Dosing Strategies Research Articles

As-Needed Pilocarpine for Radiation-Induced Xerostomia in Head and Neck Cancers.

This study aimed to evaluate the efficacy of as-needed pilocarpine for the management of radiation-induced xerostomia. Additionally, the study sought to assess the side effects associated with an as-needed regimen. A randomized, double-blinded, placebo-controlled crossover study was conducted on patients who had undergone radiation therapy for head and neck cancers and developed xerostomia. Participants took pilocarpine or placebo as needed for symptom relief at 2 weeks per treatment, which included a one-week washout period. The primary outcome measure was the severity of dry mouth symptoms, quantified using the Xerostomia Inventory (XI). The primary outcome was the change in the XI score. Among the 20 participants who completed the crossover study, there was a significant reduction in XI scores during the treatment phase with pilocarpine compared to the scores during the placebo phase. The mean difference in XI scores was -18.05 (95% CI: -17.17, -6.13, p < 0.001), with a-49.77 ± 3.22% change (p < 0.001). Only one participant withdrew due to pilocarpine side effects. As-needed pilocarpine administration is effective in relieving symptoms of radiation-induced xerostomia, with fewer side effects and reduced treatment costs compared to fixed-dose regimens. This study guides the potential shift toward flexible dosing strategies in clinical practice, promoting enhanced patient-centered, tailored care and adherence. According to the Oxford Center for Evidence-Based Medicine 2011 level of evidence guidelines Laryngoscope, 134:4542-4548, 2024.

Phase I/II Investigator-Initiated Study of Olaparib and Temozolomide in SCLC: Final Analysis and CNS Outcomes.

Temozolomide plus PARP inhibition has shown promise in small cell lung cancer (SCLC). We previously reported outcomes from the first 50 patients (cohort 1) of a phase I/II trial of olaparib/temozolomide in recurrent SCLC. Here, we report a final analysis of this trial, including a second cohort with an alternate dosing strategy and an exploratory analysis of CNS-specific outcomes. This was an open-label phase I/II trial testing the combination of olaparib and temozolomide in relapsed SCLC. The primary endpoint was ORR. Secondary endpoints were safety, PFS, and OS. We tested escalating doses of olaparib/temozolomide across two cohorts, both of which had temozolomide dosed on D1-7 of each 21-days cycle. In previously published cohort 1, olaparib was dosed on D1-7; in cohort 2 olaparib was dosed continuously. Sixty-six patients were enrolled across the two cohorts, 50 in cohort 1 and 16 in cohort 2. The confirmed ORR of cohort 1 was 41.7% (20/48 evaluable), and the confirmed ORR of cohort 2 was 7% (1/14 evaluable; closed after dose escalation to enrollment for lack of observed efficacy). Among 15/66 patients (22.7%) with untreated brain metastases at enrollment, best overall intracranial response was CR in 6/15 patients, PR in 4/15 patients, and SD in 3/15 patients for a CNS disease control rate of 87% (95% CI: 59.5-98.3%). Olaparib/temozolomide may be effective in relapsed SCLC, especially for patients with CNS disease. Ongoing analyses regarding optimal dosing schedule will inform potential for future use of this combination in SCLC.

Anti-inflammatory effect of semaglutide: updated systematic review and meta-analysis

Abstract Background Glucagon-like peptide-1 (GLP-1RA) receptor agonists possess multiple favourable metabolic, anti-inflammatory effects and their use is associated with marked body weight reduction. More importantly, this drug class has been shown to reduce cardiovascular events in patients with type 2 diabetes mellitus (T2DM) at high cardiovascular risk or with established cardiovascular disease. Accordingly, current guidelines recommend the use of GLP-1RA sas first-line antidiabetic therapies in patients at high cardiovascular risk. Semaglutide is a potent GLP-1RA used in the treatment of T2DM with proven cardiovascular benefits. It is currently available in formulations for oral and subcutaneous administration. The anti-inflammatory effect could be one of the mechanisms by which semaglutide reduces cardiovascular risk in patients with type 2 diabetes mellitus (T2DM) and/or obesity. Determining the anti-inflammatory effect of semaglutide was the objective of this systematic review and meta-analysis. Methods This meta-analysis was performed according to the PRISMA guidelines. A literature search was performed to detect randomised clinical trials that have quantified the effect of semaglutide on C-reactive protein (CRP) levels compared to placebo or a control group (other glucose-lowering drugs). The primary outcome was CRP index (final CRP/basal CRP). A random-effects model was used. Results Overall, this meta-analysis shows that semaglutide therapy was associated with lower CRP index values compared to placebo (SMD -0.56; 95% CI -0.69 to -0.43, I2 92%) or when comparing semaglutide treatment versus a control group consisting of patients medicated with other glucose-lowering drugs (SMD -0.45; 95% CI -0.68 to -0.23, I 3 82%). The stratified analysis was performed by analysing only the trials that used a placebo group as comparator, When the trials were analysed according to the different dosing schemes (subcutaneous vs. oral), the results were not statistically significantly different (oral semaglutide group: SMD -0.33; 95% CI -0.75 to 0.08, I2 95%); semaglutide subcutaneous dose group: SMD -0.69; 95% CI -0.78 to -0.60, I2 74%); interaction p = 0.098. Furthermore, when the trials were analysed according to the included populations (patients with or without T2DM), the results were similar (patients with T2DM: SMD -0.32; 95% CI -0.51 to -0.14, I2 86%); patients without T2DM: SMD -0.82; 95% CI -0.90 to -0.74, I2 58%); interaction p = &amp;lt; 0.0001. Conclusion The present meta-analysis demonstrated that the use of semaglutide was associated with a reduction in inflammation irrespective of the population evaluated or the treatment regimen used. These findings would explain one of the mechanisms by which semaglutide reduces cardiovascular events.

