Dose Route Research Articles

Medication reconciliation for patients after their discharge from intensive care unit to the hospital ward

ObjectivesThe aim of this study was to determine whether the transition of care from the intensive care unit to the ward would pose a high risk for reconciliation errors. The primary outcome of this study was to describe and quantify the discrepancies and reconciliation errors. Secondary outcomes included classification of the reconciliation errors by type of medication error, therapeutic group of the drugs involved and grade of potential severity. MethodsWe conducted a retrospective observational study of reconciliated adult patients discharged from the Intensive Care Unit to the ward. Before a patient was discharged from the intensive care unit, their last intensive care unit's prescriptions were compared with their proposed medication list in the ward. The discrepancies between these were classified as justified discrepancies or reconciliation errors. Reconciliation errors were classified by type of error, potential severity, and therapeutic group. ResultsWe found that 452 patients were reconciliated. At least one discrepancy was detected in 34.29% (155/452), and 18.14% (82/452) had at least one reconciliation errors. The most found error types were a different dose or administration route (31.79% (48/151)) and omission errors (31.79% (48/151)). High alert medication was involved in 19.20% of reconciliation errors (29/151). ConclusionsOur study shows that intensive care unit to non-intensive care unit transitions are high-risk processes for reconciliation error. They frequently occur and occasionally involve high alert medication, and their severity could require additional monitoring or cause temporary harm. Medication reconciliation can reduce reconciliation errors.

Physiologically-based pharmacokinetic modeling to inform dosing regimens and routes of administration of rifampicin and colistin combination against Acinetobacter baumannii

BackgroundCarbapenem-resistant Acinetobacter baumannii (CRAB) is resistant to major antibiotics such as penicillin, cephalosporin, fluoroquinolone and aminoglycoside, and has become a significant nosocomial pathogen. The efficacy of rifampicin and colistin combination against CRAB could be dependent on the administration routes and drug concentrations at the site of infection. ObjectiveThe objective is to predict drug disposition in biological tissues. Treatment efficacy is extrapolated by assessing respective pharmacodynamic (PD) indices, as well as parameters associated with the emergence of resistance. MethodsPhysiologically-based pharmacokinetic models of rifampicin and colistin were utilized to predict tissue exposures. Dosing regimens and administration routes for combination therapy were evaluated in terms of in vitro antimicrobial susceptibility of A. baumannii associated with targeted PD indices and resistance parameters. ResultsSimulated exposures in blood, heart, lung, skin and brain were consistent with reported penetration rates. The results demonstrated that a combination of colistin and rifampicin using conventional intravenous (i.v.) doses could achieve effective exposures in the blood and skin. However, for lung infections, colistin by inhalation would be required due to low lung penetration from intravenous route. Inhaled colistin alone provided good PD coverage but this practice could encourage the emergence of additional resistance which may be overcome by a combination regimen that includes inhaled rifampicin. ConclusionThis in silico extrapolation provides valuable information on dosing regimens and routes of administration against CRAB infections in specific tissues. The PBPK modeling approach could be a non-invasive way to inform therapeutic benefits of combination antimicrobial therapy.

Oncolytic adenoviruses and the treatment of pancreatic cancer: a review of clinical trials.

Pancreatic ductal adenocarcinoma (PDAC) remains a common and difficult cancer to treat. Surgical resection and chemotherapy are standard of care and clinical outcomes remain poor. Oncolytic adenoviruses are a unique approach to the treatment of this challenging cancer, aiming to overcome the features of this disease that pose the key obstacles to standard therapies. This paper provides a detailed review of the clinical trials of conditionally-replicative adenoviruses in pancreatic cancer to date, with a brief summary of the past preclinical literature and future prospects of this therapy. MEDLINE, Embase, and clinicaltrials.gov were searched from inception to December 23rd 2022 for clinical trials of conditionally-replicative adenoviruses used in patients with pancreatic ductal adenocarcinoma. Primary features for review included patient demographics, treatment protocol including dose and administration route, adverse events, patient responses and survival rates. The six published clinical trials suggest that objective clinical responses can be achieved with a tolerable level of side effects, even at high viral doses. The more clinically adaptable intravenous route of administration also appears to be as well tolerated as the more challenging intratumoural injections. Published clinical trials provide data of the safety and some signs of oncolytic activity of conditionally-replicative adenoviruses in patients with pancreatic cancer. Importantly, on the latest trials, the easier intravenous route of administration seems to be well tolerated and safe, providing the opportunity for further clinical evaluation. It is hoped that the ongoing clinical trials will yield more promising results of this therapeutic approach against a currently intractable disease.

