Therapeutic Index Research Articles

Principal sensory experiences of forest visitors in four countries, for evidence‐based nature therapy

Abstract To advance the theoretical and practical underpinnings for nature therapies, i.e. nature exposure as a means to improve mental health, we compared the most memorable sensory experiences reported by forest tourists in Australia, Chile, China and Japan. Sensory experiences are a fundamental driver of the psychological effects of nature exposure. We first reviewed relevant research from each country and language. We then conducted 100 on‐site interviews in Australia, 100 in Chile, and >500 in China, and compiled 1000 relevant social media posts from Japan. We analysed these datasets using directed‐content qualitative thematic analyses, both in original languages and in translated texts, and compared outcomes from each country. The key sensory experiences are universal: sights of plant shapes and colours; sounds of birdsong, running water and rustling leaves; smells of flowers, trees, and earth; taste and temperature of clean air and water; and touch of bark and rocks. Participants gave detailed descriptions of each. These fine‐grained but widespread experiences are our principal finding. These sensory experiences are at a scale that is broad enough to apply for prescriptible nature therapies in any forested region, but fine enough to be used in future quantitative research to test therapeutic designs, doses and durations. This distinguishes them from prior research, that is either too broad or too fine in scale for practical therapy design. Future research aiming to maximise the mental health benefits of nature may not need to distinguish different countries and cultures, but may need to differentiate nature experiences more finely and precisely than in most therapy‐related research to date. Read the free Plain Language Summary for this article on the Journal blog.

Potentially Inappropriate Medications and De-prescribing: An Audit of STOPP/START on an Inpatient Rehabilitation Ward

Abstract Background Polypharmacy is well recognized in older adults with many adverse outcomes. Practical tools, such as the ‘STOPP/START’ criteria, aid clinicians in de-prescribing to tackle medication related morbidity. Current research suggests these tools are insufficiently implemented in clinical practice (1). Many older adults require rehabilitation after acute hospital admissions which can provide an ideal setting for medication review and de-prescribing. Methods A retrospective audit was carried out of 35 older adults in a gerontological inpatient rehabilitation facility between 8th February and 8th April 2024. Demographic and clinical data was collected using electronic and handwritten patient records. Each patients’ medication prescription was reviewed from date of admission to rehabilitation facility. Number of medications prescribed was recorded. Using the ‘STOPP/START’ criteria, potentially inappropriate medications (PIMs were identified, and de- prescribing was noted for the PIM where taken. Results 35 patients were included in the study. No patient was excluded. Mean age was 86.14 years and mean number of prescribed medications per patient was 11. The most common presenting complaint was a fall in 57.14% of patients, in which 95% had acute fracture. Other presenting complaints for acute admission included delirium and infection. Mean clinical frailty score was 5.71. 38 PIMswere identified, totalling 10% of all medication prescriptions. Of these, 12 de-prescribing opportunities were taken, one of which was a dose reduction. The most common PIMswere prescribing of PPI at full therapeutic dose (n=12), inappropriate opioid prescribing (n=4) and hypnotics (n=7) in high-risk groups. Conclusion Polypharmacy and PIMsare common in older adults and are related to adverse outcomes, especially in frail adults at risk of falls, fracture, and delirium. The rehabilitation setting is an ideal location for use of de-prescribing tools however their implementation varies. This may be improved by education and structured medication review in collaboration with trained pharmacists.

Comparative Analysis of Cystamine and Cysteamine as Radioprotectors and Antioxidants: Insights from Monte Carlo Chemical Modeling under High Linear Energy Transfer Radiation and High Dose Rates.