Systematic review of thyroid function in NKX2-1-related disorders: Treatment and follow-up.

NKX2-1, a crucial transcription factor in thyroid, lung, and brain development, is associated with rare disorders featuring thyroid dysfunction, neurological abnormalities, and respiratory symptoms. The primary challenge in managing NKX2-1-related disorders (NKX2-1-RD) is early diagnosis of the genetic defect and treating specific endocrine disorders. Levothyroxine (LT4) serves as the standard hypothyroidism treatment, with required dosages influenced by the severity of the individual's disorder, which varies widely among affected individuals. This systematic review aims to assess the effectiveness of LT4 treatment in NKX2-1-RD and explore optimal dosing strategies. The primary focus is on the challenges associated with the prompt diagnosis of genetic defects, rather than the established treatment protocols for individual endocrine failures. Adhering to PRISMA guidelines, the review includes 42 studies involving 110 genetically confirmed NKX2-1-RD patients with hypothyroidism. The study investigates congenital hypothyroidism as the most prevalent endocrine alteration, along with gestational and overt hypothyroidism. The administration of LT4 treatment, dosages, and patient responses are analyzed. Among the findings, congenital hypothyroidism emerges as the predominant endocrine alteration in 41% of patients. Notably, LT4 treatment is administered in only 10% of cases, with a mean dose of 52 μg/day. The variability in initiation and dosage is likely influenced by the age at diagnosis. Positive responses, characterized by TSH adjustments within normal ranges, are observed in 11 monitored patients. Early detection of congenital hypothyroidism is emphasized for timely LT4 initiation. Challenges in standardization are highlighted due to the variability in clinical manifestations and diagnostic procedures across NKX2-1-RD cases. While this review provides valuable insights into thyroid and pituitary disease treatment, limited details on LT4 treatment represent a significant study limitation. Key reporting points for future case studies are proposed to enhance the understanding and management of NKX2-1-RD hypothyroidism.

Population Pharmacokinetic Modelling of Norepinephrine in Healthy Volunteers Prior to and During General Anesthesia.

Intraoperation hypotension (IOH) is commonly observed in patients undergoing surgery under general anesthesia, and even a brief episode of IOH can lead to unfavorable outcomes. To reduce the risk, blood pressure is closely measured during general anesthesia, and norepinephrine (NE) is frequently administered if hypotension is detected. Despite its routine application, information on the dose-exposure-response relationship of NE remains limited. Additionally, quantification of the influence of general anesthesia on the pharmacokinetics (PK) of NE is lacking. In this study, we aimed to describe NE PK in healthy volunteers and the influence of general anesthesia on its PK. A single-center, cross-over study was conducted in healthy volunteers. The volunteers received a step-up NE dosing scheme (0.04, 0.08, 0.12, 0.16 and 0.20 mcg-1/kg-1/min-1) first in the awake state and then under general anesthesia. General anesthesia was administered using a propofol/remifentanil Eleveld target-controlled infusion. During general anesthesia, a 30-second electrical stimulus was given as surrogate for surgical incision to the volunteers at each dosage step. Blood samples were drawn before the initial dosing and after each dosing step, and plasma NE, propofol and remifentanil concentrations were subsequently determined. A population PK model was developed using non-linear mixed effects modelling. Simulations were conducted to predict the plasma NE concentration in patients at different measured propofol concentrations. A total of 1219 samples were analyzed from 36 volunteers. A two-compartment model with a first-order elimination best described the data. Weight, age, and session effect (awake vs general anesthesia) were identified as relevant covariates on the clearance (CL) of NE. A 10% decrease in NE CL was observed after general anesthesia induction. This difference between sessions is better explained by the measured concentration of propofol, rather than the anticipated impact of cardiac output. The estimated post-stimulation NE concentration is 0.66 nmol/L-1 (95% CI 0.06-1.20 nmol/L-1) lower than the pre-stimulation NE concentration. Model simulation indicates that patients at a higher measured propofol concentration (e.g., 6 mcg/mL-1) exhibited higher NE concentrations (95% PI 18.10-43.89 nmol/L-1) than patients at a lower measured propofol concentration (e.g., 3 mcg/mL-1) (95% PI 16.81-38.91 nmol L-1). The NE PK is well described with a two-compartment model with a first-order elimination. NE CL exhibiting a 10% decrease under general anesthesia, with this difference being attributed to the measured concentration of propofol. The impact of stimulation on NE PK under general anesthesia is very limited. NL9312.