PBPK modeling to evaluate maximum tolerated doses: A case study with 3-chloroallyl alcohol.

Introduction: A physiologically based pharmacokinetic (PBPK) model for 3-chloroallyl alcohol (3-CAA) was developed and used to evaluate the design of assays for the in vivo genotoxicity of 3-CAA. Methods: Model development was supported by read across from a published PBPK model for ethanol. Read across was motivated by the expectation that 3-CAA, which like ethanol is a primary alcohol, is metabolized largely by hepatic alcohol dehydrogenases. The PBPK model was used to evaluate how two metrics of tissue dosimetry, maximum blood concentration (Cmax; mg/L) and area under the curve (AUC; mg-hr/L) vary with dose of 3-CAA and with dose route (oral gavage, drinking water). Results: The model predicted that oral gavage results in a 6-fold higher Cmax than the same dose administered in drinking water, but in similar AUCs. Predicted Cmax provided the best correlation with severe toxicity (e.g., lethality) from 3-CAA, consistent with the production of a reactive metabolite. Therefore, drinking water administration can achieve higher sustained concentration without severe toxicity in vivo. Discussion: This evaluation is significant because cytotoxicity is a potential confounder of mutagenicity testing. The PBPK model can be used to ensure that studies meet OECD and USEPA test guidelines and that the highest dose used is not associated with severe toxicity. In addition, PBPK modeling provides assurance of target tissue (e.g., bone marrow) exposure even in the absence of laboratory data, by defining the relationship between applied dose and target tissue dose based on accepted principles of pharmacokinetics, relevant physiology and biochemistry of the dosed animals, and chemical-specific information.

Measurement of Δ9THC and metabolites in the brain and peripheral tissues after intranasal instillation of a nanoformulation

BackgroundComparative bioavailability of cannabinoids following their administration by dosing routes has been studied previously, but there are no quantitative reports of distribution of Δ9THC, nor its metabolites, across various brain regions following intranasal (i.n.) administration. The aim of the present study was to determine the time course of Δ9THC transport from nose to brain and to quantify the distribution of Δ9THC and its metabolites in four brain regions.MethodsΔ9THC was formulated as a lipophilic nano-emulsion and instilled i.n. to three groups of adult mice and euthanized after 2, 4, and 8 h. Brains were dissected into 4 regions. Sensitive analytical methods (HPLC-MS) were utilized to quantify levels of Δ9THC and metabolites in brain regions and peripheral tissues. Data was expressed as mean concentrations (± SEM) of Δ9THC and metabolites in brain regions, blood, plasma, urine, and liver. Two-way analysis of variance was performed followed by post hoc multiple comparisons.ResultsPeak concentrations of Δ9THC were reached at 2 h in the brain (15.9 ng/mg), blood (4.54 μg/mL), and plasma (4.56 μg /mL). The percentage of administered dose of Δ9THC transported to the brain (5.9%) was greater than in blood (1.7%), plasma (1.6%), urine (0.4%), and liver (0.1%). Concentrations of Δ9THC and its THC-COOH metabolite in the liver reached their highest levels at 8 h.DiscussionThe present study is the first to report the uptake and distribution across brain regions of Δ9THC and its principal metabolites following i.n. administration. The systemic bioavailability (absorption into the blood) of intranasal Δ9THC was 1.7% of the administered dose, much lower than that reported by others after oral ingestion (7–10%) and inhalation (20–35%), but those prior studies did not measure the transport of Δ9THC into brain regions. Others have reported Δ9THC in the whole brain following i.n. instillation in a different species (rats) to be twice (5.9%) that following i.p. injections, while metabolites of Δ9THC in rat brain were lower after i.n. administration.ConclusionsThe intranasal route of a Δ9THC nanoformulation is an effective way to deliver cannabinoids to the brain, especially in those who cannot take the medication orally. Going forward, a metered dosing nasal spray will provide accurate and consistent doses.

