Daily Dose Research Articles

Aromatase inhibitors can improve the semen quality of aged roosters by up regulating genes related to steroid hormone synthesis

Excessive aromatase can reduce reproductive performance in aged roosters. Aromatase inhibitors (AI) can inhibit the aromatase activity and improve the semen quality of aged roosters. However, relevant molecular mechanism is still unclear. The purpose of this study was to explore the regulatory mechanism of AI letrozole improving semen quality in aged roosters by transcriptomic and proteomic sequencing. In this study, 56-week-old roosters were reared in separate cages on a standard basice diet and oral letrozole 42 days (D) at a daily dose 0.25 mg/kg. Semen quality and serum hormone were measured before (0 D) and after (42 D) letrozole administration. Reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were detected, respectively. The results indicated that semen volume, sperm motility, sperm density, MMP, testosterone (T) and gonadotropin releasing hormone (GnRH) in letrozole treatment group (LET) were significantly increased than those in control group (CN) (P<0.05); estradiol (E2) and ROS in LET were significantly lower than those in CN (P<0.05). Through transcriptomic and proteomic analysis, we identified 189 differently expressed genes (DEGs) and 64 differentially expressed proteins (DEPs) in the comparison of LET and CN. DEGs and DEPs Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) items are mainly enriched in steroid biosynthetic process, cell differentiation and proliferation, lipid metabolic process, oxidation-reduction process and electron transfer activity. Furthermore, 8 genes including STAR, CYP17A1, NSDHL, SULT1E1, EHF, NRNPA1, PLIN2 and SDHA were identified as key genes for letrozole to regulate semen quality in aged roosters. These results indicate that letrozole can up-regulate the expression of genes related to steroid hormone synthesis, cell differentiation and proliferation, electron transfer activity, and enhance mitochondrial activity, increase testicular weight, and ultimately improve the semen quality of aged roosters.

Risk assessment of aluminum, chromium and nickel exposure through ingestion of Arabica and Robusta coffee infusions prepared in aluminum and steel moka pots

The study investigates Al, Cr and Ni contents in coffee beans and infusions. The aim was to show the effect of the material from which the moka pot is made on the quality of infusions and assessing the risk connected with increased consumption of these metals based on hazard quotients calculation. Arabica and Robusta coffee samples of different origin (America, Africa, Asia) and type of processing were tested. The highest concentrations of Cr and Ni were obtained using a steel moka pot, 9.8µgL-1 and 66.8µgL-1, respectively. Drinking 3 cups of coffee per day brewed in this pot, the consumer will be exposed to a daily dose of 4.75·10-5 and 3.23·10-4mgkg-1 day-1 of Cr and Ni, respectively. On the other hand, brewing coffee in an aluminum moka pot results in a concentration of Al up to above 1mgL-1, therefore the migration of this element is significantly higher than that of Cr and Ni. Such a concentration will result in a daily dose of 5.36·10-3mgkg-1 day-1. However, the increased concentration of heavy metals due to the use of an aluminum or steel moka pot does not result in exceeding the maximum permissible dose.

The effectiveness of low-dose aspirin for the prevention of hypertensive disorders of pregnancy in a sub-Saharan Africa Country: A randomized clinical trial

ObjectiveTo evaluate whether a daily dose of low-dose aspirin (LDA) can prevent hypertensive disorders of pregnancy (HDP), including preeclampsia, among pregnant women in a South African cohort, and to assess its impact on related maternal and fetal outcomes, such as preterm birth and neonatal complications. Study designThis single-center, open-label, parallel-group randomized controlled trial (RCT) was conducted at a regional hospital in Durban, KwaZulu-Natal, South Africa, from May 2021 to March 2024. A total of 423 pregnant women, aged 18 years or older with singleton pregnancies between 12 and 20 weeks of gestation, were randomized to receive either 162 mg of LDA daily or standard care. The primary outcome was the incidence of HDP, while secondary outcomes included early-onset preeclampsia (EOPE), preterm birth, low birth weight (LBW), and neonatal death. Data analysis used relative risk (RR) and 95 % confidence intervals (CIs). ResultsOf the 423 women, 209 were in the LDA group and 214 in the control group. The incidence of HDP was significantly lower in the LDA group (6.2 % vs. 25.2 %; RR = 0.25, 95 % CI [0.14–0.44], p < 0.001), corresponding to a 75 % reduction in HDP risk, with an absolute risk reduction (ARR) of 19 % and a number needed to treat (NNT) of 5.3. EOPE was reduced (2.4 % vs. 14.0 %; RR = 0.17, 95 % CI [0.07–0.41], p < 0.001), as was preterm birth (6.7 % vs. 26.2 %; RR = 0.26, 95 % CI [0.15–0.45], p < 0.001). There were no significant differences for LBW or neonatal death. Sensitivity analysis confirmed the importance of initiating LDA before 16 weeks, showing continued reductions in HDP incidence with early initiation. ConclusionLDA significantly reduces the risk of HDP, EOPE, and preterm birth, particularly when initiated before 16 weeks of gestation. These findings support the use of LDA for preventing hypertensive disorders of pregnancy in low-resource settings and underscore the value of early intervention for improved maternal and fetal outcomes.

