Loading Dose Research Articles

Extrapolation of the Efficacy and Pharmacokinetics of Belimumab to Support its Use in Children with Lupus Nephritis.

Lupus nephritis (LN), a severe manifestation of systemic lupus erythematosus, has greater severity in children versus adults. Belimumab is approved for systemic lupus erythematosus treatment in patients aged ≥ 5 years, and for active LN in adults in the European Union, China, Japan and Latin America, and patients aged ≥ 5 years in the USA. Low prevalence of paediatric active LN makes conducting a clinical study within a reasonable period unfeasible. We describe a model-based extrapolation of belimumab efficacy and pharmacokinetics from adults to children with LN to support US Food and Drug Administration approval of intravenous belimumab 10 mg/kg (administered every 4 weeks after the loading dose) in children (aged 5-17 years) with active LN. This concept assumed that disease progression, response to belimumab, exposure-response, and the target belimumab exposure for efficacy are similar across adult and paediatric systemic lupus erythematosus and LN, evaluated against the published literature for paediatric LN and belimumab systemic lupus erythematosus and LN clinical trial data in adults and children. A two-compartmental population pharmacokinetic model, previously developed for adults with LN, was used to extrapolate belimumab pharmacokinetics to children with LN. The model captured the dependence of time-varying proteinuria on belimumab clearance, and therefore exposure. Sufficient target exposures for efficacy were achieved in children with active LN. A small proportion of children aged 5-11 years are predicted to have exposures below adult levels but no impact to efficacy is expected. Our model demonstrated that intravenous belimumab 10 mg/kg every 4 weeks is appropriate for children aged 5-17 years with active LN.

Dexmedetomidine use during orthotopic liver transplantation surgery on early allograft dysfunction: a randomized controlled trial.

Previous studies have shown a protective effect of dexmedetomidine use in kidney transplantation. In contrast, it is not known whether intraoperative administration of dexmedetomidine can reduce early allograft dysfunction (EAD) incidence following liver transplantation. To investigate the effect of dexmedetomidine use during surgery on EAD following orthotopic liver transplantation (OLT). This is a single-center, double-blinded, placebo-controlled randomized clinical trial. Three hundred thirty adult patients undergoing OLT were enrolled from 14th January 2019 to 22nd May 2022. Patients received dexmedetomidine or normal saline during surgery. One year follow-ups were recorded. Patients were randomized to two groups receiving either dexmedetomidine or normal saline intraoperatively. For patients in the dexmedetomidine group, a loading dose (1μg/kg over 10min) of dexmedetomidine was given after induction of anesthesia followed by a continuous infusion (0.5μg/kg /h) until the end of surgery. For patients in the normal saline group, an equal volume loading dose of 0.9% saline was given after the induction of anesthesia followed by an equal volume continuous infusion until the end of surgery. The primary outcome was EAD. Secondary outcomes included primary graft nonfunction, acute kidney injury, and acute lung injury/acute respiratory distress syndrome. Of 330 patients included in the intention-to-treat analysis, 165 were in the dexmedetomidine group [mean (SD) age, 49 (10) years; 117 (70.9%) men], and 165 were in the normal saline group [mean SD age, 49 (9) years; 118 (74%) men]. 39 (24.4%) patients in the dexmedetomidine group and 31 (19.4%) in normal saline group developed EAD and the difference was statistically insignificant ( P =0.28). Secondary outcomes including primary graft nonfunction and acute kidney injury was similar between the two groups. Intraoperative administration of dexmedetomidine did not reduce EAD rate after OLT.

Efficacy and safety of ritlecitinib in vitiligo patients across Fitzpatrick skin types with biomarker analyses.

Efficacy and safety of ritlecitinib (an oral JAK3/TEC family kinase inhibitor) were evaluated in patients with nonsegmental vitiligo (NSV) across Fitzpatrick skin types (FSTs). Patients with FST I-III ('light skin'; n = 247) and FST IV-VI ('dark skin'; n = 117) received once-daily ritlecitinib 50 mg (with/without 4-week loading dose), low-dose ritlecitinib or placebo for 24 weeks. At baseline, patients with light skin displayed higher CLM-1 and NCR1 serum levels than patients with dark skin (p < 0.05). At 24 weeks, ritlecitinib 50 mg improved the extent of depigmentation measured by percent change from baseline in facial-vitiligo area scoring index (placebo-adjusted mean difference [90% CI]) in patients with light (-15.2 [-24.7, -5.8]; p = 0.004) and dark (-37.4 [-50.3, -24.4]; p < 0.0001) skin, with continuous re-pigmentation through week 48. Treatment-emergent adverse events were similar across FSTs. At weeks 4 and 24, ritlecitinib 50 mg reduced CXCL11 serum levels (p < 0.001) in patients with light skin, whereas patients with dark skin had increased levels at week 4 (p = 0.05) and no significant change at week 24. Ritlecitinib 50 mg decreased IL-9 and IL-22 expression levels in dark skin compared with light skin (qPCR; p < 0.05). These differences in immune dysregulations may explain why NSV patients with dark skin respond to therapy earlier than patients with light skin.

