Administration Of Dose Research Articles

Antidepressant Effect of Enzymatic Porcine Placenta Hydrolysate in Repeated Immobilization Stress-Induced Ovariectomized Female Mice.

When postmenopausal women are under stress conditions, this exacerbates mood disorders and issues with neuroimmune systems. The porcine placenta is known to relieve menopausal depression in clinical trials, but its underlying mechanisms for depression and anti-inflammatory functions remain poorly defined. The present study was designed to examine the anti-inflammatory effects of enzymatic porcine placenta hydrolysate (EPPH) on LPS-induced levels of nitric oxide (NO), prostaglandin E2 (PGE2), corticosterone (CORT), and pro-inflammatory cytokine interleukin-1 beta (IL-1β) in RAW 264.7 macrophage cells. In addition, the neurite outgrowth of PC12 cells was evaluated to examine the effects of EPPH on neurite growth. To mimic the symptoms of women with menopause-related depression, a stressed ovariectomized (OVX) female mouse model was used to evaluate the antidepressant effects of EPPH. The female mice were randomly divided into five groups: (1) the sham-operated (Sham) group, (2) the OVX + repeated stress + saline-treated (OVX + ST) group, (3) the OVX + repeated stress + estradiol (0.2 mg/kg)-treated (positive control) group, (4) the OVX + repeated stress + EPPH (300 mg/kg)-treated (300) group, and (5) the OVX + repeated stress + EPPH (1500 mg/kg)-treated (1500) group. Female mice were OVX and repeatedly immobilization-stressed for 2 weeks (2 h/day). A tail suspension test was conducted on the 13th day, followed by the forced swimming test on the 14th day to assess the antidepressant effects of EPPH. After the behavioral tests, the levels of CORT, PGE2, and IL-1β were evaluated. In addition, c-Fos expression in the paraventricular nucleus (PVN) was evaluated using immunohistochemistry. The concentrations of NO, PGE2, and IL-1β stimulated by LPS were significantly reduced via the addition of EPPH to RAW 264.7 cells. EPPH significantly promoted neurite outgrowth in PC12 cells compared to that of the controls. In the tail suspension test, the duration of immobility was reduced in mice treated with EPPH 1500 compared to the OVX + ST group. The EPPH 1500 group had significantly decreased levels of c-Fos-positive neurons in the PVN and reduced levels of CORT and IL-1β in the serum of the Sham group. These results suggested that the high dose of EPPH administration induced the antidepressant-like effect in the ovariectomized mice with repeated stress via downregulating the levels of CORT, IL-1β, and PGE2 in the serum through reducing the expression of c-Fos in the PVN regions.

Fruit extracts of various cornelian cherry (Cornus mas L.) cultivars as antioxidant therapy for alleviating nitrative stress in erythrocytes of blood in experimental diabetes mellitus

Natural antioxidants (vitamins, bioflavonoids, anthocyanins, etc.) are used to prevent the development of oxidative-nitrative stress in diabetes mellitus (DM), which helps to restore or avert functional disorders in the cells and tissues of the body. The aim of the study is to investigate the effect of extracts of the fruit of different cultivars of the cornelian cherry, as well as their main iridoid glycoside – loganic acid, on the activity of NO-synthase and the content of stable metabolites of NO in blood erythrocytes of rats with streptozotocin-induced diabetes. Materials and methods. In the work, we used the extract of the fruits of the cornelian cherry “Podolski” cultivar (BDPA 10462), the ripe fruits of which have a red color, and the extract of the “Yantarnyi” (BDPA 14131) and “Flava” (BDPA 8795) cultivars, the ripe fruits of which have a yellow color. Loganic acid was extracted from yellow fruits of the “Yantarnyi” and “Flava” cultivars of Cornus mas L. All studied extracts were administered to rats orally for 14 days from the 10th day after the induction of DM. The dose of administration was 20 mg/kg body weight. Results. The extract of the red fruits is demonstrated the most pronounced effect in normalizing the biomarkers of nitrative stress (activity of NO-synthase and its isoforms, the content of nitrite and nitrate anions) in erythrocytes of rats with diabetes. The extract of the yellow fruits shows a positive effect on the suppression of nitrative stress, which has been indicated by a decrease in the activity of iNO-synthase to the values in the control group of animals. Loganic acid, on the contrary, inhibited the eNO-synthase. In addition, the extract of yellow fruits of cornelian cherry and loganic acid decreased the level of NO3– and increased the content of NO2– in erythrocytes of diabetic rats. Conclusions. Biomarkers of nitrative stress in erythrocytes of rats with streptozotocin-induced diabetes indicated the antioxidant properties of fruit extracts of cornelian cherry, in particular the red fruits, which contain a large amount of anthocyanins.