Low doses of 3-phenyl-lawsone or meglumine antimoniate delivery by tattooing route are successful in reducing parasite load in cutaneous lesions of Leishmania (Viannia) braziliensis-infected hamsters.

Current therapeutic ways adopted for the treatment of leishmaniasis are toxic and expensive including parasite resistance is a growing problem. Given this scenario, it is urgent to explore treatment alternatives for leishmaniasis. The aim of this study was to evaluate the effect of 3-phenyl-lawsone (3-PL) naphthoquinone on Leishmania (Viannia) braziliensis infection, both in vitro and in vivo, using two local routes of administration: subcutaneous (higher dose) and tattoo (lower dose). In vitro 3-PL showed low toxicity for macrophages (CC50 >3200 µM/48h) and activity against intracellular amastigotes (IC50 = 193 ± 19 µM/48h) and promastigotes (IC50 = 116 ± 26 µM/72h), in which induced increased ROS generation. Additionally, 3-PL up-regulated the production of cytokines such as tumor necrosis factor alpha (TNF-α), monocyte chemotactic protein 1 (MCP-1), interleukin-6 (IL-6) and IL-10 in infected macrophages. However, the anti-amastigote action was independent of nitric oxide production. Treatment of hamsters infected with L. (V.) braziliensis from one week after infection with 3-PL by subcutaneous (25 µg/Kg) or tattooing (2.5 µg/Kg) route, during 3 weeks (3 times/week) or 2 weeks (2 times/week) significantly decreased the parasite load (p<0.001) in the lesion. The reduction of parasite load by 3-PL treatment was comparable to reference drug meglumine antimoniate administered by the same routes (subcutaneous 1mg/Kg and tattoo 0.1mg/Kg). In addition, treatment started from five weeks after infection with 3-PL per tattoo also decreased the parasite load. These results show the anti-leishmanial effect of 3-PL against L. (V.) braziliensis and its efficacy by subcutaneous (higher dose) and tattoo (lower dose) routes. In addition, this study shows that drug delivery by tattooing the lesion allows the use of lower doses than the conventional subcutaneous route, which may support the development of a new therapeutic strategy that can be adopted for leishmaniasis.

Intra-Operative Adjunctive Magnesium Sulfate in Pain Management of Total Knee Arthroplasty; a Systematic Review and Meta-analysis.

There has been growing interest in the potential role of adjunctive magnesium sulfate in improving pain management. This systematic review and meta-analysis aimed to assess the effect of intra-operative adjunctive magnesium sulfate on pain management and opioid consumption in total knee arthroplasty (TKA). A comprehensive search was conducted in Medline, Embase, Scopus, Web of Science, and Cochrane Library databases, covering studies up to April 2023. The extracted data included pain management outcomes, opioid consumption, and adverse effects from the selected studies. Standardized mean differences (SMDs) were calculated for continuous outcomes, while risk ratios (RRs) were calculated for dichotomous outcomes. Meta-analysis was conducted employing random-effects models in STATA 17. In this meta-analysis of 8 randomized controlled trials involving 536 patients, adjunctive magnesium sulfate in TKA was found to significantly reduce opioid consumption during the first 24 hours after operation (SMD: -1.88, 95% confidence interval (CI): [-3.66 to -0.10]; p = 0.038). It also resulted in lower pain scores at rest 24 hours after surgery (SMD: -1.53, 95% CI: [-2.70 to -0.37]; p = 0.010). There were no significant differences in time to first rescue analgesic and adverse effects between the groups. The included studies were assessed to have low to high levels of risk of bias. This study presents evidence at low to moderate levels supporting the use of intra-operative adjunctive magnesium sulfate in TKA for improved pain management and reduced opioid consumption. However, further research is needed to address the heterogeneity and to explore optimal dosing regimens and routes of administration to maximize the benefits of magnesium sulfate in TKA.