Topographical Quantification of Retinal Fluid in Type 3 MNV and Associations With Short-Term Visual Outcomes

PurposeThis study aims to quantify the volume of intraretinal fluid (IRF), subretinal fluid (SRF), and sub-retinal pigment epithelium (sub-RPE) fluid in treatment-naïve Type 3 macular neovascularization (MNV) eyes with age-related macular degeneration (AMD) and to investigate the correlation of these fluid volumes with visual acuity (VA) outcomes at baseline and following anti-vascular endothelial growth factor (VEGF) treatment. DesignRetrospective, clinical cohort study. MethodsIn this study, we analyzed patients diagnosed with exudative AMD and treatment-naïve Type 3 MNV undergoing a loading dose of anti-VEGF therapy. Using a validated deep-learning segmentation strategy, we processed optical coherence tomography (OCT) B-scans to segment and quantify IRF (i.e., both in the inner and outer retina), SRF, and sub-RPE fluid volumes at baseline. The study correlated baseline fluid volumes with baseline and short-term VA outcomes post-loading dose of anti-VEGF injections. ResultsForty-six eyes from 46 patients were included in this study. Visual acuity was 0.51±0.30 LogMAR at baseline and 0.33±0.20 LogMAR after the loading dose of anti-VEGF (p=0.001). Visual acuity at the follow-up visit was 0.40±0.17 LogMAR in patients with no complete resolution of retinal fluid and 0.31±0.20 LogMAR in eyes without retinal fluid after treatment (P=0.225). In the multivariable analysis, the IRF volume in the inner retina (P=0.032) and the distance of the MNV from the fovea (P=0.037) were predictors of visual acuity at baseline. The baseline IRF volume in the inner retina also predicted the visual acuity at follow-up (p=0.023). ConclusionThe present study highlights the fluid volume in the inner retina as a crucial predictor of short-term visual outcomes in Type 3 MNV, underscoring the detrimental effect of IRF on neuroretinal structures.

Dual pathway inhibition with faricimab for previously treated neovascular age-related macular degeneration and diabetic macular oedema: guidance from a UK panel of retina specialists.

Some eyes with neovascular age-related macular degeneration (nAMD) and centre-involving diabetic macular oedema (DMO) fail to respond sufficiently or lose response over time to standard of care intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy. This paper explores clinical scenarios for switching to dual action angiopoietin-2 (Ang-2)/VEGF-A inhibitor faricimab (Vabysmo, Roche Products Limited) in previously anti-VEGF-treated patients. A national steering group meeting of UK retina specialists was held in London on 27 October 2023. Clinician practice and experience were reviewed together with pivotal clinical trial data and early findings from real-world settings. Roche Products Limited facilitated and funded the meeting. While there is no standardised protocol for identifying suboptimal response, the authors review relevant clinical biomarkers of disease activity used in routine clinical practice to determine patient response and guide treatment decisions. Common reasons identified for considering a change of treatment were lack of efficacy demonstrated by suboptimal anatomic or visual improvement and insufficient durability of response. The panel outline strategies for switching to faricimab among eligible patients with a prior anti-VEGF treatment history, with initial monthly loading doses or maintaining the previous treatment interval before attempting to extend, that may be integrated into current treat-and-extend (T&E) clinical pathways for treating patients with nAMD and DMO. General considerations for switching between treatments are also reviewed. Clinicians may consider a treatment switch to faricimab in nAMD and DMO patients who have suboptimal disease control or insufficient durability of response on initial anti-VEGF therapy.

Colchicine in acutely decompensated heart failure: the COLICA trial.