Acute Kidney and Liver Injury Associated With Low-Dose Liraglutide in an Obese Adolescent Patient.

In 2020, the US Food and Drug Administration approved liraglutide (glucagon-like-peptide-1-receptor-agonist) as an adjunctive therapy for weight management in adolescents aged 12 to 18 years in combination with a reduced-calorie diet and increased physical activity. The 2023 American Academy of Pediatrics guidelines recommend pharmacotherapy with glucagon-like-peptide-1-receptor-agonist as a second-line therapy in obesity management. Although reports in adults have suggested a link between liraglutide and adverse effects including hepatic injury and acute kidney injury (AKI), these effects have not previously been reported among adolescents treated with liraglutide for weight loss. We present a 17-year-old male who developed AKI and evidence of hepatic injury (significant elevation of hepatic transaminases) after 3 months administration of the lowest dosage of liraglutide (0.6 mg/day) for management of class III obesity. The patient experienced significant loss of appetite, weight loss, and melancholy during the treatment period. One month after discontinuing liraglutide, his mood had improved, his liver enzymes had returned to normal, and AKI had resolved. The Adverse Drug Reaction Probability Scale suggested a high likelihood of a causative association between liraglutide and his symptoms. Our report highlights the importance of vigilance in monitoring for these potential adverse effects among adolescents treated for obesity with any dose of liraglutide.

Gastroprotective mechanism of Talinum triangulare on ethanol-induced gastric ulcer in Wistar rats via inflammatory, antioxidant, and H+/K+-ATPase inhibition-mediated pathways

The increase in the incidence of gastric ulcer (GU) has posed major threat on public health. This research aimed to evaluate gastroprotective properties of the aqueous leaf extract of Talium triangulare (AETT) in ethanol-induced gastric ulceration. GU was induced via oral administration of single dose of 5 mLkg−1 of 90% ethanol in rats and protection of 200 mgkg−1 bw of AETT and 20 mgkg−1 bw of omeprazole was investigated for 14 d via oral treatment. Influence of AETT on anti-inflammatory, redox assays, ulcer index (UI), and gastric mucosa histological alterations were evaluated. Significant increase in myeloperoxidase (MPO) and tumor necrosis factor-alpha levels compared to untreated group established gastric inflammation in rats induced by ethanol. Gastric ulcerated group exhibited heightened oxidative stress with concurrent decline in activities of antioxidant enzymes. Ethanol exposure to rats resulted in induction of lipid peroxidation, prominently elevating gastric malondialdehyde (MDA) concentration. Nevertheless, treatment with AETT or omeprazole exhibited substantial anti-inflammatory effects within gastric mucosa by attenuating expression of markers associated with inflammation. AETT demonstrated reduction in concentrations of MDA and H2O2, thereby alleviating progression of lipid peroxidation cascades. Also, AETT exhibited mitigating effect on ethanol-induced oxidative harm by enhancing the functionality of protective enzymes and elevating glutathione (GSH) concentration. Overall, AETT exhibited enhancements in activities of cytoprotective antioxidant enzymes, mitigated impact of oxidative stress and inflammation, inhibited lipid peroxidation, and decreased UI score. These beneficial effects could be attributed to phytochemicals present in AETT including 6,10,14-trimethyl-2-pentadecanone and Phytol. Outcome of this study established the traditional herbal claims of AETT.

Evaluation of pre-exposure vaccine effectiveness against mpox during the 2022–2023 mpox outbreak in the Madrid region (Spain): a test-negative design

IntroductionAn appropriate vaccination approach is critical to control the current outbreak of mpox but there is little research providing information on its effectiveness, particularly under circumstances of limited vaccine availability.MethodsPre-exposure...

A Computational Framework for the Administration of 5-Aminovulinic Acid Before Glioblastoma Surgery.

5-Aminolevulinic Acid (5-ALA) is the only fluorophore approved by the FDA as an intraoperative optical imaging agent for fluorescence-guided surgery in patients with glioblastoma. The dosing regimen is based on rodent tests where a maximum signal occurs around 6h after drug administration. Here, we construct a computational framework to simulate the transport of 5-ALA through the stomach, blood, and brain, and the subsequent conversion to the fluorescent agent protoporphyrin IX at the tumor site. The framework combines compartmental models with spatially-resolved partial differential equations, enabling one to address questions regarding quantity and timing of 5-ALA administration before surgery. Numerical tests in two spatial dimensions indicate that, for tumors exceeding the detection threshold, the time to peak fluorescent concentration is 2-7h, broadly consistent with the current surgical guidelines. Moreover, the framework enables one to examine the specific effects of tumor size and location on the required dose and timing of 5-ALA administration before glioblastoma surgery.

