 20% of baseline. The incidence of hypotension, levels of hypotension, maternal side effects and neonatal APGAR scores at 1 and 5 minutes. Results: The incidence of hypotension was 44%, the incidence of re-hypotension was 16%. Group III: the incidence of hypotension was 28%, the incidence of re-hypotension was 2%. The neonatal APGAR scores of the two groups at both 1 minute and 5 minutes was the same (p &gt; 0.05), all cases had APGAR &gt; 7. Conclusion: Phenylephrine intravenous bolus at doses of 50 µg and 75 µg are both effective for the prevention spinal anesthesia-induced hypotension for cesarean section. However, the 75 µg phenylephrine dose was more effective than the 50 µg dose because of lower rates of hypotension and recurrent hypotension (28% and 2% vs 44% and 16%, p &lt; 0.05). In addition, both groups of prophylactic phenylephrine didn’t cause detrimental adverses for parturients and their babies. Key words: Hypotensive prophylaxis, cesarean section, phenylephrin.

Assessment of glomerular filtration and tubular secretion in baboons with life-supporting pig kidney grafts.

With pig kidney xenotransplantation nearing clinical reality, it is imperative to measure pig kidney function in the graft recipients. Our aims were (i) to compare inulin clearance after a short intravenous (IV) bolus with steady-state inulin IV infusion, (ii) to use this method to measure the glomerular filtration rate (GFR), and (iii) to determine the tubular secretory function using cefoxitin in a pig-to-baboon renal transplant model. A short IV infusion of inulin and cefoxitin were followed by a maintenance IV infusion of inulin over 5 h in seven healthy baboons, three healthy pigs, and five baboons after bilateral native nephrectomy and intra-abdominal pig renal transplantation. Blood and urine samples were collected. Serum and urinary inulin and serum cefoxitin concentrations measured by validated assays were used to calculate GFR and renal secretion. GFR calculatedwere similar by both methods. The body weight normalized total body clearance of inulin was similar in pigs and baboons despite differences in absolute clearances. Pig kidney transplanted into baboons provided similar clearance in baboons when normalized to baboon body weight and sustained filtration and secretory functions. The study documented that pig kidneys support the physiologic needs of baboons and are likely to support human recipients as well.

N,N-dimethyltryptamine affects electroencephalography response in a concentration-dependent manner-A pharmacokinetic/pharmacodynamic analysis.

N,N-dimethyltryptamine (DMT) is a psychedelic substance and is being used as a research tool in investigations of the neurobiology behind the human consciousness using different brain imaging techniques. The effects of psychedelics have commonly been studied using electroencephalography (EEG) and have been shown to produce suppression of alpha power and increase in signal diversity. However, the relationship between DMT exposure and its EEG effects has never been quantified. In this work, a population pharmacokinetic/pharmacodynamic analysis was performed investigating the relationship between DMT plasma concentrations and its EEG effects. Data were obtained from a clinical study where DMT was administered by intravenous bolus dose to 13 healthy subjects. The effects on alpha power, beta power, and Lempel-Ziv complexity were evaluated. DMT was shown to fully suppress alpha power. Beta power was only partially suppressed, whereas an increase in Lempel-Ziv complexity was observed. The relationship between plasma concentrations and effects were described using effect compartment models with sigmoidal maximum inhibitory response or maximum stimulatory response models. Values of the concentration needed to reach half of the maximum response (EC50,e ) were estimated at 71, 137, and 54 nM for alpha, beta, and Lempel-Ziv complexity, respectively. A large amount of between-subject variability was associated with both beta power and Lempel-Ziv complexity with coefficients of variability of 75% and 77% for the corresponding EC50,e values, respectively. Alpha power appeared to be the most robust response, with a between-subject variability in EC50,e of 29%. Having a deeper understanding of these processes might prove beneficial in choosing appropriate doses and response biomarkers in the future clinical development of DMT.

Effect on physiological parameters and anaesthetic dose requirement of isoflurane when tramadol given as a continuous rate infusion vs a single intravenous bolus injection during ovariohysterectomy in dogs.

Tramadol produces a significant reduction in both sevoflurane and isoflurane minimum alveolar concentrations in dogs under experimental conditions. This study aims to compare the effects of tramadol administered as a constant rate infusion (CRI) with those of tramadol administered as a single intravenous bolus on physiological parameters and isoflurane requirements in dogs undergoing ovariohysterectomy. In this study, forty female dogs undergoing ovariohysterectomy were enrolled. The bitches were anesthetized with 5 mg/kg of tiletamine/zolazepam combined with 0.05 mg/kg of acepromazine intravenously. Anesthesia was maintained with isoflurane delivered in 100% oxygen. The group A (n = 20) received tramadol 4 mg/kg in a single intravenous bolus, whereas the group B (n = 20) received tramadol 1.5 mg/kg in an intravenous bolus followed by tramadol 2.6 mg/kg/h as a CRI. The following parameters were recorded: heart rate, respiratory rate, non-invasive blood pressure, body temperature, EtCO2, SpO2 and inspired and expired concentrations of isoflurane. Parameter measurements were performed from pre-preedication (baseline) to skin suturing. The dogs were healthy subjects that demonstrated no abnormalities on laboratory investigations. Significant tachycardia was recorded after administration of tiletamine/zolazepam combined with acepromazine in both groups. Heart rate decreased after intubation but remained significantly higher compared to baseline values in both groups. Systolic blood pressure significantly decreased in both groups but the recorded values were within the physiological range. Mild reduction in body temperature was recorded in both groups. SpO2 and EtCO2 remained within the physiological range. Isoflurane requirement was significantly lower in the group B compared to the group A. Transient twitching was recorded in two dogs belonging to the group A after tramadol administration. Compared to tramadol given as a single intravenous bolus injection during ovariohysterectomy in dogs, tramadol administered as a CRI reduces isoflurane requirements in dogs anesthetized with tiletamine/zolazepam combined with acepromazine. Both tramadol given as a CRI and a single intravenous bolus injection, induce decrease in heart rate, respiratory rate and in body temperature but the values of these parameters remain within physiological range in dogs undergoing ovariohysterectomy.