Acute heart failure (AHF) promotes inflammatory activation, which is associated with worse outcomes. Colchicine has proven effective in other cardiovascular conditions characterized by inflammatory activation, but has never been evaluated in the setting of AHF. This multicenter, randomized, double-blind and placebo-controlled trial included patients with AHF, requiring ≥40 mg of intravenous furosemide, regardless of their left ventricular ejection fraction (LVEF) and inpatient or outpatient setting. Patients were randomized within the first 24 hours of presentation to receive either colchicine or placebo, with loading dose of 2 mg followed by 0.5 mg every 12 hours for 8 weeks. A total of 278 patients (median age 75 years, LVEF 40%, baseline N-terminal pro-B-type natriuretic peptide [NT-proBNP] 4390 pg/mL) were randomized to colchicine (n=141) or placebo (n=137). The primary endpoint, the time-averaged reduction in NT-proBNP levels at 8 weeks, did not differ between the colchicine group (-62.2%, 95% confidence interval [CI] -68.9% to -54.2%) and the placebo group (-62.1%, 95% CI -68.6% to -54.3%) (ratio of change 1.0). The reduction in inflammatory markers was significantly greater with colchicine: ratio of change 0.60 (p<0.001) for C-reactive protein and 0.72 (p=0.019) for interleukin-6. No differences were found in new worsening heart failure episodes (14.9% with colchicine vs. 16.8% with placebo, p=0.698); however, the need for intravenous furosemide during follow-up was lower with colchicine (p=0.043). Diarrhea was slightly more common with colchicine, but it did not result in differences in medication withdrawal (8.5% vs. 8.8%). Colchicine was safe and effective in reducing inflammation in patients with AHF, however colchicine and placebo exhibited comparable effects on reducing NT-proBNP and preventing new worsening heart failure events.

Favipiravir for COVID-19 in adults in the community in PRINCIPLE, an open-label, randomised, controlled, adaptive platform trial of short- and longer-term outcomes

BackgroundEvidence for the effect of favipiravir treatment of acute COVID-19 on recovery, hospital admissions and longer-term outcomes in community settings is limited. MethodsIn this multicentre. open-label, multi-arm, adaptive platform randomised controlled trial participants aged ≥18 years in the community with a positive test for SARS-CoV-2 and symptoms lasting ≤14 days were randomised to: usual care; usual care plus favipiravir tablets (loading dose of 3600mg in divided doses on day one, then 800mg twice a day for four days); or, usual care plus other interventions. Co-primary endpoints were time to first self-reported recovery and hospitalisation/death related to COVID-19, within 28 days, analysed using Bayesian models. Recovery at six months was the primary longer-term outcome. Trial registration: ISRCTN86534580. FindingsThe primary analysis model included 8811 SARS-CoV-2 positive mostly COVID vaccinated participants, randomised to favipiravir (n=1829), usual care (n=3256), and other treatments (n=3726). Time to self-reported recovery was shorter in the favipiravir group than usual care (estimated hazard ratio 1·23 [95% credible interval 1·14 to 1·33]), a reduction of 2·98 days [1·99 to 3·94] from 16 days in median time to self-reported recovery for favipiravir versus usual care alone. COVID-19 related hospitalisations/deaths were similar (estimated odds ratio 0·99 [0·61 to 1·61]; estimated difference 0% [-0·9% to 0·6%]). 14 serious adverse events occurred in the favipiravir group and 4 in usual care. By six months, the proportion feeling fully recovered was 74·9% for favipiravir versus 71·3% for usual care (RR = 1·05, [1·02 to 1·08]). InterpretationIn this open-label trial in a largely vaccinated population with COVID-19 in the community, favipiravir did not reduce hospital admissions, but shortened time to recovery and had a marginal positive impact on long term outcomes.

Addition of Dexmedetomidine to Propofol Anesthesia for Middle-Ear Surgeries: A Prospective Randomized Double-Blind Study.