This study conducts a comparative analysis of cystamine (RSSR), a disulfide, and cysteamine (RSH), its thiol monomer, to evaluate their efficacy as radioprotectors and antioxidants under high linear energy transfer (LET) and high-dose-rate irradiation conditions. It examines their interactions with reactive primary species produced during the radiolysis of the aqueous ferrous sulfate (Fricke) dosimeter, offering insights into the mechanisms of radioprotection and highlighting their potential to enhance the therapeutic index of radiation therapy, particularly in advanced techniques like FLASH radiotherapy. Using Monte Carlo multi-track chemical modeling to simulate the radiolytic oxidation of ferrous to ferric ions in Fricke-cystamine and Fricke-cysteamine solutions, this study assesses the radioprotective and antioxidant properties of these compounds across a variety of irradiation conditions. Concentrations were varied in both aerated (oxygen-rich) and deaerated (hypoxic) environments, simulating conditions akin to healthy tissue and tumors. Both cystamine and cysteamine demonstrate radioprotective and strong antioxidant properties. However, their effectiveness varies significantly depending on the concentration employed, the conditions of irradiation, and whether or not environmental oxygen is present. Specifically, excluding potential in vivo toxicity, cysteamine substantially reduces the adverse effects of ionizing radiation under aerated, low-LET conditions at concentrations above ~1 mM. However, its efficacy is minimal in hypoxic environments, irrespective of the concentration used. Conversely, cystamine consistently offers robust protective effects in both oxygen-rich and oxygen-poor conditions. The distinct protective capacities of cysteamine and cystamine underscore cysteamine's enhanced potential in radiotherapeutic settings aimed at safeguarding healthy tissues from radiation-induced damage while effectively targeting tumor tissues. This differential effectiveness emphasizes the need for personalized radioprotective strategies, tailored to the specific environmental conditions of the tissue involved. Implementing such approaches is crucial for optimizing therapeutic outcomes and minimizing collateral damage in cancer treatment.

Audit of Lithium Monitoring in a Mental Health for Older Persons (Dublin North City Central) Service

Abstract Background Lithium is a psychotropic medication used for the treatment of bipolar affective disorder and augmentation for treatment resistant depression. Lithium monitoring is essential due to the narrow therapeutic range of serum lithium and the potential for toxicity. Other medications with similar risk profiles, such as warfarin, have established monitoring programmes. Older adults receiving lithium therapy are at an increased risk of adverse events, given the prevalence of medical co-morbidities and changing pharmacokinetics. The authors of this audit identified the lack of formalized lithium monitoring programme in the Mental Health Service for Older Persons (MHSOP). The aim of this audit to compare monitoring practices in the MHSOP against the current gold standard Irish Medication Safety Network (IMSN) for Prescribing and Monitoring of Lithium Therapy. Methods A survey of all community medical charts identifying patients attending the service receiving lithium therapy was completed. Data collected pertained to diagnosis, treating consultant, lithium dose, if the patient received educational material, compliance with ECG and blood monitoring. Results The MHSOP active case load was 682 patients, 14 patients were prescribed lithium therapy. Cycle 1 of the audit demonstrated poor compliance of lithium monitoring against the gold standard. A lithium pack was inserted in patient files to prompt all clinicians to follow the recommended standardized monitoring of lithium therapy as per the IMSN guidelines. In cycle 2 of the audit there was an improvement in recording blood monitoring across the patient group. Conclusion The audit demonstrated improvement in compliance with international guidelines following the intervention. It was recommended that a formalized Lithium Clinic was a needed resource for the MHSOP. The lithium monitoring pack will continue to be added to clinical files, included in Non-Hospital Consultant (NCHD) induction and multi - disciplinary teaching sessions. It is proposed that the audit be repeated in one year to longitudinally assess compliance.

Novel Carbohydrate Polymer-Based Systems for Precise Drug Delivery in Colon Cancer: Improving Treatment Effectiveness With Intelligent Biodegradable Materials.

Due to their biocompatibility, biodegradability, and controlled release, carbohydrates polymers are crucial to targeted drug delivery systems, notably for colon cancer treatment. This article examines how carbohydrate polymers like chitosan, pectin, guar gum, alginate, hyaluronic acid, dextran, and chondroitin sulfate are used in improved drug delivery. Modifying these polymers improves drug loading, stability, and release patterns, enhancing chemotherapeutic drugs' therapeutic index. Chitosan nanoparticles are pH-responsive, making them perfect for cancer treatment. Pectin's resistance to gastric enzymes and colonic bacteria makes it a promising colon-specific medication delivery agent. The combination of these polymers with nanotechnology, 3D printing, and AI allows the creation of stimuli-responsive systems that release drugs precisely in response to environmental signals like pH, redox potential, or colon enzymatic activity. The review highlights intelligent delivery system design advances that reduce systemic toxicity, improve treatment efficacy, and improve patient adherence. Carbohydrate polymers will revolutionize colon cancer treatment with personalized and accurate alternatives.