Impact of seasonal malaria chemoprevention based on the number of medicines doses received on malaria burden among children aged 3-59 months in Nigeria: A propensity score-matched analysis.

Seasonal malaria chemoprevention using sulfadoxine-pyrimethamine plus amodiaquine (sulfadoxine-pyrimethamine plus amodiaquine on Day 1 and amodiaquine on both Day 2 and Day 3) is delivered to children aged 3-59 months in areas of highly season malaria transmission. While the overall population-level impact of seasonal malaria chemoprevention on malaria control has been documented in various countries and time periods, there is no clear evidence regarding seasonal malaria chemoprevention impact based on the number of medicine doses children receive in one cycle in routine programmatic conditions. Data were extracted from Nigeria's routinely collected seasonal malaria chemoprevention end-of-round coverage surveys (2021, 2022). We matched seasonal malaria chemoprevention-targeted children who received specific numbers of seasonal malaria chemoprevention medicines with those who did not receive any doses of seasonal malaria chemoprevention medicines (non-sulfadoxine-pyrimethamine plus amodiaquine) using multiple sets of propensity score matches. We performed multilevel logistic regression for each matched group to evaluate the association between the number of doses of seasonal malaria chemoprevention medicines and monthly confirmed malaria cases (caregiver-reported malaria infection diagnosed by rapid diagnostic test at a health facility following the penultimate cycle of seasonal malaria chemoprevention). Among 21,621 SMC-targeted children, 9.7% received non-sulfadoxine-pyrimethamine plus amodiaquine, 0.5% received only Day 1 sulfadoxine-pyrimethamine plus amodiaquine, 1.0% received Day 1 sulfadoxine-pyrimethamine plus amodiaquine and either Day 2 amodiaquine or Day 3 amodiaquine (sulfadoxine-pyrimethamine plus amodiaquine + amodiaquine), and 88.8% received Day 1 sulfadoxine-pyrimethamine plus amodiaquine and both Day 2 and Day 3 amodiaquine (sulfadoxine-pyrimethamine plus amodiaquine + amodiaquine + amodiaquine). Children receiving only Day 1 sulfadoxine-pyrimethamine plus amodiaquine did not have significant lower odds of rapid diagnostic tests-confirmed malaria than those receiving non-sulfadoxine-pyrimethamine plus amodiaquine (OR 0.77, 0.42-1.42). However, children receiving sulfadoxine-pyrimethamine plus amodiaquine + amodiaquine had significantly lower odds of rapid diagnostic tests-confirmed malaria than those receiving non-sulfadoxine-pyrimethamine plus amodiaquine (OR 0.42, 95% CI 0.28-0.63). Similarly, children receiving sulfadoxine-pyrimethamine plus amodiaquine + amodiaquine + amodiaquine also had significantly lower odds of rapid diagnostic test-confirmed malaria than those receiving non-sulfadoxine-pyrimethamine plus amodiaquine (OR 0.54, 95% CI 0.47-0.62). Adherence to at least one daily dose of amodiaquine administration following receipt of Day 1 sulfadoxine-pyrimethamine plus amodiaquine by eligible children is crucial to ensure the effectiveness of seasonal malaria chemoprevention. This demonstrates the importance of enhancing caregiver awareness regarding the importance of amodiaquine and identifying barriers toward amodiaquine administration at the community level.

Heparin-Functionalized Bioactive Glass to Harvest Endogenous Growth Factors for Pulp Regeneration.