Worldwide Clinical and Real-World Exposure to Baricitinib

Introduction: Baricitinib (BARI), an oral selective JAK inhibitor, is approved in many geographies for adults with rheumatoid arthritis or alopecia areata and for patients as young as age 2 years with atopic dermatitis or juvenile idiopathic arthritis. It is also approved in the US for hospitalized patients with COVID-19 infection. We report the worldwide clinical trial and real-world exposure to BARI across a range of diseases, ages and racial backgrounds. Methods: Real-world patient exposure estimates were calculated based on total mg sold, average daily dose, and average length of therapy as reported to regulatory agencies through the cumulative timeframe ending Jan. 31, 2024. Clinical trial exposures were based on actual exposures from completed trials through Feb. 13, 2024, and estimates were made for ongoing blinded trials based on the enrolment/randomization schemes Results: In the real-world setting, an estimated 1,836,600 patients have been exposed to the following BARI doses: 1 mg, ~2,000 (0.1%); 2 mg, ~524,900 (28.6%); 4 mg, ~1,309,600 (71.3%). Of these estimated exposures, ~ 57% were for COVID-19 with the remaining for all other indications combined. Across 59 clinical trials (completed and ongoing), an estimated 14,660 subjects (548 healthy volunteers and 14,112 patients) have received BARI since June 2008. Exposures from completed studies include 10,276 patients (62% female), 399 of whom were &lt;18 yrs of age (≤1 month, N=4; 1 month - ≤2 yrs, N=24; &gt;2 - ≤12 yrs, N=111; &gt;12 - ≤18 yrs, N=260), 8820 were &gt;18 to ≤65 yrs, 1027 were &gt;65 yrs, and 30 had age unknown. An additional 467 adolescent and pediatric patients down to the age of 2 have been treated with BARI for atopic dermatitis in an ongoing clinical trial, bringing the total number of patients &lt;18 years of age to 866 across dermatologic, rheumatologic, other autoimmunologic, and acute infectious diseases (excluding alopecia areata for which there is an ongoing pediatric trial). Clinical trial exposures by racial and ethnic background are as follows: Asian, N=2,491; Black, N=450; Caucasian, N=6,237; other, N=496; multiple, N=135; unknown, N=467. Conclusion: There has been extensive real-world exposure to BARI across indications and populations, and BARI is a well-studied molecule in clinical trials, across varied disease states, racial populations and ages. Since average daily dose and length of therapy may vary over time, real-world exposures are only an estimate of total patients receiving BARI. Exposures in clinical trials include patients as young as less than 1 month of age up to patients over the age of 65 years. While these exposures do not indicate efficacy or safety, they provide data to establish the overall profile of the drug and can inform on its performance over time across a variety of populations.

Neurprotective Role of Amaranthus Dubius on Penicillin Induced Experimental Epileptic Rat Model by Combating the Multineurotransmitter Deficiency

Objective: The study aims to clarify the protective effects of Amaranthus dubius (AD) in penicillin (PCN)-induced experimental epilepsy models in rats. Method: In this study, twenty-four adult male Wistar albino rats, each weighing between 200-250 grams, were utilized. The rats were allocated into four groups: a control group, an Amaranthus dubius (AD) treated control group, a PCN-induced experimental epileptic rat model group, and an AD pretreated PCN-induced experimental epileptic rat model group. All groups were administered a daily oral dosage of 400 mg/kg body weight of AD aqueous leaf extract for fourteen days via an orogastric cannula. For the experimental epileptic model, PCN was injected into designated areas of the somatosensory cortex. On the concluding fifteenth day, subsequently, the rats were humanely euthanized. Tissue specimens from the cerebral cortex (CC), cerebellum (CB), caudate nucleus (CN), pons and medulla (PM), and midbrain (MB) were extracted, measured, and homogenized to facilitate subsequent biochemical analyses. Result: Pretreatment with AD has demonstrated significant changes in the levels of antioxidants and neurotransmitters in the brain. Conclusion: Amaranthus Dubius aids in combating multi-neurotransmitter deficiencies and enhances the body's antioxidant capabilities.