Recovery of ammonia assimilating microbiome after Cr (VI) shock by bio-accelerators

The pretreatment process is often unable to completely intercept heavy metals in wastewater, facing a huge risk of leakage, increasing the difficulty of treating pollutants in the subsequent biochemical process or even leading to the collapse of the system, and facing the difficulty of inoperability and rehabilitation. Heterotrophic ammonia assimilation has the potential to maintain some stability after heavy metal shock, thanks to its rapid microbial proliferation, robust resistance to high loads, remarkable environmental adaptability, and inherent stability. Bio-accelerators dosing strategies could strengthen the performance recovery ability of traditional bio-system after heavy metal impact. However, no recovery strategies for inhibiting HAA have been reported. Herein, three bio-accelerants, specifically, vitamin A, 6-benzylaminopurine, and α-ketoglutaric acid, were investigated for their potential to restore the HAA system impacted by 20 mg/L Cr (VI). The three bio-accelerants effectively mitigated the toxicity of the HAA system, resulting in a 60.4% increase in NH4+-N removal efficiency within just 6 days with cytokinin. During toxicity remediation, three bio-accelerants facilitated the production of extracellular protein components in soluble microbial products and stimulated the secretion of extracellular polymeric substances. The three bio-accelerants enhanced competition among genera and influenced community assembly processes to regulate community structure and enhance functional gene expression. This study offers a practical approach to enhancing the HAA process and remediating microbial toxicity.

Evaluation of Effective Half-Life and Its Impact on Time to Steady State for Oral MeltDose Tacrolimus (LCPT) in De Novo Kidney Transplant Recipients.

For extended-release drug formulations, effective half-life (t1/2eff) is a relevant pharmacokinetic parameter to inform dosing strategies and time to reach steady state. Tacrolimus, an immunosuppressant commonly used for the prophylaxis of organ rejection in transplant patients, is available as both immediate- and extended-release formulations. To the best of our knowledge, the t1/2eff of tacrolimus from these different formulations has not yet been assessed. The objective of this study was to characterize the t1/2eff and terminal half-life (t1/2z) of an extended-release once-daily tacrolimus formulation (LCPT) and twice-daily immediate-release tacrolimus (IR-Tac). A noncompartmental analysis of pharmacokinetic data obtained from a phase 2 study in de novo kidney transplant recipients receiving either LCPT or IR-Tac was conducted. Intensive blood sampling was performed on days 1, 7, and 14, and tacrolimus whole blood concentrations were measured using a validated liquid chromatography with tandem mass spectrometry method. T1/2eff was estimated using within-participant accumulation ratios. T1/2z was estimated by linear regression of the terminal phase of the concentration versus time profile. The median accumulation ratios of LCPT and IR-Tac on day 14 were 3.18 and 2.06, respectively.The median (interquartile range; IQR) t1/2eff for LCPT at day 14 of dosing was 48.4 (37.4-77.9) hours, whereas the t1/2z was 20.3 (17.6-22.9) hours. For IR-Tac, the median (IQR) t1/2eff and t1/2z on day 14 were 12.5 (8.8-23.0) hours and 12.2 (9.2-15.7) hours, respectively. Consistent with its prolonged release of tacrolimus, LCPT demonstrated a higher accumulation ratio and a longer t1/2eff compared with IR-Tac. These findings underscore the pharmacokinetic differences between different drug formulations of the same moiety and may help inform dose adjustments for LCPT in kidney transplantation.