Background Middle-ear surgery commonly performed under a microscope requires a bloodless field provided by hypotensive anesthesia. Our objective wasto study the effects of dexmedetomidine on propofol consumption and intraoperative hemodynamic stability. Methods One hundred adults undergoing elective middle-ear surgery were randomized into two groups. The propofol+dexmedetomidine group (Group PD) received a loading dose of dexmedetomidine 1μg/kg in 10ml normal saline over 10min followed by infusion of the same at 0.5μg/kg/h. Propofol-only group (Group P) received 10ml normal saline over 10min followed by an infusion of the same. General anesthesia was induced with intravenous morphine, propofol, and vecuronium, and maintained with propofol, oxygen, and N2O. During microscope use, we aimed to maintain mean arterial pressure (MAP) within 60-69mmHg. Results There was no significant difference in the mean (SD) consumption of propofol [Group P 8.6 (2.1)mg/kg/h vs Group PD 8.1 (1.5)mg/kg/h, P=0.172]. The induction dose of propofol was significantly less in Group PD [1.8 (0.3) vs 2 (0.4)mg/kg, P<0.001]. Except for the baseline value, the heart rate was significantly lower in Group PD, P<0.001. The time duration during which MAP was within 60-69mmHg was higher in Group P [37.5 (36.8) vs 30.9 (38.3)min] though the difference was not statistically significant. The recovery was delayed in Group PD [25.4 (8.6) vs 17.6 (4.9)min, P<0.001]. Group PD had a significantly better operative field, P=0.0003. Conclusion The addition of dexmedetomidine did not reduce propofol consumption but reduced the induction dose of propofol. Propofol and dexmedetomidine combination provided comparable mean arterial pressure and better operative field but caused delayed recovery.

Long-Acting Injectable Antipsychotic Initiation in Child and Adolescent Patients with Psychiatric Disorders.

Objectives: There are currently no long-acting injectable antipsychotics (LAIAs) that are approved by the Food and Drug Administration for use in child and adolescent patients, however these agents are used off-label for the treatment of various psychiatric disorders. This study aims to describe the initiation and maintenance dosing strategies of LAIAs in child and adolescent psychiatry inpatients. Methods: This was a single-site retrospective chart review of patients less than 18 years of age initiated on an LAIA during an acute psychiatric hospitalization between October 1, 2015, and October 31, 2022. Patient demographics and hospital encounter information were collected and analyzed using descriptive statistics. Results: Of the 6402 unique pediatric patients discharged from the acute psychiatric hospital within the specified timeframe, 45 (0.7%) were newly initiated on an LAIA. The average age was 15.6 years (range 10-17), with a greater proportion of male (n = 26, 57.8%) and Black or African American (n = 27, 60%) patients. The LAIA agents prescribed included paliperidone palmitate (n = 21, 46.7%), aripiprazole monohydrate (n = 15, 33.3%), aripiprazole lauroxil (n = 7, 15.6%), haloperidol decanoate (n = 1, 2.2%), and risperidone microspheres (n = 1, 2.2%). Primary diagnosis via International Classification of Diseases-10 code at discharge included schizophrenia spectrum and other psychotic disorders (n = 19, 42.2%); bipolar disorder (n = 14, 31.1%); disruptive, impulse control, and conduct disorders (n = 6, 13.3%); autistic disorder (n = 5, 11.1%); and attention-deficit/hyperactivity disorder (n = 1, 2.2%). Seventeen patients (37.8%) received a loading dose regimen and/or a maintenance dose regimen that differed from adult package-insert dosing. The mean length of stay was 23.7 days, and 14 patients (31.1%) were readmitted to the psychiatric hospital within 6 months of discharge. The mean number of days to readmission was 71.9 days. Conclusions: This retrospective study is the first to focus on LAIA initiation and maintenance dosing strategies of multiple agents in both a child and adolescent patient population. Further research is required to evaluate the impact of LAIAs on clinical outcomes in this patient population.

Vitamin D in the critically ill - update 2024.

This review aims to summarize the latest publications on vitamin D focused on critically ill patients. Vitamin D deficiency is common in critically ill patients (children and adults) and associated with a higher risk for mortality and morbidity as well as sepsis, acute respiratory failure, acute renal failure and prolonged ICU stay. As it is an inexpensive substance with a wide safety margin, acute treatment in form of a loading dose in addition to ongoing maintenance therapy is an interesting option in the ICU. The potential benefit of acute native (biologically inactive) vitamin D treatment has not fully been answered but even a small survival benefit demonstrable in very large analyses could be relevant to critical care. To date, less than 5000 patients cumulative have been enrolled in randomized controlled trials concerning vitamin D, with substantial heterogeneity in trial design regarding population (with or without deficiency, coronavirus disease 2019, different age groups, underlying illnesses), metabolite, dosing, outcome, and more. More research is needed, but vitamin D supplementation represents a simple intervention with an excellent safety profile. As adequate vitamin D is essential to the health of multiple organ systems, rapid normalization of deficiency states could translate to benefits across the wide range of diagnoses and organ dysfunctions experienced in the ICU setting. As a minimum, we recommend administering the standard daily dose of vitamin D3 in the critically ill patient.