Multidrug Combinations against SARS-CoV-2 Using GS-441524 or Ivermectin with Molnupiravir and/or Nirmatrelvir in Reconstituted Human Nasal Airway Epithelia.

Background. The emergence, global spread, and persistence of SARS-CoV-2 resulted in an unprecedented need for effective antiviral drugs. Throughout the pandemic, various drug development and treatment strategies were adopted, including repurposing of antivirals designed for other viruses along with a multitude of other drugs with varying mechanisms of action (MoAs). Furthermore, multidrug treatment against COVID-19 is an ongoing topic and merits further investigation. Method/Objectives. We assessed the efficacy of multidrug treatment against SARS-CoV-2 in reconstituted human nasal epithelia, using combinations of molnupiravir and nirmatrelvir as a baseline, adding suboptimal concentrations of either GS-441524 or ivermectin, attempting to increase overall antiviral activity while lowering the overall therapeutic dose. Results. Nirmatrelvir combined with molnupiravir, GS-441524, or ivermectin at suboptimal concentrations show increased antiviral activity compared to single treatment. No triple combinations showed improved inhibition of SARS-CoV-2 replication beyond what was observed for double treatments. Conclusions. In general, we observed that the addition of a third compound is not beneficial for antiviral activity, while various double combinations exhibit increased antiviral activity over single treatment.

Anticoagulation strategies in patients with coexisting traumatic intracranial hematomas and cerebral venous sinus thrombosis: an observational cohort study

PurposePost-traumatic cerebral venous sinus thrombosis (ptCVT) is a rare but serious complication of traumatic brain injury (TBI). Managing ptCVT is challenging due to the concurrent risk of traumatic intracranial hematoma (ICH) expansion. Limited data exists on the safety and efficacy of anticoagulation therapy (ACT) in these cases.MethodsThis single-center observational cohort study included adult TBI patients with concurrent ICH and ptCVT. Low-molecular-weight heparin (LMWH) or heparin infusion was used to treat all ptCVTs based on institutional protocols. The outcomes of interest were hemorrhagic and thrombotic complications.ResultsOut of 1,039 TBI-patients admitted between 2006 and 2020, 32 met the inclusion criteria. The median time from injury to ptCVT diagnosis was 24 h. ACT was initiated at a median of 9 h after ptCVT diagnosis. Patients were administered either heparin infusion (n = 8) or LMWH at dosages ranging from 28 to 72% of the therapeutic level (n = 24). There were no hemorrhagic complications, even in patients receiving LMWH at ≥ 50% of the therapeutic dose. Thrombotic complications occurred in 3 patients (9.4%) – two cases of thrombus progression and one venous infarct. The patients who developed thrombotic complications differed from those who did not by having a 17-h delay in ACT initiation after diagnosis or by receiving an initial LMWH dose at 28% of the therapeutic level.ConclusionLMWH at approximately 50% of the therapeutic level was effective for managing ptCVT associated with TBI in our retrospective dataset, with no risk of hematoma expansion. Prospective trials are warranted to confirm these results.

Dosimetric calibration of anatomy-specific ultra-high dose rate electron irradiation platform for preclinical FLASH radiobiology experiments.