Safety of the reduced fixed dose of mycophenolate mofetil confirmed via therapeutic drug monitoring in de novo kidney transplant recipients.

Mycophenolate mofetil (MMF) is usually prescribed with a reduced fixed dose in Asian kidney transplant recipients (KTRs). However, the clinical efficacy and safety of the fixed dose have not yet been investigated via therapeutic drug monitoring. We evaluated whether reduced fixed-dose MMF is an optimal dosing strategy to achieve the therapeutic target of mycophenolic acid (MPA) exposure in Korean KTRs. This open-label, prospective study enrolled 50 de novo KTRs prescribed with tacrolimus, corticosteroid, and fixed-dose MMF (1.0-1.5 g/day). The trough level (C0) and area under the curve (AUC0-12 hr) of MPA were measured at 1 and 24 weeks after kidney transplantation (KT). The relationship of body weight (BW)-adjusted MMF dose with MPA C0 and MPA AUC0-12 hr was assessed using linear regression analysis. The initial fixed dose of MMF of 1.44 ± 0.16 g/day was adjusted in 24 patients (48.0%) and then reduced to a mean dose of 1.19 ± 0.31 g/day at 24 weeks after KT. Most patients (≥84.0%) attained the minimum required MPA C0 of 1.0 μg/mL and MPA AUC0-12 hr of 30 μg × hr/mL at 1 and 24 weeks. The BW-adjusted MMF dose demonstrated significant positive correlations with MPA C0 and MPA AUC0-12 hr at 1 and 24 weeks after KT. Moreover, 14 patients (28.0%) reported MPA-related adverse events that were predictable based on MPA AUC0-12 hr (cutoff level, 46.4 μg × hr/mL). The current reduced fixed-dose MMF strategy can help achieve the therapeutic target of MPA exposure in tacrolimus-treated Korean KTRs during the early posttransplant period.

Population pharmacokinetics of cabotegravir following intramuscular thigh injections in adults with and without HIV.

Cabotegravir intramuscular gluteal injection is approved for HIV treatment (with rilpivirine) and prevention. Thigh muscle is a potential alternative injection site. We aim to characterize cabotegravir pharmacokinetics and its association with demographics following intramuscular thigh injection in comparison with gluteal injection using population pharmacokinetic (PPK) analysis. Fourteen HIV-negative participants received 600 mg single thigh injection in phase 1 study 208832 and 118 participants with HIV received thigh injections 400 mg monthly 4× or 600 mg once-every-2-months 2× after ≥3 years of gluteal injections in phase 3b study ATLAS-2M provided 1,249 cabotegravir concentrations from 366 thigh injections and 1,998 concentrations from 1,618 gluteal injections. The established gluteal PPK model was modified by adding thigh injection compartment and fit to pharmacokinetic data following both gluteal and thigh injections, enabling within-person comparison in ATLAS-2M. Gluteal parameters were fixed. Similar to the gluteal absorption rate constant (KAgluteal), the thigh absorption rate constant (KAthigh) was slower in females than males and in participants with higher BMI. KAthigh was strongly correlated with KAgluteal (correlation coefficient 0.766), best described by the additive linear relationship KAthigh = KAgluteal + 0.0002527 h-1. Terminal half-life of thigh injection was 26% (male) and 39% (female) shorter than gluteal injection. Relative bioavailability of thigh to gluteal was estimated to be 89.9%. The impact of covariates on cabotegravir exposure following thigh injections was ≤35%. In conclusion, cabotegravir absorption following thigh injection was correlated with, faster than, and 10% less bioavailable than gluteal injection, and correlated with sex and BMI. The cabotegravir thigh PPK model can inform dosing strategies and future study design.

A Sequential Population Pharmacokinetic Model of Zilovertamab Vedotin in Patients with Hematologic Malignancies Extrapolated to the Pediatric Population.

Recently a number of antibody-drug conjugate (ADC) pharmacometric models have been reported in the literature, describing one or two ADC-related analytes. The objective of this analysis was to build a population pharmacokinetic (popPK) three-analyte ADC model to describe efficacy and safety of zilovertamab vedotin, an ROR1-targeting ADC conjugated to monomethyl auristatin E (MMAE). Data from a phase 1 study of zilovertamab vedotin in subjects with hematologic malignancies was used in a stepwise ADC modeling strategy based on the simplified ADC popPK model proposed by Gibiansky. This choice provided opportunity to model three analytes: conjugated monomethyl auristatin E (acMMAE), total monoclonal antibody (total mAb), and free MMAE. The model was extrapolated to the pediatric population using a clearance maturation function and accounting for weight dependent pharmacokinetic (PK) changes. The simplified model provided a good structure to fit the adult acMMAE, total mAb, and free MMAE data. Analysis showed that MMAE was released through deconjugation of the payload and full proteolytic degradation of the acMMAE. Deconjugation was associated with an immediate release of MMAE, proteolytic clearance introduced a delay in the release of MMAE. Simulation of the model extrapolated to the pediatric population was the basis for pediatric dosing strategies forzilovertamab vedotinthat were approved in the United States and European Union. The total mAb, acMMAE, and free MMAE model showed a good fit to the data. The pediatric population can match the acMMAE adult exposure at the same weight-based dose regimen without concerns that the toxic MMAE concentration will reach higher levelsthan found in adults.