CSF1R Inhibition in Patients with Advanced Solid Tumors or Tenosynovial Giant Cell Tumor: A Phase I Study of Vimseltinib.

Tenosynovial giant cell tumor (TGCT) is a locally aggressive neoplasm caused by dysregulation of the colony-stimulating factor 1 (CSF1) gene and overexpression of the CSF1 ligand. Surgery is the standard of care for most patients, but there are limited treatment options for patients with TGCT not amenable to surgery. This study evaluates vimseltinib, an investigational, oral, switch-control tyrosine kinase inhibitor designed to selectively and potently inhibit the CSF1 receptor. This first-in-human, multicenter, open-label phase I/II study of vimseltinib in patients with malignant solid tumors (N = 37) or TGCT not amenable to surgery (N = 32) followed a pharmacologically guided 3 + 3 study design (NCT03069469). The primary objectives were to assess safety and tolerability, determine the recommended phase II dose, and characterize the pharmacokinetics; exploratory objectives included pharmacodynamics and efficacy. Vimseltinib was well tolerated; the majority of non-laboratory treatment-emergent adverse events were of grade 1/2 severity. There was no evidence of cholestatic hepatotoxicity or drug-induced liver injury. The recommended phase II dose was determined to be 30 mg twice weekly (no loading dose), and vimseltinib plasma exposure increased with the dose. In patients with TGCT, the median treatment duration was 25.1 months (range, 0.7-46.9), and the objective response rate as assessed by independent radiological review using RECIST version 1.1 was 72%. Vimseltinib demonstrated long-term tolerability, manageable safety, dose-dependent exposure, and robust antitumor activity in patients with TGCT not amenable to surgery.

Evaluation of preprocedural statin loading on clinical outcomes in patients undergoing elective percutaneous coronary intervention.

High-dose statin therapy before percutaneous coronary intervention (PCI) is thought to reduce the occurrence of Peri-procedural Myocardial Infarction (PPMI), which is associated with increased mortality and prolonged hospitalization, especially in statin naïve patients. This study aims to investigate the effect of rosuvastatin loading dose on PPMI and major adverse cardiac and cerebrovascular events (MACCE) in patients undergoing elective PCI, considering their statin use. One hundred sixty-five patients with stable coronary artery disease (CAD) without heart failure (HF) or chronic kidney disease (CKD) were included in the study. They were divided into two groups: patients already on statin treatment (n:126) and statin naive patients (n:39). Both groups were randomly assigned to high-dose (40 mg) rosuvastatin (n:86) or a non- loading dose group (n:79). The primary endpoint was the incidence of PPMI, and the secondary endpoint was MACCE. The mean age of study population was 59 ± 9.4 years with 77% being male (n = 127). The median follow-up (FU) time was 368 day. Thirty patients were diagnosed with PPMI after PCI (19 in the high-dose group and 11 in the no-loading-dose group). Meanwhile, less than half of study population (77 patients, 46.7%) had complex lesion type (B2, C) and 88 of those (53.3%) had simple lesion type (A, B1). PPMI was observed more frequently in statin-naive patients (23%) than in statin users (17%), although the difference was not statistically significant. Only two patients (1.2%) experienced MACCE during the FU period. One of these patients, who had a type C lesion, belonged to group A2 and underwent Target Vessel Revascularization (TVR) on the 391st day. The other patient, with a type B1 lesion, was in group A1 and was hospitalized due to Acute Coronary Syndrome (ACS) on the 40th day of FU. Pre-procedural administration of high dose rosuvastatin in patients with stable coronary artery disease did not decrease PPMI, independent of chronic statin use.

The crucial relationship between vancomycin minimum inhibitory concentration and therapeutic efficacy against methicillin-resistant coagulase-negative staphylococci

The area under the curve (AUC)/minimum inhibitory concentration (MIC) ratio was used as an indicator of the clinical efficacy of vancomycin. However, the target AUC/MIC has not been set for methicillin-resistant coagulase-negative staphylococci (MR-CNS), and the effectiveness of vancomycin in strains with high MIC is unknown. Therefore, we aimed to investigate the relationship between the vancomycin MIC and therapeutic efficacy in patients with MR-CNS bacteremia. The primary outcome was the difference in treatment failure rate when the MR-CNS vancomycin MIC was 1 or 2 µg/mL. The treatment failure rate did not significantly differ between the two groups (MIC 1 vs. MIC 2: 27.0% vs. 31.0%; p = 0.779). As a result of multivariate analysis, AUC/MIC0–24 h ≤230 was extracted as risk factor for treatment failure, suggesting the importance of a sufficient initial loading dose and early blood concentration monitoring to increase AUC/MIC0–24 h for successful treatment.