FLASH radiation therapy (RT) offers a promising avenue for the broadening of the therapeutic index. However, to leverage the full potential of FLASH in the clinical setting, an improved understanding of the biological principles involved is critical. This requires the availability of specialized equipment optimized for the delivery of conventional (CONV) and ultra-high dose rate (UHDR) irradiation for preclinical studies. One method to conduct such preclinical radiobiological research involves adapting a clinical linear accelerator configured to deliver both CONV and UHDR irradiation. We characterized the dosimetric properties of a clinical linear accelerator configured to deliver ultra-high dose rate irradiation to two anatomic sites in mice and for cell-culture FLASH radiobiology experiments. Delivered doses of UHDR electron beams were controlled by a microcontroller and relay interfaced with the respiratory gating system. We also produced beam collimators with indexed stereotactic mouse positioning devices to provide anatomically specific preclinical treatments. Treatment delivery was monitored directly with an ionization chamber, and charge measurements were correlated with radiochromic film measurements at the entry surface of the mice. The setup for conventional dose rate irradiation utilized the same collimation system but at increased source-to-surface distance. Monte Carlo simulations and film dosimetry were used to characterize beam properties and dose distributions. The mean electron beam energies before the flattening filter were 18.8 MeV (UHDR) and 17.7 MeV (CONV), with corresponding values at the mouse surface of 17.2 and 16.2 MeV. The charges measured with an external ion chamber were linearly correlated with the mouse entrance dose. The use of relay gating for pulse control initially led to a delivery failure rate of 20% (±1 pulse); adjustments to account for the linac latency improved this rate to<1/20. Beam field sizes for two anatomically specific mouse collimators (4 × 4 cm2 for whole-abdomen and 1.5 × 1.5 cm2 for unilateral lung irradiation) were accurate within<5% and had low radiation leakage (<4%). Normalizing the dose at the center of the mouse (∼0.75cm depth) produced UHDR and CONV doses to the irradiated volumes with>95% agreement. We successfully configured a clinical linear accelerator for increased output and developed a robust preclinical platform for anatomically specific irradiation, with highly accurate and precise temporal and spatial dose delivery, for both CONV and UHDR irradiation applications.

Selecting the Best Pharmacokinetic Models for a Priori Model-Informed Precision Dosing with Model Ensembling.

When utilizing population pharmacokinetic (popPK) models for a priori dosage individualization, selecting the best model is crucial to obtain adequate doses. We developed and evaluated several model-selection and ensembling methods, using external evaluation on the basis of therapeutic drug monitoring (TDM) samples to identify the best (set of) models per patient for a priori dosage individualization. PK data and models describing both hospitalized patients (n = 134) receiving continuous vancomycin (26 models) and patients (n = 92) receiving imatinib in an outpatient setting (12 models) are included. Target attainment of four model-selection methods was compared with standard dosing: the best model based on external validation, uninformed model ensembling, model ensembling using a weighting scheme on the basis of covariate-stratified external evaluation, and model selection using covariates in decision trees that were subsequently ensembled. Overall, the use of PK models improved the proportion of patients exposed to concentrations within the therapeutic window for both cohorts. Relative improvement of proportion on target for best model, unweighted, weighted, and decision trees were - 7.0%, 2.3%, 11.4%, and 37.0% (vancomycin method-development); 23.2%, 7.9%, 15.6%, and, 77.2% (vancomycin validation); 40.7%, 50.0%, 59.5%, and 59.5% (imatinib method-development); and 19.0%, 28.5%, 38.0%, and 23.8% (imatinib validation), respectively. The best (set of) models per patient for a priori dosage individualization can be identified using a relatively small set of TDM samples as external evaluation. Adequately performing popPK models were identified while also excluding poor-performing models. Dose recommendations resulted in more patients within the therapeutic range for both vancomycin and imatinib. Prospective validation is necessary before clinical implementation.

Radiation Therapy in the Management of Head and Neck Mucosal Melanoma.

Mucosal melanoma of the head and neck (HNMM) is a rare but highly aggressive malignancy, often diagnosed at an advanced stage with poor prognosis. This review discusses current treatment strategies, emphasizing the role of radiotherapy in managing this challenging disease. A comprehensive analysis of 33 studies provides updated information on techniques and outcomes, highlighting the consistent benefit of adjuvant radiation in improving local control. Advances in conformal techniques, such as intensity-modulated radiotherapy (IMRT), have significantly reduced toxicity rates. Preliminary data on proton and carbon ion therapies suggest the potential for further enhancement of the therapeutic ratio, despite limited availability. Although recent studies report 3-year local control rates as high as 90%, overall survival within the same time frame remains well below 50-60%, underscoring the need for continued improvement in systemic therapies to address the persistent issue of distant metastases.

Targeting Oxidative Stress: The Potential of Vitamin C in Protecting against Liver Damage after Electron Beam Therapy.