The Role of Propofol in Alcohol Withdrawal Syndrome: A Systematic Review.

The objective of this review was to evaluate the efficacy and safety of propofol in the treatment of critically ill patients diagnosed with alcohol withdrawal syndrome (AWS). A review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria, and Embase, MEDLINE (PubMed), Cochrane CENTRAL, and Web of Science were queried for results through June 2024. Studies providing efficacy or safety data associated with propofol with a reported diagnosis of AWS in critically ill patients were included. Studies evaluating pediatric patients, those without quantitative and qualitative outcome data, and those not readily translatable to English were excluded. Five retrospective cohort analyses of 218 patients were included in this systematic review. Patients were found to have both significant and non-significant increases in time to resolution of AWS symptoms when treated with propofol versus the AWS standard of care. Adjunct treatment with propofol was generally associated with reductions in total benzodiazepine use and increases in both ICU length of stay and duration of mechanical ventilation. The results of this systematic review provide the evidence necessary to support the use of propofol as an efficacious and safe medication in the management of severe and refractory AWS. Further investigation is required to determine optimal dosing strategies and durations of therapy. The results of this systematic review demonstrate the clinical utility of propofol as part of the management strategy for severe and refractory AWS.

Prognostic evaluation using radiomics after stereotactic body radiotherapy in early-stage lung cancer

Non-small cell lung cancer (NSCLC), the leading cause of cancer-related deaths, is the most common subtype of lung cancer with an incidence of 85%. Stereotactic body radiotherapy (SBRT) is a curative treatment option for patients with early-stage NSCLC who cannot undergo surgery due to medical reasons or who refuse surgery. Radiomics non-invasively extracts advanced imaging features invisible to the human eye from medical images. Radiomics has prognostic value in predicting oncological outcomes after lung SBRT. Although studies on this subject are available in the literature, they are quite heterogeneous. There is a need for large-scale multicenter studies in which standard imaging techniques are used to obtain radiomic features, artificial intelligence-based segmentations are used to eliminate differences between contours, and SBRT dose schemes with appropriate therapeutic indexes are applied. This review aimed to interpret the existing studies and emphasize the clinical importance of radiomics, which can contribute to personalized treatment. A comprehensive literature search was conducted through the PubMed database using a wide range of keywords, which yielded 11 peer-reviewed articles published between 2017 and 2024. Seven articles evaluated computed tomography radiomics, and four evaluated fluorodeoxyglucose positron emission tomography-computed tomography radiomics. Oncological outcomes are not always identical in patients with a similar history receiving similar treatments at the same stage and age. Clinical, demographic, or treatment-related data are insufficient to predict prognosis and determine personalized treatment. Incorporating radiomics to these data can help establish models with higher accuracy and achieve personalized treatment.

Population Pharmacokinetic and Pharmacodynamic of Atorvastatin in Chinese Lung Transplant Recipients.

Atorvastatin is a widely prescribed cholesterol-lowering drug that inhibits 3-hydroxy-3-methylglutaryl coenzyme A reductase to reduce lipid levels. This study aimed to establish a population pharmacokinetic and pharmacodynamic model for atorvastatin in Chinese lung transplant recipients (LTRs), particularly those using voriconazole (VOR) and with different genotypes. It evaluated precise dosing regimens and analyzed the correlation between atorvastatin exposure and clinical outcomes. A nonlinear mixed-effects model was used for the population pharmacokinetic/pharmacodynamic (PK/PD) analysis. A one-compartment population PK model was developed, incorporating VOR, SLCO2A1 rs76906503, and SLC22A8 rs2187383 to assess apparent clearance and volume of distribution. LDL-C was modeled as a biomarker to evaluate atorvastatin efficacy. A Monte Carlo simulation was conducted to assess various dosing schemes and the effects of different covariates on achieving the target LDL concentration. The correlation between atorvastatin exposure and clinical outcomes was also evaluated. Results indicated that the average probability of target attainment for optimal dosing regimens across various covariate results exceeded 45.8%. Dosages of 10, 20, and 40 mg were deemed suitable for LTRs. A lower dose was recommended for LTRs taking VOR or with mutant-type genotypes to avoid overexposure and adverse reactions. The population PK/PD model offers valuable guidance for evaluating atorvastatin dosing regimens in clinical settings, particularly for LTRs using VOR and those with different genotypes.