Changes in Macular Pigment Optical Density after Intravitreal Faricimab in Neovascular Age-Related Macular Degeneration: A Pilot Study.

Background: This study aimed to evaluate the effects of faricimab intravitreal injections in patients with exudative age macular degeneration (nAMD) after the loading dose using spectral domain optical coherence tomography (SD-OCT) and macular pigment optical density (MPOD). Methods: In this observational prospective study, we enlisted a total of 12 consecutive eyes of 12 patients (six females, six males; mean age 70.47 ± 2.46 years) affected by nAMD who consecutively presented to the Eye Clinic of the University of Naples "Federico II" and Monaldi Hospital of Naples, from June 2023 to December 2023. All patients received four once-monthly intravitreal injections of faricimab (6 mg/0.05 mL) (loading phase). At baseline and 1 month after the fourth faricimab monthly injection, all patients underwent assessment of best correct visual acuity (BCVA) and ophthalmic examination, including slit-lamp biomicroscopy, intraocular pressure (IOP), fundus biomicroscopy, SD-OCT, and MPOD. Results: A total of 12 eyes of 12 patients (six women, six men; mean age 70.47 ± 2.46 years) were included in this study. A statistically significant raise in BCVA and MOPD parameters was shown between baseline and after the loading phase (p < 0.001). Conclusions: Intravitreal injections of faricimab led in the short term to a significant functional and MPOD improvement along with a decrease in central macular thickness (CMT) and thus appears to be an effective treatment option without relevant adverse effects. MOPD may be considered as a prognostic factor associated with a good visual prognosis after intravitreal injections treatment.

Decreased Kidney Function Explains Higher Vancomycin Exposure in Older Adults.

Older adults face a higher risk of vancomycin-related toxicity given their (patho)-physiological changes, making early management of supratherapeutic exposure crucial. Yet, data on vancomycin exposure in older adults is scarce. This study aims to compare vancomycin concentrations between older and younger patients, emphasizing supratherapeutic concentrations and the effect of patient characteristics. This observational retrospective study was conducted in the University Hospital of Leuven (EC Research S65213). We analyzed early (first) vancomycin concentrations between older (≥ 75 years) and younger patients. Multivariable analyses were conducted to evaluate the association between baseline patient characteristics with supratherapeutic exposure (logistic regression), and dose-normalized concentrations (linear regression). We included 449 patients aged ≥ 75 years (median 80) and 1609 aged < 75 years (median 61). In univariable analysis, the first-measured vancomycin concentrations were significantly higher in older adults (p < 0.001), who more frequently reached supratherapeutic concentrations (30.7% versus 21%; p < 0.001). In multivariable analysis, factors associated with supratherapeutic concentrations were decreased the estimated glomerular filtration rate calculated by using the Chronic Kidney Disease Epidemiology Collaboration equation (eGFRCKD-EPI) [odds ratio (OR) of 0.98, confidence interval (CI) 0.97-0.98]. Supratherapeutic concentrations had inverse association with giving lower loading dose (OR of 0.59, CI 0.39-0.90), and lower maintenance dose (OR of 0.45, CI 0.26-0.77). Factors that predicted increased dose-normalized concentrations included decreased eGFRCKD-EPI (coefficient of -0.05, CI -0.06 to -0.04), lower body weight (coefficient of -0.04, CI -0.05 to -0.03), increased blood urea nitrogen (coefficient of 0.02, CI 0.01-0.03), and delayed time to therapeutic drug monitoring (TDM) sampling (coefficient of 0.08, CI 0.06-0.09). The absence of age as a significant factor in the multivariable analysis suggests that eGFRCKD-EPI mediated the relationship between age and vancomycin exposure. Older adults may benefit more from vancomycin TDM.