Pulp and periapical diseases can lead to the cessation of tooth development, resulting in compromised tooth structure and functions. Despite numerous efforts to induce pulp regeneration, effective strategies are still lacking. Growth factors (GFs) hold considerable promise in pulp regeneration due to their diverse cellular regulatory properties. However, the limited half-lives and susceptibility to degradation of exogenous GFs necessitate the administration of supra-physiological doses, leading to undesirable side effects. In this research, a heparin-functionalized bioactive glass (CaO-P2O5-SiO2-Heparin, abbreviated as PSC-Heparin) with strong bioactivity and a stable neutral pH is developed as a promising candidate to addressing challenges in pulp regeneration. Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and thermogravimetric analysis reveal the successful synthesis of PSC-Heparin. Scanning electron microscopy and X-ray diffraction show the hydroxyapatite formation can be observed on the surface of PSC-Heparin after soaking in simulated body fluid for 12 h. PSC-Heparin is capable of harvesting various endogenous GFs and sustainably releasing them over an extended duration by the enzyme-linked immunosorbent assay. Cytological experiments show that developed PSC-Heparin can facilitate the adhesion, migration, proliferation, and odontogenic differentiation of stem cells from apical papillae. Notably, the histological analysis of subcutaneous implantation in nude mice demonstrates PSC-Heparin is capable of promoting the odontoblast-like layers and pulp-dentin complex formation without the addition of exogenous GFs, which is vital for clinical applications. This work highlights an effective strategy of harvesting endogenous GFs and avoiding the involvement of exogenous GFs to achieve pulp-dentin complex regeneration, which may open a new horizon for regenerative endodontic therapy.

THE EFFECT OF MIMOSINE FROM SIMPLICIA OF THE LAMTORO LEAF ON THE HISTOPATOLOGICAL OF WHITE RATS’ TESTIS

Lamtoro leaves (Leucaena leucocephala) are often used as cattle feed. Lamtoro leaf feeding causes decrease in sperm concentration, in diameter of the seminiferous tubules, impaired spermatogenesis, cell degeneration and atrophy. This research aims to determine the histopathology of the testes of white rat given mimosine at different doses. This research uses 20 of 2 months old male Wistar strain white rat with 300-350 g body weight. This research used a completely randomized design (CRD) with 4 treatments, which is P0 (negative control), P1 (positive control) is given mimosine standard 5 mg/day/head, P2 is given lamtoro leaf simplicia 50 mg/day/head and P3 is given leaf simplicia lamtoro 150 mg/day/head. Treatment was given for 14 days orally and on the 15th day a necropsy of testicular organ was taken. Histopathological examination was carried out based on the presence of congestion and necrosis lesions in the seminiferous tubules. Data from testicular histopathological examination results were scored based on severity consisting of, 0 = no lesions; 1= mild lesion (focal); 2= moderate lesion (multifocal); 3 = severe (diffuse), then analyzed with the Kruskal-Wallis and Mann-Whitney tests. The results of the study showed that administration of mimosine from lamtoro leaf simplisia could cause congestion and necrosis compared to control and treatment. Administration of mimosine dose 5 mg/day/ head (P1) causes congestion and necrosis while administration of mimosine from lamtoro leaf simplicia dose 50 mg / head / day (P3) does not cause lesions and dose 150 mg/day/ head (P2) causes congestion in the testicles.

Piloting a Hospital-Based Rapid Methadone Initiation Protocol for Fentanyl.

Treating acute opioid withdrawal and offering medications for opioid use disorder (OUD) is critical. Hospitalization offers a unique opportunity to rapidly initiate methadone for OUD; however, little clinical guidance exists. This report describes our experience during the first 9 months following introduction of a hospital-based rapid methadone initiation protocol. We conducted a retrospective chart review of hospitalized patients with OUD seen by our interprofessional addiction medicine consult service at an urban academic center between December 2022 and August 2023. We identified patients who initiated methadone using the rapid methadone initiation protocol, which includes dose recommendations (maximum 60 mg day 1, 70 mg day 2, 80 mg day 3, 100 mg days 4-7) and strict inclusion and exclusion criteria (end organ failure, arrhythmia, concurrent benzodiazepine or alcohol use, age >65). There were 171 patients that received methadone for OUD during the study period. Of those, 25 patients (15%) received rapid methadone initiation. The average total daily dose of methadone on days 1-7 was 53.0 mg, 69.2 mg, 75.4 mg, 79.5 mg, 87.1 mg, 92.2 mg, and 96.6 mg, respectively. There were no adverse events requiring holding a dose of scheduled methadone, naloxone administration, or transfer to higher level of care. A rapid methadone initiation protocol for OUD can be implemented in the inpatient setting. Patients up-titrated their methadone doses quicker than with traditional induction methods, and there were no serious adverse events. Appropriate patient selection may be important to avoid harms.

Obinutuzumab in untreated primary membranous nephropathy: An observational case series.