Background: Radiation-induced liver disease (RILD) is a severe complication arising from radiotherapy, particularly when treating abdominal malignancies such as hepatocellular carcinoma. The liver's critical role in systemic metabolism and its proximity to other abdominal organs make it highly susceptible to radiation-induced damage. This vulnerability significantly limits the maximum safe therapeutic dose of radiation, thereby constraining the overall efficacy of radiotherapy. Among the various modalities, electron beam therapy has gained attention due to its ability to precisely target tumors while minimizing exposure to surrounding healthy tissues. However, despite its advantages, the long-term impacts of electron beam exposure on liver tissue remain inadequately understood, particularly concerning chronic injury and fibrosis driven by sustained oxidative stress. Objectives: to investigate the molecular and cellular mechanisms underlying the radioprotective effects of vitamin C in a model of radiation-induced liver disease. Methods: Male Wistar rats (n = 120) were randomly assigned to four groups: control, fractionated local electron irradiation (30 Gy), pre-treatment with vitamin C before irradiation, and vitamin C alone. The study evaluated the effects of electron beam radiation and vitamin C on liver tissue through a comprehensive approach, including biochemical analysis of serum enzymes (ALT, AST, ALP, and bilirubin), cytokine levels (IL-1β, IL-6, IL-10, and TNF-α), and oxidative stress markers (MDA and SOD). Histological and morphometric analyses were conducted on liver tissue samples collected at 7, 30, 60, and 90 days, which involved standard staining techniques and advanced imaging, including light and electron microscopy. Gene expression of Bax, Bcl-2, and caspase-3 was analyzed using real-time PCR. Results: The present study demonstrated that fractional local electron irradiation led to significant reductions in body weight and liver mass, as well as marked increases in biochemical markers of liver damage (ALT, AST, ALP, and bilirubin), inflammatory cytokines (IL-1β, IL-6, and TNF-α), and oxidative stress markers (MDA) in the irradiated group. These changes were accompanied by substantial histopathological alterations, including hepatocyte degeneration, fibrosis, and disrupted microvascular circulation. Pre-treatment with vitamin C partially mitigated these effects, reducing the severity of the liver damage, oxidative stress, and inflammation, and preserving a more favorable balance between hepatocyte proliferation and apoptosis. Overall, the results highlight the potential protective role of vitamin C in reducing radiation-induced liver injury, although the long-term benefits require further investigation. Conclusions: The present study highlights vitamin C's potential as a radioprotective agent against electron beam-induced liver damage. It effectively reduced oxidative stress, apoptosis, and inflammation, particularly in preventing the progression of radiation-induced liver fibrosis. These findings suggest that vitamin C could enhance radiotherapy outcomes by minimizing liver damage, warranting further exploration into its broader clinical applications.

Therapeutic drug monitoring-guided piperacillin dosing in critically ill patients undergoing continuous renal replacement therapy: a systematic review.

Continuous renal replacement therapy (CRRT) complicates antibiotic dosing in critically ill patients due to altered pharmacokinetics. The optimal dosing of piperacillin remains unclear. Therapeutic drug monitoring (TDM) can personalize piperacillin therapy and improve outcomes. This review investigates the effects of TDM-guided piperacillin dosing on pharmacokinetic target attainment and clinical outcomes in CRRT patients, analyses correlations with clinical outcomes, provides optimal dosing strategies for piperacillin and identifies future research areas. A systematic search of PubMed, Scopus and Web of Science was conducted until December 2023, identifying studies on piperacillin pharmacokinetics and clinical outcomes in adult CRRT patients. Data on study characteristics, piperacillin exposures, TDM use, target attainment rates, mortality and length of stay were extracted. The risk of bias was assessed using the Newcastle-Ottawa Scale. Eleven observational studies were included. High pharmacokinetic variability was evident, with piperacillin target non-attainment in up to 74% of cases without TDM. Two studies with routine TDM showed increased target attainment rates of 80%-100%. Mortality ranged from 17% to 56%, with supratherapeutic concentrations (≥100 mg/L) associated with higher mortality. The impact of optimized piperacillin exposures on outcomes was inconclusive. Most studies demonstrated a low risk of bias. TDM-guided piperacillin dosing in CRRT patients improved target attainment rates (≥80%). Mortality rates ranged from 17% to 56%, with inconsistent correlations between drug exposures and survival. Supratherapeutic concentrations were linked to higher mortality. Standardized TDM protocols are needed. Future research should establish clear exposure-response relationships and the impact of TDM on clinical outcomes.