Assessment of effect of two different doses of dexmedetomidine infusion on emergence agitation and quality of recovery after nasal surgery

: To evaluate two different doses of dexmedetomidine infusion on emergence agitation and measurement of hemodynamics, bispectral index, cortisol levels, and quality of recovery in patients who underwent nasal surgery under general anaesthesia.94 individuals of either sex between the ages of 18 and 65 who experienced nasal surgery under general anesthesia were split into two groups for this randomized experimental study. Before induction, each group received loading doses of dexmedetomidine (DEX) infusion at a rate of 1 µg/kg over a period of 10 minutes. Group B underwent a standard induction and then received an infusion of 0.4μg/kg/h of dexmedetomidine every hour until they were extubated, while group A received an infusion of 0.8μg/kg/h. Sevoflurane was employed for maintenance. During emergence, the frequency of agitation, cough hemodynamic parameters, and recovery traits were assessed. Patients received the Quality of Recovery (QoR-40) questionnaire 24 hours following surgery.The hemodynamic reaction to laryngoscopy and intubation was blunted and the intubating circumstances were improved by both doses equally well. Group A's intraoperative mean PR and MAP were significantly (P&amp;#60;0.05) lower than group B's. Coughing was more common among the subjects in group A. A statistically significant difference was found between groups in comparing emergence agitation. Cortisol levels were significantly higher postoperatively in the 0.4µg/kg dose of dexmedetomidine 0.8µg/kg/ group (p=0.001). Global QoR-40 score at 24 h after surgery showed a better global recovery profile in group A. :Although a greater dose of DEX may have more hemodynamic adverse effects, it may also reduce the incidence of emergent agitation, the surgical stress response, and a smoother recovery profile.

Temporal Effect of CYP3A4/5 Induction on Ticagrelor's Pharmacodynamic Effects: A Case Series.

Ticagrelor is contraindicated in combination with cytochrome P450 3A4 and 3A5 enzyme (CYP3A4/5) inducers due to increased clearance, causing diminished antiplatelet effects. The emergent nature of acute coronary syndromes (ACS) may preclude scrutinization of home medications before P2Y12 inhibitor administration. The purpose of this case series is to establish the temporal impact of CYP3A4/5 enzyme induction on ticagrelor's pharmacodynamic effect by utilizing VerifyNow platelet aggregation studies. This was a retrospective case series of three patients who were taking a CYP3A4/5-inducing medication and loaded with ticagrelor for ACS. The duration of ticagrelor's antiplatelet effect was dramatically shortened in the presence of background CYP3A4/5 induction. The offset of antiplatelet effect, defined by platelet reactivity units (PRU), was 10-24hours in the presence of CYP3A4/5 enzyme induction compared to the anticipated 36-48 hours. This was consistent across CYP3A4/5-inducing medications including carbamazepine, phenobarbital, and phenytoin. This study demonstrates rapid return of platelet function after a ticagrelor loading dose in the presence of CYP3A4/5-inducing medications. Monitoring of PRU every 6-12hours with subsequent loading with clopidogrel or prasugrel should be considered. Larger scale studies are warranted to confirm these results.

Pro Re Nata brolucizumab for early onset and treatment-naïve diabetic macular edema: A prospective study.

To determine the efficacy and safety of brolucizumab therapy administered on a pro re nata (PRN) basis without loading dose in treatment naïve patients with diabetic macular edema (DME) for 1 year follow-up. Patients with recent DME (<6 months) received a mandatory brolucizumab injection at inclusion and other injections could be given on a PRN basis with an 8-week interval (between injections) at minimum. Rescue therapy with other anti-VEGF was possible in case of incomplete DME resolution after the second brolucizumab with a minimum of 1-month treatment free interval between 2 injections. The primary outcome measure was the change in (BCVA) at 12 months. Secondary outcome measures included the change in central subfield thickness (CST), the change in hard exudate surface area and microaneurysms at 1 year. A total of 53 patients were included. At 12 months, the mean (SD) number of injections was 2.6 (0.8) in addition to the first mandatory injection. The mean (SD) interval between 2 consecutive injections was 3.2 (1.4) months. The mean (SD) BCVA improved from 0.62 (0.1) logMAR to 0.40 (0.16) logMAR (p = 0.012). The mean CST reduced from 397.0 (47.2) µm to 224.5 (28.1) µm (p = 0.013). The hard exudate surface area decreased significantly (p = 0.012) as did microaneurysms (p = 0.02). Seven patients required at least 1 rescue therapy. No patients experienced intra-ocular inflammatory adverse events. Brolucizumab therapy for DME is a safe and effective modality for the treatment of recent DME and has the potential to reduce the number of injections.