As an initial treatment for primary membranous nephropathy (PMN), there remains a significant proportion of patients for whom rituximab is not fully effective. Here, we aimed to assess the effectiveness and safety of obinutuzumab as initial treatment in patients with PMN. In this observational case series, patients diagnosed with PMN and treated with obinutuzumab as initial treatment were included. Treatment response was assessed by 24-h urine total protein (24 h UTP) and serum albumin, and immunologic remission was assessed by phospholipase A2 receptor (PLA2R) antibodies. Twelve patients with PMN receiving obinutuzumab as initial treatment were included. Over 6 months, a statistically significant reduction in 24 h UTP levels (p = 0.003) and an increase in serum albumin levels were observed (p < 0.001). By the 6-month follow-up, two patients (16.7%) achieved complete remission, eight (66.6%) reached partial remission, and two (16.7%) showed no remission. Immunological remission was observed in 44.4% of evaluable patients (n = 9) after 3 months, increasing to 100% (6/6) at 6 months. Except for cases 1, 2, and 3, the total B cell counts in the remaining patients fell to less than 5 cells/μL before the administration of the second dose of obinutuzumab, including seven patients with counts as low as 0 cells/μL. Mild to moderate treatment-related adverse events (TRAEs) were reported in 58.3% (7/12) of the patients. No serious TRAEs were reported. Obinutuzumab demonstrates promising potential as an initial treatment for PMN, with good effectiveness and a manageable safety profile. Further large-scale prospective studies are needed to confirm these findings.

Geniposide dosage and administration time: Balancing therapeutic benefits and adverse reactions in liver disease treatment

Gardenia jasminoides Ellis, a staple in herbal medicine, has long been esteemed for its purported hepatoprotective properties. Its primary bioactive constituent, geniposide, has attracted considerable scientific interest owing to its multifaceted therapeutic benefits across various health conditions. However, recent investigations have unveiled potential adverse effects associated with its metabolite, genipin, particularly at higher doses and prolonged durations of administration, leading to hepatic injury. Determining the optimal dosage and duration of geniposide administration while elucidating its pharmacological and toxicological mechanisms is imperative for safe and effective clinical application.This study aimed to evaluate the safe dosage and administration duration of geniposide in mice and investigate its toxicological mechanisms within a comprehensive dosage-duration-efficacy/toxicity model. Four distinct mouse models were employed, including wild-type mice, cholestasis-induced mice, globally farnesoid X-activated receptor (FXR) knock out mice, and high-fat diet-induced (HFD) NAFLD mice. Various administration protocols, spanning one or four weeks and comprising two or three oral doses, were tailored to each model's requirements. Geniposide has positive effects on bile acid and lipid metabolism at doses below 220 mg/kg/day without causing liver injury in normal mice. However, in mice with NAFLD, this dosage is less effective in improving liver function, lipid profiles, and bile acid metabolism compared to lower doses. In cholestasis-induced mice, prolonged use of geniposide at 220 mg/kg/day worsened liver damage. Additionally, in NAFLD mice, this dosage of geniposide for four weeks led to intestinal pyroptosis and liver inflammation. These results highlight the lipid-lowering and bile acid regulatory effects of geniposide, but also warn of potential negative impacts on intestinal epithelial cells, particularly with higher doses and longer treatment durations. Therefore, achieving optimal therapeutic results requires a decrease in treatment duration as the dosage increases, in order to maintain a balanced approach to the use of geniposide in clinical settings.

Translational PK/PD and the first-in-human dose selection of a PD1/IL15: an engineered recombinant targeted cytokine for cancer immunotherapy.

Interleukin 15 (IL-15) is a potential anticancer agent and numerous engineered IL-15 agonists are currently under clinical investigation. Selective targeting of IL-15 to specific lymphocytes may enhance therapeutic effects while helping to minimize toxicities. We designed and built a heterodimeric targeted cytokine (TaCk) that consists of an anti-programmed cell death 1 receptor antibody (anti-PD-1) and an engineered IL-15. This "PD1/IL15" selectively delivers IL-15 signaling to lymphocytes expressing PD-1. We then investigated the pharmacokinetic (PK) and pharmacodynamic (PD) effects of PD1/IL15 TaCk on immune cell subsets in cynomolgus monkeys after single and repeat intravenous dose administrations. We used these results to determine the first-in-human (FIH) dose and dosing frequency for early clinical trials. The PD1/IL15 TaCk exhibited a nonlinear multiphasic PK profile, while the untargeted isotype control TaCk, containing an anti-respiratory syncytial virus antibody (RSV/IL15), showed linear and dose proportional PK. The PD1/IL15 TaCk also displayed a considerably prolonged PK (half-life range ∼1.0-4.1 days) compared to wild-type IL-15 (half-life ∼1.1h), which led to an enhanced cell expansion PD response. The PD was dose-dependent, durable, and selective for PD-1+ lymphocytes. Notably, the dose- and time-dependent PK was attributed to dynamic TMDD resulting from test article-induced lymphocyte expansion upon repeat administration. The recommended first-in-human (FIH) dose of PD1/IL15 TaCk is 0.003mg/kg, determined based on a minimum anticipated biological effect level (MABEL) approach utilizing a combination of in vitro and preclinical in vivo data. This work provides insight into the complex PK/PD relationship of PD1/IL15 TaCk in monkeys and informs the recommended starting dose and dosing frequency selection to support clinical evaluation of this novel targeted cytokine.