Optimizing the individual dosing of paroxetine in major depressive disorder with therapeutic drug monitoring.

Previous studies have examined the correlation between paroxetine concentrations and therapeutic efficacy in patients diagnosed with major depressive disorder (MDD), but findings have been contradictory. This study aimed to investigate the relationships among plasma concentrations, severity of symptoms, and adverse drug reactions (ADRs) to optimize individual dosing. Eighty-seven MDD patients, after completing treatment with paroxetine, were divided into low-concentration (LC, n = 38), medium-concentration (MC, n = 27), and high-concentration (HC, n = 22) groups, based on cutoff value concentrations with the 50% response rate and the laboratory alert level from the 2017 consensus guidelines for therapeutic drug monitoring in neuropsychopharmacology. The severity of depression and anxiety was evaluated using a 17-item Hamilton Depression Scale (HAMD-17) and Hamilton Anxiety Scale (HAMA), respectively. Dosage, plasma concentrations, scale scores, and ADRs were recorded across the three groups at different treatment stages to define the therapeutic reference range. The 4-week plasma concentration of paroxetine (65.00 ng/mL) could predict the clinical response in MDD patients at 8 weeks. Symptom relief in patients with 4-week paroxetine concentrations ranging from 65.00 to 120.00 ng/mL at 8 weeks was greater than in those with concentrations below 65.00 ng/mL, with no significant difference observed above this range. In addition, more cases of liver injury and weight gain were observed in patients with high paroxetine concentrations. Our results support that early paroxetine concentration may predict clinical efficacy and the incidence of ADRs, thus improving individual dosing regimens for MDD patients.

A new strategy for monitoring of direct oral anticoagulants in patients with cyanotic and complex congenital heart disease

BackgroundPatients with congenital heart disease (CHD) often require an oral anticoagulation. Vitamin K antagonists (VKA) are the standard treatment, however, an increased hematocrit in patients with secondary erythrocytosis due to cyanosis complicates the correct measurement of the international normalized ratio. Direct oral anticoagulants (DOAC) could be an alternative, but data on their efficacy and safety in complex and cyanotic CHD patients are scarce. This study proposes a new strategy of DOAC monitoring in these patients using D-dimers and DOAC trough levels. MethodsThis is a retrospective study including cyanotic and complex CHD patients requiring oral anticoagulation. Clinical, cardiac imaging and laboratory data were collected before and after start of DOAC. The new monitoring strategy consists of determination of D-dimers and DOAC trough levels at 1–4 weeks, 1–6 months, 6–12 months, >1 year after start of DOAC. ResultsEleven patients were included. For 10 patients D-dimers and DOAC trough levels were in target range. In one patient, D-dimers increased continuously after start of DOAC despite dose escalation, suggesting insufficient DOAC efficacy and finally requiring a switch to VKA. D-dimers subsequently decreased under VKA to the therapeutic range. In three patients, one thromboembolic and two minor bleeding complications occurred. No major complications were observed. ConclusionsWe propose a new strategy of monitoring of oral anticoagulation with DOAC and report its implementation in clinical routine. Highlighting the importance of pharmacokinetic and -dynamic monitoring, this strategy could improve safety and efficacy of DOAC in cyanotic and complex CHD which, however, requires a prospective validation.

Influence of CYP2C9 phenotypes on phenytoin plasma concentration in neurosurgical Brazilian patients.