Real-world mepolizumab treatment in eosinophilic granulomatosis with polyangiitis reduces disease burden in the United States.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare, chronic inflammatory disease characterized by asthma and small/medium vessel vasculitis. Mepolizumab is approved for use in EGPA disease management alongside oral corticosteroids (OCS), but evidence of its real-world impact is limited. To compare real-world treatment patterns and health outcomes, particularly OCS use, EGPA-related hospitalizations/relapses, and asthma exacerbations pre- and post-mepolizumab initiation in US patients with EGPA. Patients with EGPA receiving ≥2 mepolizumab doses were identified using administrative claims data from Komodo Health's Comprehensive Dataset (December 2016-March 2020). Outcomes assessed pre- and post-mepolizumab initiation included corticosteroid/other medication use, EGPA-related hospitalizations/relapses, and asthma exacerbations. Overall, 114 patients were identified; of these, 60 (53%) received mepolizumab 300 mg at index. Average daily OCS dose per dispensing was significantly lower post- versus pre-mepolizumab initiation (21.2 vs 26.8 mg/day, 21% relative reduction, P<0.001); mean number of OCS bursts also decreased (0.9 vs 1.8, 50% relative reduction, P<0.001). Patients experienced significantly lower rates of EGPA-related hospitalization (0.86 vs 1.55 per person-year [PPY], 49% relative reduction, P=0.004) and EGPA relapse (3.18 vs 3.94 PPY, 19% relative reduction, P=0.004) post- versus pre-initiation. Most patients (91%) had an asthma diagnosis at baseline; among these patients, asthma exacerbation rates were significantly lower post- versus pre-initiation (1.05 vs 1.84 PPY, 42% relative reduction, P=0.004). Mepolizumab was associated with significant steroid-sparing benefits and significantly reduced rates of EGPA-related hospitalizations, EGPA relapses, and asthma exacerbations in this real-world study of US patients with EGPA, confirming the benefits of mepolizumab treatment seen in clinical trials.

The distinctive pharmacokinetic profile of rezafungin, a long-acting echinocandin developed in the era of modern pharmacometrics.

Echinocandin drugs are the current first-line therapy for fungal infections caused by Candida spp. Most patients require once-daily intravenous (IV) administration in a hospital or outpatient setting for treatment, which may negatively impact their quality of life and stress healthcare resources. Similar to other echinocandins, the novel FDA-, EMA-, and Medical and Healthcare Products Regulatory Agency-approved echinocandin, rezafungin (CD101), exhibited strong antifungal activity against several fungal pathogens and a low drug-drug interaction liability, which are important for medically complex patients. A pharmacometric-based approach has been adopted throughout the development of rezafungin, which contrasts with older echinocandins where dosing regimens were largely derived empirically, and only recently based on pharmacometric guidance. This state-of-the-art approach used model-based simulations incorporating pre-clinical and clinical data as it became available to optimize the dosing regimen for rezafungin. The enhanced stability of the molecular structure and the safety profile of rezafungin allow for the administration of once-weekly IV doses, compared to the daily dosing requirement for other echinocandin drugs, with this distinctive pharmacokinetic profile of rezafungin resulting in a front-loaded dosing regimen with high exposures early in therapy for enhanced fungal killing. The long shelf-life of rezafungin makes this echinocandin more flexible in terms of storage and manufacturing. Demonstrated across clinical development, rezafungin may provide patients with next-generation first-line antifungal treatment for the treatment of candidaemia and invasive candidiasis.

Population Pharmacokinetics of Vancomycin in Intensive Care Patients with the Time-Varying Status of Temporary Mechanical Circulatory Support or Continuous Renal Replacement Therapy.

This study characterized the population pharmacokinetics (PK) of vancomycin in patients treated with and without continuous renal replacement therapy (CRRT) or temporary mechanical circulatory support (tMCS), including extracorporeal membrane oxygenation or extracorporeal ventricular assist device. Critically ill adults with and without tMCS or CRRT prescribed vancomycin were enrolled for population PK modeling. MonteCarlo simulation provided dosing recommendations based on the probability of target attainment (PTA), achieving a 24-h area under curve (AUC24h) of 400-600mg*h/L. Twenty-five patients with 184 plasma samples were analyzed. The median age was 61.0years. The final model was a two-compartment PK model. CRRT, serum creatinine, and body weight were significant predictors of clearance. CRRT was a covariate on the central volume of distribution. tMCS significantly decreased the intercompartmental clearance. The simulated mean trough levels at the 48th hour were lower in the tMCS group (13.4 versus 14.2mg/dL in non-tMCS, p < 0.001) in a 70-kg subject with a creatinine of 1mg/dL and a daily dose of 20mg/kg, but the PTA was similar (61.8% versus 62.2%). A reduction of maintenance dose from 30 to 10mg/kg/day with loading dose from 25 to 15mg/kg is recommended while serum creatinine progresses from 0.5 to 4.0mg/dL. For CRRT, the optimal regimen consists of 20-25mg/kg loading and maintenance of 15mg/kg/day. The dosing strategy of vancomycin can be based on body weight or renal function, regardless of tMCS. Intercompartmental clearance decreases under tMCS, which can mislead a dosing adjustment based on trough level.

Efficacy and safety of safinamide in Parkinson's disease patients with motor fluctuations without levodopa dosage escalation over 18 weeks: KEEP study.