Effects of dexmedetomidine on early postoperative cognitive function and postoperative inflammatory response: a systematic review and network meta-analysis.

Dexmedetomidine (DEX) has demonstrated potential as an effective agent for enhancing early postoperative cognitive function. However, there is ongoing debate regarding its optimal dosage and impact on early postoperative inflammatory response. This study aimed to assess and prioritize the effects of varying doses of DEX on early postoperative cognitive function and inflammatory response, in order to identify the most effective intervention dosage. Randomised controlled trials (RCTs) and retrospective cohort studies (RCS) from PubMed, Embase, and Cochrane Library up to January 28, 2024, were included. The Mini-Mental State Examination (MMSE) was utilized to assess the impact of varying doses of DEX on cognitive function during the early postoperative period as the primary outcome, peripheral blood levels of IL-6 and TNF-α were considered as secondary outcomes. Meta-analysis and Bayesian Network Meta-Analysis (NMA) were conducted using R. Funnel plots were generated using Stata 15.0. A total of 29 studies involving 2,807 patients and 25 different doses of DEX were included. DEX was given at a loading dose of 0.3-1.0 μg/kg followed by a maintenance dose of 0.1-0.5 μg/kg/h, or at a uniform intraoperative dose of 0.4-0.7 μg/kg/h. Network meta-analysis revealed most doses of DEX were significantly more effective than normal saline (NS) in improving postoperative MMSE scores (on days 1, 3, and 7) and lowering IL-6 and TNF-α levels. Probability results showed that a 1 μg/kg loading dose followed by a 0.6 μg/kg/h maintenance dose was the best dosing regimen for improving MMSE scores on postoperative days 1 (97.3%), 3 (100%), and 7 (99.9%), as well as for reducing postoperative blood IL-6 levels (1.3%). On the other hand, 0.3 μg/kg followed by 0.2 μg/kg/h was the optimal dosing regimen for reducing postoperative blood TNF-α levels (6.6%). Compared with NS, intraoperative intravenous DEX improved early postoperative cognitive function and postoperative inflammatory response in patients undergoing elective surgery. In particular, a 1 μg/kg loading dose and a 0.6 μg/kg/h maintenance dose resulted in the best improvement in postoperative MMSE scores and blood IL-6 levels, while a 0.3 μg/kg loading dose followed by a 0.2 μg/kg/h maintenance dose is the optimal regimen for lowering postoperative blood TNF-α levels.Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=433932, identifier CRD42023433932.

Model-informed Evidence for Clinical Non-inferiority of Every-2-Weeks Versus Standard Weekly Dosing Schedule of Cetuximab in Metastatic Colorectal Cancer.

Cetuximab was initially developed and approved as a first-line treatment in patients with unresectable metastatic colorectal cancer (mCRC) for weekly administration (250 mg/m2 Q1W with 400 mg/m2 loading dose). An every-2-weeks schedule (500 mg/m2 Q2W) was approved recently by several health authorities. Being synchronized with chemotherapy, Q2W administration should improve patients' convenience and healthcare resource utilization. Herein, we present evidence of non-inferiority of Q2W cetuximab, compared with Q1W dosing using pharmacometrics modeling and clinical trial simulation (CTS). Pooled data from five phase I-III clinical trials in 852 patients with KRAS wild-type mCRC treated with Q1W or Q2W cetuximab were modeled using a population exposure-tumor size (TS) model linked to overall survival (OS); exposure was derived from a previously established population pharmacokinetic model. A semi-mechanistic TS model adapted from the Claret model incorporated killing rate proportional to cetuximab area under the concentration-time curve over 2 weeks (AUC) with Eastern Cooperative Oncology Group (ECOG) status as covariate on baseline TS. The OS was modeled with Weibull hazard using ECOG, baseline TS, primary tumor location, and predicted percent change in TS at 8 weeks as covariates. Model-based simulations revealed indistinguishable early tumor shrinkage and survival between Q2W vs. Q1W cetuximab. CTS evaluated OS non-inferiority (predefined margin of 1.25) in 1,000 trials, each with 2,000 virtual patients receiving Q2W or Q1W cetuximab (1:1), and demonstrated non-inferiority in 94% of cases. Taken together, these analyses provide model-based evidence for clinical non-inferiority of Q2W vs. Q1W cetuximab in mCRC with potential benefits to patients and healthcare providers.