Adeno-associated virus (AAV)-based gene therapy products: What are toxicity studies in non-human primates showing us?

A number of adeno-associated virus (AAV)-based gene therapy products have entered clinical development, with a few also reaching marketing approval. However, as our knowledge of them grows from nonclinical and clinical testing, it has become apparent that various actual and theoretical safety issues can arise from their use. This review of 19 Good Laboratory Practice (GLP)-compliant toxicity studies in non-human primates (NHPs) with AAV-based gene therapy products via a variety of different dose routes in the period 2017–2021 showed results ranging from no study findings different from controls, or findings considered to be non-adverse, to actual toxicity, with changes highlighting careful monitoring in the clinic. Similar findings were found from a review of a number of published toxicity studies in NHPs. It was confirmed that studies have a role in evaluating for dorsal root ganglion (DRG) and/or peripheral nerve toxicity, hepatotoxicity, adverse immunogenicity and, to a lesser degree, insertional mutagenesis as well as other potential unacceptable findings such as adverse inflammation for ocular therapy candidates. Overall, it was demonstrated that toxicity (and biodistribution) studies in NHPs are a vital part of the safety assessment of AAV-based gene therapy products prior to clinical entry.

Taking medicine in the right way: Most important but most neglected

Proper use of medicine or taking medicine in correct order is essential to cure any disease. According to the WHO, lack of adherence to treatment regimens leads to major problems among patients, mostly with chronic illnesses. "Right administration" depends on at least 5 right factors--right patient, right drug, right time, right dose and right route. "Medicines won't work if you don't take it right"--This simple fact is not understood by most people in the world, as a result still more than half of the patients with chronic diseases in the developed world do not take their medicine correctly-says WHO.

594. An Open-Label Study in Healthy Volunteers to Determine the Absolute Bioavailability of, the Effect of Food and Dosing by Nasogastric Tube upon the Pharmacokinetics of a Single Oral Dose of Olorofim (OLO)

Abstract Background OLO is a novel antifungal active vs. Aspergillus (including azole-resistant strains), resistant moulds (e.g., Lomentospora prolificans), and dimorphic moulds. Information on absolute bioavailability and effect of food upon the pharmacokinetics (PK) of OLO when administered as a 30 mg tablet, including feasibility of alternative enteral delivery, is required for appropriate guidance on dosing. Methods Healthy male and female subjects in Cohorts A and B (6/cohort; high carbohydrate /low fat meals at 8 and 24 h for Cohort A and low carbohydrate/high fat meals for Cohort B ) participated in 3 treatment periods; single doses of 150 mg OLO as a 2-h IV infusion, a fasted PO dose (after overnight fast), and a fed single PO dose (30 min after starting a high fat breakfast). Healthy subjects in Cohort C participated in 2 treatment periods and received fasted single doses of 150 mg OLO either PO as intact tablets or via NG tube (tablets dispersed in water). PK sampling was performed for 120 h after each dose, with at least 10 days between dosing occasions per subject. Results The absolute bioavailability of a fasted single PO dose of OLO was found to be 67%. Administering OLO in the presence of food resulted in slight reduction in overall exposure, with an approximate 30% reduction in Cmax (Table 1). Multiple post-dose OLO peaks were observed for most subjects regardless of dose route or fed state; peaks typically coincided with meal times (Figure). OLO systemic exposure was similar for intact tablets given PO and tablets dispersed in water given via NG tube (Table). Statistical Analysis of Olorofim PK parameters for Cohorts A, B and C Conclusion OLO (30 mg tablet) has good oral bioavailability and based upon the minimal impact of a high-fat breakfast upon overall exposure, can be administered with or without food. No dose adjustment is needed if switching from oral dosing with intact tablets to dosing tablet in water via NG tube. Disclosures Karen Cornelissen, PhD, F2G: Employee Paul A. Newell, MB BS, AstraZeneca: Stocks/Bonds|F2G: Stocks/Bonds John H. Rex, MD, Advent Life Sciences: Operating Partner|Advent Life Sciences: Ownership Interest|AMR Action Fund: Advisor/Consultant|AstraZeneca: Stocks/Bonds|Basilea Pharmaceutica: Advisor/Consultant|Bugworks Research, Inc.: Advisor/Consultant|F2G, Limited: Employee|F2G, Limited: Stocks/Bonds|Forge Therapeutics: Advisor/Consultant|GlaxoSmithKline: Advisor/Consultant|Pfizer Pharmaceuticals: Honoraria|Sumitovant: Advisor/Consultant Samuel Israel, MBBS, Labcorp: Eemployee James Bush, MB ChB, PhD, Labcorp: Employee (Salaried)|Labcorp: Stocks/Bonds.