This multicentre, prospective, single-arm study evaluated safinamide as add-on therapy to levodopa in Korean patients with Parkinson's disease (PD) with motor fluctuations with≥1.5 h of "off" time daily, who took levodopa≥3 times/day (n = 199). Baseline levodopa and dopamine agonist doses were maintained without escalation during the 18-week treatment period. Participants received safinamide 50 mg/day for 2 weeks and 100 mg/day thereafter. PD diaries and questionnaires (Parkinson's Disease Questionnaire, PDQ-39; Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale, MDS-UPDRS part 3 and part 4; King's Parkinson's Disease Pain Scale, KPPS; Mini-Mental State Examination, MMSE) were assessed at baseline and at week 18. Treatment-emergent adverse events (TEAEs) were recorded. Mean disease duration was 6.6 years, and mean levodopa equivalent daily dose was 721.1 mg/day. At week 18, significant improvements from baseline were seen for the co-primary endpoints, mean daily "off" time (-1.3±2.4 h, p<0.001) and quality of life (QoL) based on PDQ-39 summary index (-2.7±10.3, p<0.001), Moreover, significant improvements were seen in motor symptoms and motor complications (MDS-UPDRS part 3 and 4), daily "on" time without dyskinesia (all p<0.001) and pain (KPPS; p = 0.013). TEAEs occurred in 40.2% of patients, with most being mild in severity. In conclusion, safinamide at a dosage of 100 mg/day significantly improved motor symptoms, QoL, and pain, and demonstrated a favourable safety profile without levodopa dosage escalation during the 18-week treatment period in Korean patients with PD.Trial registration number and date: NCT05312632, First Posted: April 5, 2022.

Nifedipine May Be an Inhibitor of Clozapine Metabolism, as Seen in 5 Patients: 2 from a US Double-Blind Study and 3 from a German TDM Study

Background: Clozapine is the only licensed antipsychotic for treatment-refractory schizophrenia. Therapeutic drug monitoring (TDM) refers to the measurement of clozapine concentration. Clozapine TDM can be used to optimize treatment, particularly by identifying pharmacokinetic interactions between clozapine and comedications. Methods: We identified 5 cases of patients with available clozapine concentrations who were concomitantly receiving nifedipine and clozapine. These cases were drawn from 2 independent datasets: 2 from a double-blind, randomized clinical trial in the United States and 3 from a German TDM naturalistic database. As an index of clozapine clearance, we used the trough-level concentration-to-dose (C/D) ratios to estimate the minimum therapeutic doses. To estimate dose-correction factors for nifedipine treatment, we included only clozapine concentrations at steady state. We divided the clozapine minimum therapeutic doses (MTD) from the on-condition by the off-nifedipine condition. Results: In 4 patients, the ratio of on/off nifedipine for MTD ranged between 0.58 and 0.82. Another patient had no data and had to be compared with published control data (female smoker of African ancestry), providing a correction factor of 0.52 after eliminating 5 concentrations contaminated by the development of obesity. Conclusions: In the absence of access to TDM, when prescribing nifedipine to clozapine-treated patients, we recommend reducing the daily dose of clozapine by one-third because of the weak inhibition of clozapine metabolism. With access to TDM, TDM should guide dosing as unusual patients may need larger dose reductions, as it is possible that in some patients, nifedipine may be a moderate inhibitor requiring halving clozapine dose. Further prospective studies are warranted.

Effect of aspirin on biomarker profile in women at high-risk for preeclampsia.

There is limited evidence in the literature regarding the temporal changes of preeclampsia-related biomarkers during pregnancy in high-risk women who develop preeclampsia despite the administration of aspirin prophylaxis. To compare the temporal changes in mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), placental growth factor (PlGF), and soluble fms-like tyrosine kinase-1 (sFlt-1) across gestation in women screened high-risk for preterm preeclampsia receiving aspirin prophylaxis and low-risk women without aspirin treatment. This was a prospective longitudinal nested case-control study of 2007 women with singleton pregnancies who participated in the first-trimester screen-and-prevent program for preeclampsia at the Prince of Wales Hospital, Hong Kong SAR, China, between January 2020 and May 2023. The risk of developing preterm preeclampsia was determined using the Fetal Medicine Foundation triple test (maternal factors, MAP, UtA-PI and PlGF). High-risk women (adjusted risk ≥1:100) were administered a daily dose of aspirin at either 100 or 160 mg according to maternal weight, starting before 16 weeks until 36 weeks or until delivery or the onset of preeclampsia before 36 weeks. Low-risk women were matched based on maternal age, weight, and the date of the scan. The participants were followed up at 12-15+6, 20-24+6 and 30-37+6 weeks to measure MAP, UtA-PI, PlGF and sFlt-1 at each visit. The level of biomarker was expressed as multiple of median (MoM). Log10 transformation was applied to make the data Gaussian distribution prior to statistical analysis. A linear mixed-effects analysis was performed to compare the longitudinal changes of these biomarkers across gestation between the study groups. Our study involved 403 low-risk women without preeclampsia, 1471 high-risk women without preeclampsia, and 133 high-risk women who developed preeclampsia. The low-risk group had significantly lower estimated marginal mean log10 MAP MoM, log10 UtA-PI MoM, log10 sFlt-1 MoM and higher estimated marginal mean log10 PlGF MoM across gestation than the high-risk groups (p values <0.001). Among high-risk women, those who developed preeclampsia experienced a significantly higher estimated marginal mean log10 MAP MoM (0.06378 vs 0.02985; p<0.001), log10 UtA-PI MoM (0.08651 vs 0.02226; p<0.001), log10 sFlt-1 MoM (0.13204 vs 0.01234; p<0.001) and lower estimated marginal mean log10 PlGF MoM (-0.33504 vs -0.16388; p<0.001) across gestation in comparison to those without preeclampsia. In the individual gestational timepoint analysis, compared to high-risk women without preeclampsia, those who developed preeclampsia experienced higher log10 MAP MoM in all three trimesters, higher log10 UtA-PI MoM and lower log10 PlGF MoM in the second- and third-trimesters, and higher log10 sFlt-1 MoM in the third-trimester. The study has demonstrated that high-risk women who develop preeclampsia experience consistently high MAP level from the first-trimester and remain unchanged during pregnancy, high UtA-PI level and low PlGF level starting from the second-trimester, and high sFlt-1 level in the third-trimester compared to those who do not develop preeclampsia despite the administration of low-dose aspirin. These findings underscore the role of these biomarkers in further risk stratification for the development of preeclampsia among high-risk women following aspirin administration.