Patterns of oxytocin use for induction and augmentation of labour among healthcare providers in Nigeria

BackgroundThe practice of intrapartum use of oxytocin for induction and augmentation of labour is increasing worldwide with documented wide variations in clinical use, especially dose administrations. There is also evidence of intrapartum use by unauthorized cadre of staff.AimThis study assessed the patterns – frequency of intrapartum use of oxytocin, the doses and routes of administration for induction and augmentation of labour, and identified the predictors of oxytocin use for induction and augmentation of labour by healthcare providers in Nigeria.MethodsThis was a cross-sectional study conducted among healthcare providers – doctors, nurses/midwives and community health workers (CHWs) in public and private healthcare facilities across the country’s six geopolitical zones. A multistage sampling technique was used to select 6,299 eligible healthcare providers who use oxytocin for pregnant women during labour and delivery. A self-administered questionnaire was used to collect relevant data and analysed using STATA 17 statistical software. Summary and inferential statistics were done and further analyses using multivariable regression models were performed to ascertain independent predictor variables of correct patterns of intrapartum oxytocin usage. The p-value was set at < 0.05.ResultsOf the 6299 respondents who participated in the study, 1179 (18.7%), 3362 (53.4%), and 1758 (27.9%) were doctors, nurses/midwives and CHWs, respectively. Among the respondents, 4200 (66.7%) use oxytocin for augmentation of labour while 3314 (52.6%) use it for induction of labour. Of the 1758 CHWs, 37.8% and 49% use oxytocin for induction and augmentation of labour, respectively. About 10% of the respondents who use oxytocin for the induction or augmentation of labour incorrectly use the intramuscular route of administration and about 8% incorrectly use intravenous push. Being a doctor, and a healthcare provider from government health facilities were independent positive predictors of the administration of correct dose oxytocin for induction and augmentation of labour. The CHWs were most likely to use the wrong route and dose administration of oxytocin for the induction and augmentation of labour.ConclusionOur study unveiled a concerning clinical practice of intrapartum oxytocin use by healthcare providers in Nigeria – prevalence of intrapartum use of oxytocin, inappropriate routes of administration for induction and augmentation of labour, varied and inappropriately high start dose of administration including unauthorized and high intrapartum use of oxytocin among CHWs.

Cross-Sectional Investigation of Activated Clotting Time after Administration of Different Intravenous Heparin Doses in Patients Undergoing On-Pump Coronary Artery Bypass Graft Surgery

IntroductionAchieving optimal anticoagulation during coronary artery bypass graft (CABG) surgery remains a challenge, with variations in heparin response attributed to differences in demographic and clinical factors. Deviations from the target activated clotting time (ACT) during CABG have been linked to adverse outcomes. This study aimed to assess the impact of different intravenous heparin doses on ACT in patients undergoing on-pump CABG. MethodsA cross-sectional study was conducted on 54 patients scheduled for CABG surgery with cardiopulmonary bypass in 2021. ACT measurements were taken 5 minutes after the initial bolus dose of 200 IU/kg and a secondary dose of 100 IU/kg heparin. Demographic and clinical data, including ACT measures, hemoglobin levels, bypass time, and mortality, were collected. ResultsThe study population predominantly comprised of male patients, with a mean age of 61.18 ± 8.81 years. The patients and received 4 (3-4) grafts over 75 (65-80) minutes. Baseline ACT was 149.91±17.48 seconds, increasing to 410 (359-472) and 604 (542-679) seconds after the initial and additional heparin, respectively. Only 22.2% of the study subjects achieved target ACT>480 seconds with 200 IU/kg, and the remaining 77.8% required an additional 100 IU/kg heparin to reach the target ACT. No cases of heparin resistance, mortality, or dropouts were reported at the end of the study. Preoperative and postoperative hemoglobin levels were positively correlated (r=0.59, p<0.0001). ConclusionA 300 IU/kg heparin dose appears safer than lower doses for initiating cardiopulmonary bypass in on-pump CABG. Preoperative hemoglobin optimization may help minimize perioperative hemoglobin drop. Further research is needed to refine dosing strategies and personalize CABG management.