Cervical change times during induction in nulliparas using vaginal or buccal misoprostol

Aim To determine if the time to cervical change and time to active labor were different when misoprostol was administered by a vaginal or buccal route for cervical ripening in nulliparas undergoing labor induction at term. Methods This was a secondary analysis of nulliparous participants in the IMPROVE Study—A comparison of vaginal versus buccal misoprostol for cervical ripening for labor induction at term: a triple-masked randomized controlled trial (NCT 02408315). The parent study was a non-inferiority randomized controlled trial in which patients beginning induction with a modified Bishop score ≤6 received either vaginal or buccal misoprostol and simultaneous placebo via the opposite route. The primary outcome of the parent study was time to delivery. Primary outcomes for this secondary analysis were the time to active labor (at least 6 cm dilated) and time to change in cervical dilation. Kaplan–Meier analysis was used to compare routes for time to active labor and multistate Markov modeling was used to compare sojourn times at each cervical dilation. Results Of the 300 participants enrolled in the parent trial, 124 (41.3%) were nulliparous; 59 (47.6%) nulliparous participants underwent induction with vaginal misoprostol and 65 (52.4%) received buccal dosing. Nulliparas receiving vaginal dosing required fewer doses of misoprostol to reach active labor (median 2 vs 3, p = .003). However, this did not result in shorter time to active labor (median vaginal 23.1 h, 95% CI = [21.6, 27.2 h]; buccal 25.6 h [21.5, 29.3 h], p = .45) or higher rate of vaginal delivery within 24 h; (33.9% vs 35.4%, p = .86). There was also no significant difference in time to active labor after adjusting for covariates (adjusted HR for dose route (buccal vs vaginal) = 0.91 [0.61, 1.36], p = .649). Among people that delivered vaginally, the mean sojourn times, measuring cervical dilation state change, were not significantly different, with mean duration to active labor of 20.5 [17.6, 24.5] h for buccal and 21.8 [17.7, 28.2] h for vaginal dosing (p = .092). Satisfaction and preference for dosing routes were not different between groups. Conclusion Buccal and vaginal dosing of misoprostol for cervical ripening in nulliparas appear to have similar times to active labor and progression of cervical change during ripening.

Optimization of the Solvent and In Vivo Administration Route of Auranofin in a Syngeneic Non-Small Cell Lung Cancer and Glioblastoma Mouse Model.

The antineoplastic activity of the thioredoxin reductase 1 (TrxR) inhibitor, auranofin (AF), has already been investigated in various cancer mouse models as a single drug, or in combination with other molecules. However, there are inconsistencies in the literature on the solvent, dose and administration route of AF treatment in vivo. Therefore, we investigated the solvent and administration route of AF in a syngeneic SB28 glioblastoma (GBM) C57BL/6J and a 344SQ non-small cell lung cancer 129S2/SvPasCrl (129) mouse model. Compared to daily intraperitoneal injections and subcutaneous delivery of AF via osmotic minipumps, oral gavage for 14 days was the most suitable administration route for high doses of AF (10-15 mg/kg) in both mouse models, showing no measurable weight loss or signs of toxicity. A solvent comprising 50% DMSO, 40% PEG300 and 10% ethanol improved the solubility of AF for oral administration in mice. In addition, we confirmed that AF was a potent TrxR inhibitor in SB28 GBM tumors at high doses. Taken together, our results and results in the literature indicate the therapeutic value of AF in several in vivo cancer models, and provide relevant information about AF's optimal administration route and solvent in two syngeneic cancer mouse models.