De-intensification of basal-bolus therapy by replacing prandial insulin with once-weekly subcutaneous semaglutide in individuals with well-controlled type 2 diabetes: A single-centre, open-label randomised trial (TRANSITION-T2D).

The study aims to examine the outcome of replacement of prandial insulin with once-weekly subcutaneous semaglutide in people with type 2 diabetes reasonably controlled on multiple daily insulin injections (MDI). This single-centre, randomised, open-label trial enrolled a statistically predetermined sample of 60 adults with HbA1c ≤7.5% (58 mmol/mol) receiving MDI, with a total daily dose (TDD) ≤120 units/day. Participants were assigned 2:1 to subcutaneous semaglutide 1.0 mg plus insulin degludec, or to continue MDI. The primary outcome was percentage of subjects maintaining HbA1c ≤7.5% (58 mmol/mol) at Week 26. At Week 26, 90% of semaglutide and 75% of MDI subjects maintained HbA1c ≤7.5% (≤58 mmol/mol) (p = 0.18). Mean changes (95% CI) in HbA1c, weight and percentage body weight for semaglutide versus MDI, respectively, were -0.5% (-0.7, -0.3) versus 0.0% (-0.3, 0.3; p = 0.009); -8.9 kg (-9.9, -7.8) versus 1.5 kg (-0.1, 3.1; p < 0.001); and -8.6% (-9.6, -7.6) versus 1.4% (0.0, 2.8; p < 0.001). Insulin TDD decreased 56.0% (-62.3, -49.7) with semaglutide and increased 6.7% (-2.5, 16.0) with MDI (p < 0.001). Among semaglutide subjects, 58% reduced insulin TDD > 50%, 97.5% stopped prandial insulin and 45% lost >10% body weight. Participant treatment satisfaction scores trended higher with semaglutide. Hypoglycaemia frequency was similar between groups. In people with type 2 diabetes well controlled (HbA1c ≤7.5% [≤58 mmol/mol]) on MDI ≤120 units/day, replacing multiple daily injections of prandial insulin with once-weekly subcutaneous semaglutide can maintain and even improve HbA1c, lower body weight and lessen the burden of management.

CSIG-03. MT-125 INHIBITS NON-MUSCLE MYOSIN IIA AND IIB, SYNERGIZES WITH ONCOGENIC KINASE INHIBITORS, AND PROLONGS SURVIVAL IN GLIOBLASTOMA

Abstract We have shown that members of the non-muscle myosin II (NMII) family of molecular motors are non-redundant drivers of both invasion and proliferation in glioblastoma (GBM), consistent with the canonical roles NMII isoforms play in cell motility and cytokinesis. However, we have also found that NMII also has a non-canonical role by regulating oncogenic signaling pathways relevant to GBM pathogenesis. This unexpected finding has led us to identify and characterize MT-125, a highly specific small molecule inhibitor of the two predominant NMII isoforms in GBM (NMIIA and NMIIB), and we have studied its effects in pre-clinical GBM models. MT-125 has high brain penetrance and retention; an excellent safety profile in rodents and canines with no changes in metabolic or hematologic indices after prolonged administration; is well-tolerated with daily dosing for at least 85 consecutive days; blocks GBM invasion and cytokinesis, consistent with the canonical roles of NMII; and prolongs median survival by 35% as a single agent in murine GBM models. MT-125 increases signaling along both the PDGFR- and MAPK-driven pathways through a mechanism that involves the upregulation of reactive oxygen species, leading to oncogene addiction to these pathways. As a consequence, MT-125 is synthetically lethal when combined with FDA-approved, CNS-permeant inhibitors of PDGFR and mTOR in vitro. Combining MT-125 with sunitinib, a PDGFR inhibitor, or paxalisib, a combined PI3 Kinase/mTOR inhibitor, in vivo doubles median survival in a highly aggressive murine orthotopic GBM model. Furthermore, combining MT-125 with sunitinib produces tumor free remissions of &amp;gt;100 days--2.5-fold greater than median survival of either drug alone—in approximately 40% of mice. Our results provide a powerful rationale for developing NMII targeting strategies to treat cancer and demonstrate that MT-125 has strong clinical potential for the treatment of GBM.