Trimethoprim-sulfonamide: a valid antimicrobial treatment in foals?

Trimethoprim-sulfonamide (TMPS) combinations are widely used to treat a range of infectious diseases in horses, but some equine practitioners are reluctant to use them for treatment of both neonatal and older foals. Considering the emergence of increased antimicrobial resistance, the use of protected antimicrobials commonly prescribed to foals should be avoided and alternative first-line therapy considered, where appropriate. This review examines the characteristics and pharmacokinetics of TMPS and its suitability for treatment of foals. Data regarding dosage and route of administration are reported on the basis of recent publications in foals. The review intends to share significant information about the common infections that are most likely responsive to TMPS treatment in foals and, as such, where TMPS might be considered a suitable first-line therapeutic option.

Factors associated with feeding behavior in the early neonatal period focusing on early skin-to-skin contact and epidural analgesia: A prospective observational study at a single hospital in Japan

BackgroundThe feeding behavior of newborns is influenced by the conditions of both the mother and newborn before and after birth. AimsThis study aimed to investigate the factors associated with newborn feeding behavior, focusing on skin-to-skin contact (SSC) as a promoting factor and epidural analgesia as an inhibiting factor, using the Japanese version of the Infant Breastfeeding Assessment Tool (IBFAT). Study DesignProspective observational study conducted in Japan. ParticipantsA total of 176 pairs of healthy mothers and their healthy full-term newborns. Outcome MeasuresThe primary outcome was newborn feeding behaviors measured using the Japanese version of IBFAT within about one day of birth. Stepwise multiple regression analysis was performed to explore the relationship between IBFAT scores and variables that might influence newborn feeding behavior. ResultsMultiple regression analysis revealed that lower IBFAT scores were associated with a higher dose of epidural fentanyl (β = −0.40), and higher IBFAT scores were associated with a longer duration of SSC (β = 0.26), even after adjusting for gestational weeks and Apgar scores. The dose and duration of synthetic oxytocin administration were not associated with IBFAT scores in the multivariate analysis. ConclusionsOur study showed a dose-dependent relationship between fentanyl and SSC, suggesting that consistently implementing SSC for the maximum duration possible may enhance newborn feeding behaviors, which are reduced by fentanyl administration.

THE EFFECT OF 4-VINYLCYCLOHEXENE DIEPOXIDE ON FEMALE NUTRIA (MYOCASTOR COYPUS) FERTILITY IN CAPTIVITY-A PILOT STUDY.

The nutria (Myocastor coypus) is a globally widespread invasive species. Attempts to eradicate nutria by shooting, poisoning, and trapping have been mostly unsuccessful, leading to calls for the development of new control methods. The compound 4-vinylcyclohexene diepoxide (VCD) is known to cause follicular atresia in mammals and may control conception when administered orally. It was hypothesized that VCD administered PO will cause follicular destruction in female nutria. VCD (250 mg/kg PO) was administered or coconut oil, as a control, to five nutria females each for 12 d. Sixty days following VCD exposure, males were introduced to the females. Over the following 7 mon, the effect of VCD on nutria fertility was assessed by conducting ultrasound monitoring to determine pregnancy status and measuring blood serum progesterone and estradiol levels. Finally, after performing ovariectomies, viable follicles were counted on histologic ovarian cortical sections. It was found that the female estrous cycles became synchronized, suggesting a Whitten effect in this species. Also, an increase in the females' serum progesterone levels following the introduction of males occurred, suggesting a male presence effect. Orally administered doses of 250 mg/kg VCD for 12 d had no significant effect on nutria pregnancy rates or on the number of follicles in the ovaries examined. Further studies, using a higher dose or longer administration period, are necessary to conclude whether orally administered VCD can be used as a contraceptive agent for nutria.

A first-in-human study of CRISPR/Cas9-engineered tumor infiltrating lymphocytes (TILs) product GT316 as monotherapy in advanced solid tumors.