To investigate the association of CYP2C9 metabolic phenotypes with phenytoin plasma concentration ([PTH]) in neurosurgical patients from the Brazilian Public Health System. Patients (n = 170) were treated with phenytoin (300 mg/day) perioperatively as prophylaxis for postoperative seizures. Two to 10 days after surgery, a blood sample was collected for quantification of [PTH] and genotyping of CYP2C9*2 and *3 alleles. CYP2C9 metabolic phenotypes, NM (normal), IM (intermediate), and PM (poor) metabolizer, were inferred from CYP2C9 diplotypes. Linear regression modeling was applied to identify predictors of [PTH]. Wide (22-fold) interindividual variation in [PTH] was observed (2.2-47.5 mg/l). [PTH] associated significantly (Kruskal-Wallis P < 0.005) with CYP2C9 phenotypes and there was a significant trend (Jonckheere-Terpstra test, P < 0.0001) for [PTH] increase in the order NM < IM < PM. [PTH] was within the target therapeutic range (10-20 mg/l) in 34.7% of patients, while 39.4% and 25.9% had [PTH] below and above the range, respectively. CYP2C9 phenotypes associated significantly (chi-square P = 0.004) with the distribution of patients in [PHT] therapeutic categories and the Cramér's V test pointed to moderate magnitude of the effect of CYP2C9 phenotypes (V = 0.211). Diplotype-predicted CYP2C9 metabolic phenotypes are associated significantly with [PTH] in neurosurgical Brazilian patients receiving phenytoin for postsurgery seizure prophylaxis. [PHT] increased progressively in the phenotype order NM < IM < PM, and all PM patients had [PHT] above the target therapeutic range, consistent with the CPIC guideline 'strong' recommendation for phenytoin dosing adjustments in PMs.

Long-term outcomes following proton therapy for pediatric spinal low-grade glioma.

Due to its rarity, no standard treatment guidelines exist for pediatric spinal low-grade glioma (LGG-S). Proton therapy (PT) offers an attractive modality to minimize toxicity. Herein, we present the first published series of pediatric patients who received PT for progressive LGG-S. We identified eight consecutive patients with nonmetastatic LGG-S treated with PT. Cumulative incidence method was used to estimate local control (LC), freedom from distant metastases (FFDM), and freedom from progression (FFP). The Kaplan-Meier product limit method assessed overall survival (OS). Toxicity was assessed according to the Common Terminology Criteria for Adverse Events Version 5.0. Median age at diagnosis was 4 years. All patients underwent attempted resection and developed recurrence/progression prior to referral for PT, with median duration between initial surgery and PT of 4.4 years. Median age at the start of PT was 8 years. Most patients (n=5) received PT as ≥third line treatment. Seven patients were treated with PT to the primary tumor. Most patients (n=7) received between 45-50.4 CGE. Median follow up was 7.8 years. The 10-year estimates for LC, FFDM, FFP, and OS were 85, 88, 73, and 55%, respectively. One patient experienced malignant transformation and two developed pseudoprogression following PT. No pulmonary, gastrointestinal, or musculoskeletal toxicities were observed during or after PT. Despite negative selection bias our experience suggests PT for pediatric LGG-S offers long-term disease control with limited toxicity. The favorable therapeutic ratio of PT suggests it should be considered among first-line therapy in children with nonmetastatic, unresectable LGG-S.

Concentration-QTc analysis of soticlestat in healthy adults: An alternative to a thorough QT study.

This study aimed to examine the cardiac and overall safety and pharmacokinetic (PK) profiles of soticlestat (TAK-935), an oral, first-in-class selective cholesterol 24-hydroxylase inhibitor. Data came from a randomised, phase 1 study of soticlestat in 33 healthy Japanese adults (NCT04461483); 24 adults in Part 1 (single-dose soticlestat 200-1200 mg or placebo) and 9 in Part 2 (soticlestat 100-300 mg twice daily or placebo for 21 days). PK sample collection was paired with 12-lead electrocardiogram data from continuous Holter recordings. The concentration-QTc relationship was analysed using a linear mixed-effects model. QTc prolongation safety margins were determined for two scenarios of calculated high clinical exposures: scenario 1 (NCT05064449) involved coadministration of single-dose soticlestat 300 mg with itraconazole or mefenamic acid and scenario 2 (NCT05098054) involved single-dose soticlestat 300 mg administration in participants with mild/moderate hepatic impairment (implementing a 3-fold dose reduction for moderate severity). Based on concentration-QTc analysis, placebo-corrected change-from-baseline QT values (90% confidence intervals), corrected for heart rate (Fridericia's method), were 0.94 ms (-2.35, 4.23) for soticlestat and 0.63 ms (-3.15, 4.41) for its N-oxide metabolite plasma concentrations at therapeutic doses (soticlestat 300 mg twice daily); safety margins were >2-fold for scenarios of calculated high clinical exposures. No (Part 1) and five (83.3%; Part 2) participants experienced treatment-emergent adverse events (all mild). There was no evidence for QT prolongation with soticlestat at therapeutic doses or in two scenarios of high clinical exposures, which resulted in regulatory agencies waiving requirements of a thorough QT study. Safety/PK findings aligned with previous soticlestat clinical studies.