Evaluation of Gender-Specific Variation in Lead-induced Nephrotoxicity in Wistar Rats

The kidney is sensitive to heavy metals because of its intensive metabolic activity and multiple functions namely those of excretion and pollutants concentration. The study aimed to evaluate the gender-specific variation in lead-induced nephrotoxicity in Wistar rats. 10 male and 10 female Wistar rats (180-220g) were each divided into 2 groups (n=5 each): Control (M), Lead alone (M), Control (F), Lead alone (F). Male and female rats of the experimental groups were administered a daily dose of 100 mg/kg/bw of lead acetate dispersed in distilled water for 21 days. All rats were anesthetized and sacrificed 24 hours after the last administration. Blood samples were collected via cardiac puncture for biochemical analysis, kidney tissues were harvested, homogenized, and analyzed for antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase) and lipid peroxidation (measured by malondialdehyde levels). Results indicated a significantly (p&lt;0.01) lower weight gain in the lead-only female (F) group compared to the lead-only male (M) group. Lead acetate exposure caused oxidative damage, evidenced by significantly reduced antioxidant enzyme levels and increased lipid peroxidation in both male and female groups, with the effects being more pronounced in females (p&lt;0.05). Serum creatinine and Urea levels in the lead alone (M) and lead alone (F) group were increased when compared to their respective control groups (p&lt;0.05) however serum creatinine was significantly (p&lt;0.001) higher in lead alone (F) than lead alone (M). The electrolyte function increased significantly in this study (p&lt;0.05) when compared with their control groups. Sodium ion in lead alone (F) increased significantly (p&lt;0.01) when compared to lead alone (M). The study concludes that lead exposure induced nephrotoxicity in both male and female rats, but more significantly pronounced in females than the males. This increased severity may have been mediated by the higher lead-induced oxidative stress observed in the female rats compared to males.

DDEL-08. MEGADOSE BOSWELLIA SERRATA CAUSES SIGNIFICANT DECREASE IN CEREBRAL EDEMA WITH MINIMAL TOXICITY IN BRAIN TUMOR PATIENTS

Abstract Boswellia serrata has been shown to reduce cerebral edema following radiation in brain tumors by Kirste et al in a prospective, randomized, placebo-controlled, double-blind pilot trial. In the study dose of Boswellia used was 4200mg/day, and was well tolerated. We report 2 patients who took doses 10x that which was recommended, after inadvertently buying much higher doses online. Both patients obtained significant reduction in cerebral edema and enhancing disease on MRI. The daily dose of 42000mg/day was tolerated well, with only mild dysphonia in one patient. The optimal dosing of Boswellia serrata to treat cerebral edema is not known, and should be studied further.

Serum Sodium Concentration During Arginine Vasopressin Infusion in Critically Ill Children

Background: Intravenous arginine vasopressin is increasingly used for the treatment of critically ill children. It bears the risk of hyponatraemia with potential severe long-term sequelae, but data on hyponatraemia as a side effect of continuous vasopressin infusion for paediatric intensive care patients is scarce. Methods: In this retrospective analysis performed at a tertiary care paediatric intensive care unit with 2000 annual admissions, patients were included if they were treated with intravenous vasopressin between 2016 and 2022. Baseline sodium concentrations, lowest sodium concentrations during arginine vasopressin treatment, and time to lowest sodium concentration (nadir) were derived. Results: In total, 170 patients with a median age of 4 months [interquartile range, IQR, 0–33] were included, 92.4% underwent surgery, and 28.8% died. Median arginine vasopressin dose rate was 0.027 IU/kg/h [0.019–0.036] and arginine vasopressin was started 3.2 [0–26] h after intensive care admission. Median arginine vasopressin application duration was 13.6 h [6.2–32.6]. Baseline sodium was 141 mmol/L [138–145], and lowest median sodium during arginine vasopressin infusion was 137 mmol/L [132–141] (nadir at 8.4 h [1.0–28.1] after arginine vasopressin start). Hyponatraemia (&lt;135 mmol/L) occurred in 38.2% of patients during AVP treatment, and physicians administered a median of 10.2 mmol/kg/d [6.2–16.4] sodium during arginine vasopressin therapy. Conclusions: Under arginine vasopressin infusion, hyponatraemia was common, although high daily doses of sodium were administered to keep the serum values in physiologic ranges. This emphasises the need for close electrolyte monitoring and sodium substitution in children and adolescents under arginine vasopressin treatment to avoid hyponatraemia and related sequelae.