2549 Background: A next-generation TIL product GT316 was engineered with CRISPR/Cas9 to genetically disrupt two key immunoregulatory targets identified from a genome-wide CRISPR screening platform and demonstrated significantly enhanced anti-tumor efficacy and persistence in pre-clinical animal studies with ameliorated TIL exhaustion profile. A first-in-human trial was initiated to evaluate the preliminary safety and efficacy of GT316 in advanced solid tumors. Methods: The first-in-class study is to enroll patients (pts) with advanced treatment-refractory solid tumors, especially gynecological tumors. Once the optimal biological dose (OBD) is identified, a monotherapy expansion phase will be initiated for pts with various solid tumors. Enrolled pts were preconditioned with a nonmyeloablative (NMA) lymphodepletion regimen and treated by infusion of the GMP-grade G316 product followed by IL-2 administration. Results: As of January 22, 2024, the dose escalation study enrolled 4 pts, all of whom were female with a median age of 58 years with 1 to 9 prior lines of systemic treatment. The median number of infused TIL cells was 1.0E+10. All pts experienced TRAEs with the majority being grade 1 or 2. Grade 3/4 TRAEs included lymphocyte count decreased, white blood cell count decreased, monocyte count decreased and neutrophil count decreased, which were related to the NMA regimen. No dose-limiting toxicities (DLTs) or TIL-related grade≥3 TRAEs were observed. Median time on study was 33.4 wks (8–35 wks). One pt with treatment-refractory cervical cancer experienced a confirmed complete response (CR) after 4 wks and the duration of response is 32 wks by now (RECIST 1.1). One ovarian cancer pt with 9 lines of previous systemic therapies experienced a confirmed partial response (PR) after 4 wks and the duration of response is 22 wks by now (RECIST 1.1). Response data will be continuously collected. The other two ovarian cancer pts experienced stable disease (SD) and progressive disease (PD), respectively. Despite varying doses of TILs (3.2E+09 to 1.90E+10) and IL-2 (up to 3.0E+05 IU/kg), all pts receiving GT316 showed robust TIL expansion post-infusion, which is positively correlated with administrated IL-2 doses. Enhanced IFN-γ secretion could be detected in the serum of the CR and PR pts compared to the SD and PD pts, indicating potential tumor antigen-specific response. Conclusions: The first-in-human study of GT316, a CRISPR/Cas9-dual KO anti-exhaustion TIL product, demonstrates good tolerability with encouraging preliminary anti-tumor efficacy as a monotherapy in pts with advanced solid cancers. The infusion of GT316 was associated with robust TIL expansion and IFN-γ secretion. Updated data with additional follow-up will be continuously collected, and OBD will be determined based on the overall data of safety and preliminary efficiency. Clinical trial information: NCT06145802 .

Metabolic changes due to dexamethasone premedication in patients with breast cancer.

e24127 Background: The treatment for patients diagnosed with breast cancer is based, in the curative intent scenario, on chemotherapy (CT) such as anthracyclines and taxanes. We are aware that some drugs are widely used and necessary before CT administration to avoid unwanted side effects. Dexamethasone is part of the arsenal of these medications, however, pathological conditions resulting from high doses of administration of this corticosteroid are clinically evident in these patients. In this study we aim to evaluate whether omitting a dose of corticosteroid therapy as a premedication after the second week of treatment with taxane can prevent or reduce the incidence of metabolic changes, and its impact on a patient's quality of life (QoL). Methods: A prospective, randomized, open label study. Breast cancer patients with indication for adjuvant or neoadjuvant treatment with doxorubicin, cyclophosphamide and paclitaxel + trastuzumab (AC-T+ TTZ) chemotherapy were randomized to standard arm, with dexamethasone 10 mg IV administered pre-paclitaxel in all cycles and experimental arm, where dexamethasone was omitted from the premedication from the third to the last taxane application. Results: 86 patients were included, 43 patients in each arm. Premedication was administered every cycle and/ or week before the administration of chemotherapy drugs. Patients had lab analysis and QoL EORTC QLQ-C30 before the beginning of the CT, before the third application of Paclitaxel and 24 hours after the last administration. We observed an increase in ACTH in the experimental group, which is predictable since high doses of corticosteroids suppress the hormone pathway; a drop of insulin levels in its levels in the experimental group and stability in its serum levels in the control group; a stability of GH and IGF-1 in the control group and a more pronounced drop in circulating levels of this hormone in the experimental group. The control group had a greater increase in the excretion of aldosterone, probably due water retention caused by the use of dexamethasone. There were no adverse events reported in the experimental group and also hypersensitivity or anaphylactic reactions were not observed. The EORTC-QLQ-C30 scores related to diarrhea, constipation, inappetence and insomnia were better in the experimental group, as well the average score for global health. Conclusions: The omission of dexamethasone in patients in the experimental group improved QOL scores related to common AEs during CT, mainly GI and also insomnia. Insulin levels were also lower in this group. The potential reduction of the incidence of metabolic syndrome seems palusible but would require larger sample size. The short term safety and tolerability of this regimen warrants its use in larger populations. Clinical trial information: NCT04350229 .