Antibiotic Use in Medical-Surgical Intensive Care Units and General Wards in Latin American Hospitals

Abstract Objectives To identify antibiotic stewardship (AS) opportunities in Latin-American medical-surgical intensive care units (MS-ICUs) and general wards (Gral-wards). Methods We conducted serial cross-sectional point-prevalence surveys in MS-ICUs and Gral-wards in 41 Latin-American hospitals, between March 2022-February 2023. Patients &amp;gt;18 years of age on the units of interest were evaluated for antimicrobial use (AU) monthly (MS-ICUs) or quarterly (Gral-wards). Antimicrobial data were collected using a standardized form by the local AS teams and submitted to the coordinating team for analysis. Results We evaluated AU in 5,780 MS-ICU and 7,726 Gral-ward patients. Hospitals’ median bed-size was 179 (IQR 125, 330), 52% were non-profit. The aggregate AU prevalence was 53.5% in MS-ICUs and 25.5% in Gral-wards. Most (88%) antimicrobials were prescribed to treat infections, 7% for surgical prophylaxis, and 5% for medical prophylaxis. Healthcare-associated infections led to 63% of MS-ICU and 38% of Gral-ward AU. Carbapenems, piperacillin-tazobactam, intravenous (IV) vancomycin, and ampicillin-sulbactam represented 50% of all AU to treat infections. A minority of IV vancomycin targeted therapy was associated with documented methicillin-resistant Staphylococcus aureus infection or underwent therapeutic drug monitoring. In both units, 17% of antibiotics prescribed as targeted therapy represented de-escalation, while 24% and 15% in MS-ICU and Gral-ward, respectively, represented an escalation of therapy. In Gral-wards, 32% of antibiotics were used without a microbiologic culture ordered. Half of surgical prophylaxis antibiotics were prescribed for &amp;gt; first 24 hours. Conclusions Based on this cohort, areas to improve AU in Latin-American hospitals include antibiotic selection, de-escalation, duration of therapy, and dosing strategies.

Multicenter Analysis of Valganciclovir Prophylaxis in Pediatric Solid Organ Transplant Recipients

Abstract Background Valganciclovir (VGCV) prophylaxis against cytomegalovirus (CMV) infection and disease has provided an important advance in the management of pediatric solid organ transplantation (SOT) recipients over the past two decades. However, there remain significant questions regarding its relative safety and efficacy, optimal dosing strategies, and toxicities including neutropenia and lymphopenia. We performed a multi-center retrospective study of children post SOT who were to receive at least 3 months of valganciclovir. The primary outcomes were CMV DNAemia while receiving prophylaxis (breakthrough) and post-prophylaxis CMV DNAemia within the first year. Methods The study population included patients ≤ 20 years of age at the time of their first transplant between January 2016 and December 2019 from 8 US centers in PIDTRAN Network. Data for each patient was extracted from the electronic medical record and entered into a REDcap database hosted by St. Jude Children’s Research Hospital. Variables analyzed included demographics, donor/recipient CMV serostatus, immunosuppression, trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis use, rejection, other viral or bacterial infections and one-year survival. Statistics were performed using STATA software for univariate and multivariate models; p-value&amp;lt; 0.05 was considered statistically significant. Results 749 pediatric SOT patients were enrolled over the 3-year study period. Breakthrough DNAemia occurred in 85 (11.4%) patients and post-prophylaxis CMV DNAemia was documented in an additional 46 (6.9%) patients. CMV disease occurred in only 30 patients (4%). In univariate analysis, there were no differences in age, sex, race/ethnicity, or immunosuppression comparing those who experienced breakthrough or post-prophylaxis CMV DNAemia compared to those without CMV DNAemia, but there were differences based on transplanted organ (p&amp;lt; 0.001, liver and lung &amp;gt; heart &amp;gt; kidney) and CMV risk status (high and intermediate) (p&amp;lt;0.001). Neutropenia (p&amp;lt;0.001) and lymphopenia (p=0.003) as well as VGCV discontinuation or dose reduction for perceived toxicity (p&amp;lt;0.001) were associated with breakthrough CMV infection. Bacteremia (p=0.001), EBV viremia (p=0.02), and adenovirus viremia (p=0.002) were also documented more in those with breakthrough compared to those who never had CMV DNAemia. In an adjusted Cox regression hazard model using all significant univariate variables, transplanted organ, CMV risk status, toxicity related VGCV modification (p=0.005), and bacteremia (p=0.01) were independently associated with breakthrough CMV infection. Breakthrough CMV was also associated with rejection (p=0.01) in a separate logistic multivariable model. Both liver (p&amp;lt;0.001) and heart transplant (p&amp;lt;0.001) patients had a greater risk of rejection over the first year of transplantation, but only liver transplant patients had a greater risk of rejection with breakthrough CMV infection (p=0.004). Post prophylaxis CMV DNAemia was associated with mortality at 1 year in the univariate analysis in the full cohort (p=0.001). Conclusion Rates of CMV disease when using valganciclovir prophylaxis were low in this large, multicenter cohort of pediatric SOT recipients. However, breakthrough CMV infection continues to be a problem in intermediate- and high-risk CMV patients and is associated with significant morbidity and rejection, particularly in the liver transplant population. Alternative approaches to prevent breakthrough and post-prophylaxis CMV and with a better safety profile should be studied in pediatric SOT patients.