A retrospective evaluation of supratherapeutic dosing of paracetamol among hospitalised adult patients

Abstract Introduction Paracetamol has a maximum daily dose of 4g/24 hours, with a lower maximum dose (60mg/kg/day) for those weighing under 50kg. Various studies have reported on the extent of supratherapeutic dosing in hospital inpatients.1,2,3 Furthermore, there have been a number of datix incidents of supratherapeutic dosing of paracetamol in our hospital. We investigated how often adult patients are administered too high a daily dose. Aim To ascertain the extent of greater than maximum administration (4g/24 hours) paracetamol for adult inpatients and where the patient’s weight has been recorded, to report on excessive administration for low body weight patients (less than 50kg). Method A retrospective analysis of inpatients 18 years and older administered paracetamol from August 1st 2022 to July 31st 2023. The download from the e-prescribing system (EPS) included various patient characteristics. This dataset was subsequently cleaned and duplicates identified. Microsoft Access was used to run queries to produce a working dataset. As this project falls under the definition of service evaluation, according to UK NHS Research Ethics Committees, formal ethical approval was not required. This project was registered on the hospital’s clinical audit database. Results 30,716 adults (mean age 59, 41% male) received one or more doses during their stay and 10.2% of these received a supratherapeutic daily dose. Females received 61.2% of the supratherapeutic doses, with 1,909 (10.6%) of 18,088 females receiving doses higher than should have been administered. Of the 30,716 adult patients, 1108 of them weighed less than 50kg and 420 (37.9%) of these received a supratherapeutic dose (based on their weight) on one or more days. Of the total 383,222 doses recorded, 82,327 (21.5%) doses were recorded and administered under “as required” (PRN) doses, and 78.5% (n=300,895) as scheduled doses. 2446 (10.4%) of 23,459 adults who received ≥1 scheduled doses had an unintentional overdose on one or more days, with 26,714 total overdoses recorded. 315 (2.2%) of 14,159 adults who received one or more doses PRN, received 1,873 total overdoses. Discussion / Conclusion Overall we found 10.2% of adult patients received a daily dose over their patient-specific maximum dose, on at least 1 day. Older studies report slightly lower proportions (6.01%, 6.6%)1,2 than a more recent study (at 17.4%).3 A greater proportion of relative overdosing based on weight, as we found, has been reported elsewhere.3 We also observed that scheduled doses were nearly five times more likely to be the final dose of a supratherapeutic dose on at least one day, and scheduled doses appeared to be present nearly twice as often as PRN when a patient received one or more supratherapeutic dose. It is unclear why such a discrepancy occurred. Our EPS database enabled more extensive data collection than some other published reports, however limitations include possibly counting overdoses not clinically relevant e.g. fifth dose scheduled for hour 25 but given at hour 24. We did not include paracetamol combination products in our analysis. These results will be shared with nursing staff and consideration will be given to any possible alert for our EPS.

Comparative bioavailability study of supplemental oral Sucrosomial® vs. oral conventional vitamin B12 in enhancing circulatory B12 levels in healthy deficient adults: a multicentre, double-blind randomized clinical trial

BackgroundVitamin B12 is essential for neurological function, red blood cell formation, and DNA synthesis. Deficiency can lead to diverse health conditions, including megaloblastic anemia and neurological issues. Oral supplementation is a standard treatment for B12 deficiency. The Sucrosomial® carrier system offers an innovative approach that enhances supplemental nutrient absorption and bioavailability.ObjectivesThis study aimed to compare the effectiveness of oral Sucrosomial® vitamin B12 formulation vs various conventional B12 supplements, randomly selected from local pharmacies, in increasing and maintaining circulatory B12 levels in healthy deficient adults (200–300 pg/mL).MethodsA randomized, double-blind clinical trial was conducted across three centers in Pakistan from April to July 2024. At KEMU, participants received either Sucrosomial® vitamin B12 or Mecogen SL B12; at LRH, Sucrosomial® B12 or B-SUB B12; and at LUMHS, Sucrosomial® B12, Evermin B12, or Neuromax B12. Participants took a daily single dose of 1,000 μg of the assigned B12 formulation for 7 days. Serum B12 levels were measured at baseline (day 0) and on days 1, 3, 5, and 7.ResultsSucrosomial® B12 was significantly more effective than conventional B12 formulations in increasing and maintaining higher serum B12 levels across all time points. At KEMU, it reached a peak concentration of 454 ± 3.9 pg/mL by day 5, compared to 274 ± 11.1 pg/mL with Mecogen SL B12. At LRH, it peaked at 496 ± 34.4 pg/mL by day 5 versus 304 ± 49.4 pg/mL for B-SUB B12. At LUMHS, it reached 592.7 ± 74.3 pg/mL by day 7, compared to 407.24 ± 41.6 pg/mL for Evermin B12 and 263.82 ± 23.8 pg/mL for Neuromax B12. Sucrosomial® B12 was the only formulation to surpass the deficiency-borderline threshold (200–300 pg/mL) within 24 h of the first dose and was well tolerated with no reported side effects.ConclusionSucrosomial® vitamin B12 demonstrated superior efficacy in rapidly and consistently elevating and maintaining higher circulatory B12 levels compared to conventional supplements. Its characteristic absorption mode and proven efficacy suggest it could effectively address B12 deficiency in a broad range of populations, including those with gastrointestinal conditions and pernicious anemia, thereby supporting overall health.Clinical trial registrationclinicaltrials.gov, NCT06376591.

Comprehensive evaluation of skin exposure to PBDEs and PCBs in diverse South China populations via dermal wipe sampling.