Electroporation in Head-and-Neck Cancer: An Innovative Approach with Immunotherapy and Nanotechnology Combination.

Squamous cell carcinoma is the most common malignancy that arises in the head-and-neck district. Traditional treatment could be insufficient in case of recurrent and/or metastatic cancers; for this reason, more selective and enhanced treatments are in evaluation in preclinical and clinical trials to increase in situ concentration of chemotherapy drugs promoting a selectively antineoplastic activity. Among all cancer treatment types (i.e., surgery, chemotherapy, radiotherapy), electroporation (EP) has emerged as a safe, less invasive, and effective approach for cancer treatment. Reversible EP, using an intensive electric stimulus (i.e., 1000 V/cm) applied for a short time (i.e., 100 μs), determines a localized electric field that temporarily permealizes the tumor cell membranes while maintaining high cell viability, promoting cytoplasm cell uptake of antineoplastic agents such as bleomycin and cisplatin (electrochemotherapy), calcium (Ca2+ electroporation), siRNA and plasmid DNA (gene electroporation). The higher intracellular concentration of antineoplastic agents enhances the antineoplastic activity and promotes controlled tumor cell death (apoptosis). As secondary effects, localized EP (i) reduces the capillary blood flow in tumor tissue ("vascular lock"), lowering drug washout, and (ii) stimulates the immune system acting against cancer cells. After years of preclinical development, electrochemotherapy (ECT), in combination with bleomycin or cisplatin, is currently one of the most effective treatments used for cutaneous metastases and primary skin and mucosal cancers that are not amenable to surgery. To reach this clinical evidence, in vitro and in vivo models were preclinically developed for evaluating the efficacy and safety of ECT on different tumor cell lines and animal models to optimize dose and administration routes of drugs, duration, and intensity of the electric field. Improvements in reversible EP efficacy are under evaluation for HNSCC treatment, where the focus is on the development of a combination treatment between EP-enhanced nanotechnology and immunotherapy strategies.

Translational Models to Predict Target Concentrations for Pre-Exposure Prophylaxis in Women.

The HIV epidemic remains a significant public health burden. Women represent half of the global HIV epidemic, yet there is an urgent need for a variety of prevention options to meet the needs of more women. Pre-exposure prophylaxis (PrEP) is a valuable prevention tool that uses antiretrovirals before a potential HIV exposure to prevent virus transmission. Development of effective preventive drug regimens for women is dependent on convenient dosing schedules and routes of administration, and on identifying defined target concentrations in mucosal tissues that provide complete protection against HIV transmission. There is a critical need for a translational model that can accurately predict in vivo target concentrations that are completely protective against HIV infection. There is no gold-standard preclinical model to predict PrEP efficacy. In this study, we review the strengths and limitations of three different preclinical models and their utility in predicting target concentrations in the female genital tract: humanized mice, non-human primates, and the ex vivo tissue model.

WITHDRAWN: Technology targeting immunocompromised patients for COVID-19 vaccine in community pharmacies