Outcomes from the International Society of Nephrology Haemolytic Uraemic Syndromes International Forum

The haemolytic uraemic syndromes (HUS) are a heterogeneous group of conditions only some of which are mediated by complement (CaHUS). We report the outcome of the 2023 International Society of Nephrology HUS International Forum where a global panel of experts considered the current state of the art, identified areas of uncertainty, and proposed optimal solutions. Areas of uncertainty and areas for future research included: the nomenclature of HUS; novel complement testing strategies; identification of biomarkers; genetic predisposition to aHUS; optimal dosing and withdrawal strategies for C5 inhibitors; treatment of kidney transplantation recipients; disparity of access to treatment; and the next generation of complement inhibitors in CaHUS. The current rationale for optimal patient management is described.

Protamine Dosing for Heparin Reversal Following Cardiopulmonary Bypass: A Double-Blinded Prospective Randomized Control Trial Comparing Two Strategies.

Drug shortages are a frequent challenge in current clinical practice. Certain drugs, (e.g., protamine) lack alternatives and inadequate supplies can limit access to services. Conventional protamine dosing uses heparin ratio-based calculations for heparin reversal following CPB and may result in excess protamine utilization, and potential harm due to its intrinsic anticoagulation. We hypothesized that a fixed 250-mg protamine dose would be comparable, as measured by the activated clotting time, to a 1:1 (1 mg for every 100 U) protamine to heparin ratio-based strategy for heparin reversal and that protamine would be conserved. In a single-center, double-blinded trial, consenting elective adult cardiac surgical patients without pre-existing coagulopathy or ongoing anticoagulation, and a calculated initial heparin dose of ≥ 27500 U were randomized to receive, following CPB, protamine as a fixed dose (250 mg) or a ratio-based dose (1 mg:100 U heparin). The primary outcome was the activated clotting time following initial protamine administration, assessed by Student's t-test. Secondary outcomes included total protamine, the need for additional protamine, and the cumulative 24-h chest tube output. There were 62 and 63 patients in the fixed- and ratio-based dose groups, respectively. The mean post-protamine ACT was not different between groups (-2.0 s, 95% CI -7.2 to 3.3 s, P = 0.47). Less total protamine per case was administered in the fixed-dose group (2.1 50-mg vials, 95% CI -2.4 to -1.8, P < 0.0001). There was no difference in the cumulative 24-h chest tube output (difference = -77 ml, 95% CI 220 to 65 ml, P = 0.28). A 1: 1 heparin ratio-based protamine dosing strategy compared to a fixed 250-mg dose resulted in the administration of a larger total dose of protamine no difference in either the initial ACT or the amount postoperative chest-tube bleeding.

Physiologically based pharmacokinetic modeling of long-acting extended-release naltrexone in pregnant women with opioid use disorder.