This study analyzed skin wipe samples from the forehead, palm, forearm, and lower leg of 120 volunteers across different age groups-preschoolers, thresholders, middle-aged, and elderly-with each group comprising 30 individuals with a balanced sex ratio from a city in South China. The research aimed to assess the occurrence, concentration, and associated health risks of polybrominated diphenyl ethers (PBDEs) and polychlorinated biphenyls (PCBs) adsorbed onto human skin from environmental sources. We identified 13 PBDE congeners and 10 PCB congeners across all samples, with average detection frequencies of 48% for PBDEs and 16% for PCBs, with concentrations ranging from non-detectable (ND) to 4200 and ND to 2300ng/m2, respectively. Skin concentrations of both PBDEs and PCBs decreased in the order of face > hand > arm > shank (ANOVA, P < 0.001), suggesting higher exposure to uncovered skin areas than to those covered by clothing, regardless of age or sex. The daily average dose of dermal (DADderm) and oral (DADoral) for PBDEs spanned from 7.0 × 10-4-0.19ng/kg/d and ND-15 ng/kg/d, respectively, whereas the PCB exposure doses ranged from ND-7.8ng/kg/d (DADderm) and ND-2.0ng/kg/d (DADoral), respectively. Preschool children displayed notably higher DADoral levels than the other groups (P < 0.0001), which was attributed to their more frequent hand-to-mouth activity. Preschool boys exhibiting a higher DADderm (P < 0.05) and both preschool boys and university women showing elevated DADoral levels (P < 0.01 and P < 0.05, respectively). Health risk assessments concluded that the carcinogenic risks from BDE209 and PCBs were within acceptable limits (10-4) for all sampled populations.

Trends in antibiotic use in a UK secondary care prior to and during the COVID-19 pandemic: a cross-sectional retrospective study

Abstract Introduction Antimicrobial resistance (AMR) is a rapidly escalating global health challenge. To address this, the UK Government developed a 5-year action plan, 'Confronting Antimicrobial Resistance 2024 to 2029,' aimed at optimising antimicrobial use.1 The World Health Organisation (WHO) promotes antimicrobial stewardship (AMS) and developed the AWaRe classification system to guide global AMS implementation. The defined daily dose (DDD) standardises antibiotic use comparisons.2 The COVID-19 pandemic significantly impacted health services, particularly in secondary care, potentially exacerbating AMR due to increased antibiotic use.3 Aim To evaluate changes in antibiotic use in a UK secondary care setting following the onset of the COVID-19 pandemic in 2020 compared to 2019. Methods This cross-sectional retrospective study evaluated antibiotic use among adult patients admitted to an NHS Foundation Trust in England. The focus was on those prescribed antibiotics for respiratory tract infections (RTIs) and pneumonia in 2019 and 2020. Data from 640 patient records were extracted using a validated tool based on the WHO AWaRe classification, with antibiotic use measured using the Defined Daily Dose (DDD). The study included patients aged 25 and above, immunocompromised individuals, pregnant women, and those treated for RTIs. It was registered under ISRCTN number 14825813 and received ethical approval from the University of Hertfordshire Ethics and Health Research Authority (HRA). The Citizens Senate reviewed the study protocol, ensuring public and patient involvement. Results The results show a notable increase in the Defined Daily Dose (DDD) of several antibiotics during the COVID-19 pandemic. In the "Access" category, amoxicillin usage rose from 1.33 DDD pre-pandemic to 4.33 DDD in 2020. Co-amoxiclav remained nearly constant at around 15 DDD but showed a marked increase compared to other antibiotics. In the "Watch" category, azithromycin increased from 3 to 9 DDD, and clarithromycin from 32 to 35.5 DDD. Levofloxacin usage doubled from 13 to 26 DDD. The "Reserve" category showed no significant increase, indicating stable consumption. Discussion and conclusion Understanding trends in antibiotic prescribing during the COVID-19 pandemic is pivotal for effective management in secondary care settings. The significant increase in the "Watch" category of antibiotics, particularly macrolides like azithromycin and clarithromycin, highlights the need for stringent antimicrobial stewardship. This rise may reflect changes in prescribing behaviour due to the pandemic. Monitoring antibiotic use is vital to mitigate the AMR challenge. Additionally, the increased use of levofloxacin during the pandemic, despite MHRA safety alerts about its potentially severe side effects, highlights the importance of cautious antibiotic prescribing and prompt discontinuation at the first signs of adverse reactions. The COVID-19 pandemic has significantly influenced antibiotic prescribing trends, highlighting the urgent need for sustainable antimicrobial stewardship in secondary care. This study reveals a notable increase in "Watch" category antibiotics, particularly azithromycin and clarithromycin, underscoring the need for stringent stewardship. Optimised antibiotic use is crucial for patient safety, improving treatment quality, and saving lives. The increased reliance on levofloxacin, despite known risks, emphasises the importance of careful prescribing. Prioritising responsible antibiotic use is essential to combat antimicrobial resistance, necessitating enhanced monitoring and stewardship efforts.