BackgroundMedication targeting by community pharmacists may assess medical history of patients for recommendation of clinical services through review of their prescription history. Previous studies have implemented medication targeting to identify patients eligible for vaccine recommendations. Targeting of immunosuppressing medications may impact the rate of third primary doses of COVID-19 vaccine administered to immunocompromised patients.ObjectivesThe primary objective was to determine the impact of medication targeting on the rate of third primary doses of COVID-19 vaccine given to immunocompromised patients.MethodsThis observational, retrospective cohort study occurred within one division of a large community pharmacy chain. Included patients were greater than 18 years of age with record of at least one immunosuppressing medication dispensed one year prior to study enrollment and 2 primary COVID-19 vaccine doses in the pharmacy dispensing system. An intervention for pharmacist recommendation of a third primary dose of COVID-19 vaccine was automatically loaded into their prescription profiles. The proportion of patients with completed interventions and confirmation of third dose administration was collected with demographic characteristics.ResultsThe pharmacy dispensing system identified 1670 interventions through medication targeting, though 69 interventions met criteria for study inclusion. Baseline characteristics of the included population were a mean age of 51.8 years of primarily female sex (69.6%) and Caucasian race (78.3%). Third primary COVID-19 vaccine dose administration and completed pharmacist recommendation was recorded for 2 (2.9%) patients.ConclusionMedication targeting identified immunocompromised patients for the recommendation of a third primary dose of COVID-19 vaccine. Improved specification for targeting of dosing regimen and route of administration may result in greater accuracy of appropriate recommendations identified.

Chemotherapy Dose Shapes the Expression of Immune-Interacting Markers on Cancer Cells.

Tumor and immune cells interact through a variety of cell-surface proteins that can either restrain or promote tumor progression. The impacts of cytotoxic chemotherapy dose and delivery route on this interaction profile remain incompletely understood, and could support the development of more effective combination therapies for cancer treatment. Here, we found that exposure to the anthracycline doxorubicin altered the expression of numerous immune-interacting markers (MHC-I, PD-L1, PD-L2, CD47, Fas, and calreticulin) on live melanoma, breast cancer, and leukemia cells in a dose-dependent manner in vitro. Notably, an intermediate dose best induced immunogenic cell death and the expression of immune-activating markers without maximizing expression of markers associated with immune suppression. Bone marrow-derived dendritic cells exposed to ovalbumin-expressing melanoma treated with intermediate doxorubicin dose became activated and best presented tumor antigen. In a murine melanoma model, both the doxorubicin dose and delivery location (systemic infusion versus local administration) affected the expression of these markers on live tumor cells. Particularly, local release of doxorubicin from a hydrogel increased calreticulin expression on tumor cells without inducing immune-suppressive markers, in a manner dependent on the loaded dose. Doxorubicin exposure also altered the expression of immune-interacting markers in patient-derived melanoma cells. Together, these results illustrate how standard-of-care chemotherapy, when administered in various manners, can lead to distinct expression of immunogenic markers on cancer cells. These findings may inform development of chemo-immunotherapy combinations for cancer treatment. The online version contains supplementary material available at 10.1007/s12195-022-00742-y.

55 The Humoral Response of Newborn Calves Vaccinated Against Bovine Respiratory Complex and Supplemented with Autolyzed Yeast

Abstract The Bovine Respiratory Complex (BRC) significantly impacts morbidity and mortality in dairy calves between 1 and 3 months of age, called the immunological gap. The calves receive colostrum and milk immunoglobulins; however, these animals are still developing their specific immune system and cannot present a robust active humoral response. Vaccines against intranasal BRC are recommended for calves from the first week of age; although they do not prevent the disease, they can mitigate the condition. The yeast-based products have been studied as immunomodulators due to the ß-glucans interaction with the innate immune system. Thus, the objective of this study was to evaluate the effects of autolyzed Saccharomyces cerevisiae yeast supplementation in the humoral response of newborn calves vaccinated against BRC. For this, 20 calves with no respiratory changes and who received colostrum at adequate immunoglobulin levels were vaccinated against BRC (Inforce 3, Zoets, Brazil) intranasal route in a single dose at 30 days of age. The animals were divided into the Control group (n = 10), and autolyzed yeast supplemented group [AY] (RumenYeast at 10 g/animal/day, ICC Brazil Company). The calves received the supplementation once a day in the milk from the 15th at 51st days of age. Blood samples were collected at 15, 33, 36, and 51 days to measure the serum IgG and IgA of the calves Serum IgA increased at 51 days in the AY group compared to the other moments (P=0.03) and both immunoglobulins of the AY group were greater than the control group at 51 days (P=0.08 and 0.007, respectively), as shown in Figure 1. In conclusion, the AY supplementation could potentially improve the vaccine response against BRC in calf-dependent on colostral immunity.