Opioid use disorders (OUD) are a major issue in the U.S. Current treatments for pregnant women, like methadone and buprenorphine require daily dosing and have adverse effects. Monthly injectable naltrexone (XR-NTX) mitigates these adverse effects but is not recommended during pregnancy due to limited pharmacokinetic and safety data. This study developed a physiologically based pharmacokinetic (PBPK) model to describe XR-NTX pharmacokinetics during pregnancy, and to predict dosing recommendations. Model predictions were successfully validated with observed data. Maternal plasma XR-NTX profiles were simulated for 400 non-pregnant virtual females at the approved dose of 380 mg, then randomized to continue with either 380, 285, 190, or 95 mg during pregnancy. The non-pregnant virtual females had a mean predicted Cmax, AUC0-7days, and AUC0-28days of 23.3 ng/mL, 142 ng·d/mL, and 148 ng·d/mL, respectively. Maternal XR-NTX exposure (AUC0-28days) were predicted to increase by 1.37, 1.43, and 1.72 times during the first, second, and third trimester of pregnancy. However, the fetal-to-maternal exposure (AUC0-28days) was lower in the first (15%), second (7%), and third (9%) trimesters. A dose of 285 mg of XR-NTX in pregnancy during the first/second trimester and dose of 190 mg in the third trimester were predicted to provide maternal exposures that were comparable to non-pregnant levels at the standard dose. This study provides crucial insights into XR-NTX pharmacokinetics and proposes a dosing strategy during pregnancy, potentially aiding further clinical investigations and decision making regarding XR-NTX use during pregnancy.

Integrated spectral based monitoring, optimization and control of the combined ozonation and powdered activated carbon adsorption process to remove organic micropollutants from secondary effluent

In this study, an innovative approach for the integrated monitoring, optimization and control of the combined ozonation (O3) and powdered activated carbon (PAC) adsorption process is introduced making use of spectral surrogates (UVA254 and EEM-PARAFAC components). The combined O3-PAC process is designed to remove organic micropollutants (µP) from secondary effluent. Therefore, the removal of 6 µP with varying ozone reactivity was systematically studied in both O3 and PAC as stand-alone systems and in the combined O3-PAC system. For the latter, adsorption experiments were performed with µP spiked into ozonated secondary effluent (sequential system) and with µP spiked into the initial secondary effluent before ozonation (integrated system). In accordance with Swiss standards, the goal was to achieve 80% atrazine removal (as a model O3 recalcitrant compound) at optimized O3 and PAC doses. An ozone dose ranging from 0.45 to 0.65 mg O3/mg DOC was more cost-effective in promoting subsequent PAC adsorption (less than 40%), particularly at low PAC doses (1-2 mg PAC/mg (initial (DOC))). The classical ideal adsorbed solution theory (IAST) model could not be used to predict the subsequent PAC dose after ozonation in the integrated system. Therefore, correlation models were established between (i) the reduction of spectral surrogates during both O3 and PAC dosing and µP removal, (ii) the reduction of spectral surrogates during ozonation and the related PAC dose of the subsequent adsorption process and (iii) between the reduction of spectral surrogates during ozonation and the integrated process. Based on these correlation models, an online spectral control strategy was developed and implemented. Finally, the optimal dosing strategy for 80% atrazine removal was determined as 0.5 mg O3/mg DOC and 1.4 mg PAC/mg (initial) DOC.

Inflammation Decreases Ciclosporin Metabolism in Allogeneic Hematopoietic Stem Cell Transplantation Recipients.

Graft-versus-host disease (GVHd) remains a significant challenge following allogeneic hematopoietic stem cell transplantation (HSCT). Prevention of GVHd relies mainly on the use of calcineurin inhibitors, notably ciclosporin that exhibits complex pharmacokinetics influenced by many factors including drug-drug interactions (DDIs). Due to the downregulation of drug metabolizing enzymes and transporters, it has been postulated that inflammation may be a contributing factor to the variability observed in ciclosporin pharmacokinetics. This study aimed to assess the impact of inflammation, as indicated by C-reactive protein (CRP) levels, on the metabolism of ciclosporin in adult allogeneic HSCT recipients. A retrospective observational study was conducted at Rennes University Hospital involving 71 adult HSCT patients. The relationship between the intensity of inflammation (no-to-mild, moderate, and severe), and the metabolism of ciclosporin (estimated by the concentration/dose ratio) was assessed. Severe inflammation significantly decreased the metabolism of ciclosporin, as evidenced by higher concentration/dose ratios. Thanks to the daily dose adjustment, inflammation did not influence the blood levels of ciclosporin. Interestingly, DDIs did not emerge as a significant covariate in influencing ciclosporin metabolism. This is likely because the CYP3A4 inhibitory potential of interacting drugs may be masked in HSCT patients where metabolism is already upstream downregulated by inflammation. The study highlights the intricate relationship between inflammation and ciclosporin pharmacokinetics in HSCT patients. This underscores the necessity for therapeutic monitoring and the potential adjustment of dosage strategies based on the inflammatory status. These insights could contribute to the development of more personalized, optimized, and effective management strategies for HSCT recipients.