Lipoma: An Unusual Iodine-131 Uptake on Whole-Body Scanning: A Case Report

Whole-body radioiodine scintigraphy plays a major role in detecting metastases or recurrence of differentiated thyroid cancers. However, radioactive iodine uptake is not specific to thyroid tissue, and many physiological and pathological variants can bind radioactive iodine, resulting in false positives that can compromise the correct interpretation of results. We report the case of a 73-year-old patient with papillary thyroid carcinoma who underwent surgery 2 years ago, and whose whole-body scan, performed in the face of rising thyroglobulin levels, revealed abnormal fixation on the thigh, and further investigations suggested a lipoma. Our aim in reporting this case is to contribute to the knowledge of new false positives linked to iodine-131 fixation, in order to avoid unusual diagnostic errors that can lead to the unnecessary administration of therapeutic doses of iodine-131 or to aberrant surgical interventions.

Effects of Secondary Amine and Molecular Weight on the Biological Activities of Cationic Amphipathic Antimicrobial Macromolecules.

Cationic amphipathic antimicrobial agents inspired by antimicrobial peptides (AMPs) have shown potential in combating multidrug-resistant bacteria because of minimal resistance development. Here, this study focuses on the development of novel cationic amphipathic macromolecules in the form of dendrons and polymers with different molecular weights that employ secondary amine piperidine derivative as the cationic moiety. Generally, secondary amine compounds, especially at low molecular weights, have stronger bacteriostatic, bactericidal, and inner membrane disruption abilities than those of their primary amine counterparts. Low molecular weight D2 dendrons with two cationic centers and one hydrophobic dodecyl chain produce outstanding synergistic activity with the antibiotic rifampicin against Escherichia coli, where one-eighth of the standalone dose of D2 dendrons could reduce the concentration of rifampicin required by up to 4000-fold. The low molecular weight compounds are also less toxic and therefore have higher therapeutic index values compared to compounds with larger molecular weights. This study thus reveals key information that may inform the design of future synthetic AMPs and mimics, specifically, the design of low-molecular-weight compounds with secondary amine as the cationic center to achieve high antimicrobial potency and biocompatibility.

Exposure–response relationships of mirvetuximab soravtansine in patients with folate receptor‐α‐positive ovarian cancer: Justification of therapeutic dose regimen

AimsThis study aimed to investigate exposure–response (ER) relationships in efficacy and safety for mirvetuximab soravtansine (MIRV) which is a first‐in‐class antibody–drug conjugate approved for the treatment of folate receptor‐α‐positive platinum‐resistant ovarian cancer.MethodsMIRV was characterized in 4 clinical studies. Exposure metrics for MIRV, its payload and a metabolite were derived from a population pharmacokinetic model. Efficacy was analysed in MIRV‐treated patients (n = 215) in a recent confirmatory, randomized, chemotherapy‐controlled MIRASOL trial and safety was evaluated in patients pooled across all 4 clinical studies (n = 757).ResultsIn the MIRASOL trial (NCT04209855), MIRV demonstrated significant benefit over chemotherapy in progression‐free survival (PFS), objective response rate (ORR) and overall survival (OS). The most common adverse events (AEs) included ocular disorders, peripheral neuropathy and pneumonitis. For PFS, ORR and OS, the trough concentration of MIRV was the predictor consistently found in ER models for efficacy. In contrast, for ocular AEs (as well as the time to onset of ocular AEs) and peripheral neuropathy, the area under the concentration–time curve (AUC) of MIRV was identified as the exposure metric in ER models for safety. No exposure parameters were found to correlate with pneumonitis. Covariates in all models did not show clinically meaningful impact on efficacy or safety. Logistic regression models for ORR and ocular AEs based on AUC of MIRV were used to justify the clinical dose regimen approved for MIRV.ConclusionThe trough concentration of MIRV correlated with efficacy whereas the AUC of MIRV was associated with major AEs. The ER relationships supported the selected therapeutic dose regimen.