Design and Characterization of Novel Small Molecule Activators of Excitatory Amino Acid Transporter 2.

Excitotoxicity in the brain is a causal factor in several neurological and neurodegenerative disorders. Excitatory amino acid transporter 2 (EAAT2), an astrocytic glutamate transporter involved in the clearance of >80% of synaptic glutamate, is considered a therapeutically relevant target for excitotoxicity. We have previously designed GT951, an activator of EAAT2 with nanomolar efficacy but limited in vivo bioavailability. In this study, a pharmacophore-based screening and optimization resulted in the design of GTS467 and GTS511. GTS467 and GTS511 have low nanomolar efficacy in the glutamate uptake assay. Pharmacokinetic profiles (PK) of GTS511 show a >6 h half-life and higher bioavailability in plasma and the brain under all three routes of administration in rats. Similarly, GTS467 has high oral bioavailability (80-85%) in the brain and plasma with a >1 h half-life under all three dosing routes. These encouraging efficacy and PK profiles suggest that GTS511 and GTS467 can be further developed to treat neurological disorders caused by excitotoxicity.

Down-Regulation of CXCR4 in Mesenchymal Stem Cells by Septic Serum.

Sepsis is one of the main concerns of health and one of the leading causes of death in hospitals. It is essential to manage sepsis in hospitalized patients. In recent years, cell therapy has been considered as a new approach to treat sepsis. This study evaluated the effect of CXCR4 as one of the main proteins involved in the homing of mesenchymal stem cells in the sepsis serum in mice model. Mouse sepsis model was induced by injection of E.coli and biochemical analyses was done to confirm the organ failure. Mesenchymal stem cells (MSCs) derived from bone marrow were separated into sepsis and control groups. In the sepsis serum group, MSCs were treated with sepsis serum at two time points: 24 and 48h. Quantitative RT-PCR and flow cytometry were performed to determine the mRNA expression of CXCR4 in sepsis serum group compared to control group. Also, a migration assay was done to assess the migration capacity of bone marrow MSCs during inflammation and treatment in sepsis. Our result showed that treatment with sepsis serum can control migration by decrease in CXCR4 level (P ≤ 0.05) compared to control group. Moreover it was also reported that sepsis serum decreased mRNA expression of CXCR4 in MScs. In our study, MSCs treated with septic serum were no longer able to migrate . Probably many variables such as source, dose, injection time, and injection route of MSCs after sepsis induction in the animal models are key factors for successful cell therapy.

Implementation of antimicrobial stewardship programs

Background: The antimicrobial stewardship program (ASP) is a coordinated intervention designed to improve and measure the appropriate antibiotics use by selecting an optimal antibiotic drug regimen, including dosing, therapy duration, and administration route. The implementation of ASPs decreases the consumption, cost, and adverse effects of antibiotic use. Additionally, it improves the clinical outcomes, and decreases Clostridium difficile infection and antimicrobial resistance.Current Concepts: To overcome the antimicrobial resistance and implement ASPs worldwide, various efforts are underway, such as enacting ASP guidelines, developing core elements for ASP implementation, introducing ASPs to the healthcare accreditation system, and providing healthcare facilities with adequate incentives to implement ASPs. In Korea, ASP guidelines were published in September 2021, and core elements for ASP implementation are being developed at the time of writing. However, there is a shortage of personnel required for the ASP team, including healthcare workforce and infectious disease specialists for leading the team Moreover, financial support for ASP implementation in the National Health Insurance Service is not provided yet. The awareness of hospital leadership and clinicians prescribing antibiotics for ASP implementation is still low. The reimbursement system establishment and workforce for ASPs are prerequisite for the implementation of ASPs.Discussion and Conclusion: At the national level, it is necessary to provide financial support for ASPs in healthcare facilities, nurture the healthcare workforce in performing ASPs, and advocate ASP education and publicity.