Optimal Regimen Research Articles

Solid ovarian tumor: A diagnostic and management dilemma

Abstract Pure Sertoli cell tumors (SCTs) are an uncommon type of ovarian sex cord–stromal tumor. The variety of symptoms, solid in nature and different histopathological presentation make it difficult the proper diagnosis and optimal treatment regimens in such tumor. Due to nonspecific clinical appearance, diagnosis is mistaken by ultrasound as fibroid or uterine mass. Intraoperative surprises and suspicious for malignancy due to the solid nature of the tumor lead to surgical management dilemma. The diagnosis is confirmed by histopathological examination only. The prognosis is excellent as most are detected in the early stages and surgical management is often curative in most cases. In this case, a 22 year old unmarried female presented to us with irregular periods for 5 years. Her trans-abdominal ultrasound revealed a solid hypoechoic mass of 5 x 6 centimeter size, in close approximate to the uterus on the right side, with probable diagnosis of broad ligament fibroid. On operative laparoscopy, uterus and left ovary was normal, the mass was originated from the right ovary, which was removed and its histopathological and immunohistochemistry report shows elevated alpha inhibin and steroidogenic factor 1 (SF 1) (Sex cord stromal marker) which is suggestive pure Sertoli cell tumor. There was no family/personal history of malignancy. She was treated with surgical resection and remains clear of disease. Prognostic indicators for SCTs include degree and type of heterologous element differentiation. Thorough characterization of such elements is crucial for adequate diagnosis and treatment.

Preclinical evaluation of cyclophosphamide and fludarabine combined with CD19 CAR-T in the treatment of B-cell hematologic malignancies in vivo.

Chimeric antigen receptor T (CAR-T) cell therapy has achieved marked therapeutic success in ameliorating hematological malignancies. However, there is an extant void in the clinical guidelines concerning the most effective chemotherapy regimen prior to chimeric antigen receptor T (CAR-T) cell therapy, as well as the optimal timing for CAR-T cell infusion post-chemotherapy. We employed cell-derived tumor xenograft (CDX) murine models to delineate the optimal pre-conditioning chemotherapy regimen and timing for CAR-T cell treatment. Furthermore, transcriptome sequencing was implemented to identify the therapeutic targets and elucidate the underlying mechanisms governing the treatment regimen. Our preclinical in vivo evaluation determined that a combination of cyclophosphamide and fludarabine, followed by the infusion of CD19 CAR-T cells five days subsequent to the chemotherapy, exerts the most efficacious therapeutic effect in B-cell hematological malignancies. Concurrently, RNA-seq data indicated that the therapeutic efficacy predominantly perturbs tumor cell metabolism, primarily through the inhibition of key mitochondrial targets, such as C-Jun Kinase enzyme (C-JUN). In summary, the present study offers critical clinical guidance and serves as an authoritative reference for the deployment of CD19 CAR-T cell therapy in the treatment of B-cell hematological malignancies.

Immune checkpoint inhibitors versus chemotherapy as second-line therapy for advanced oesophageal squamous cell carcinoma: a systematic review and economic evaluation.

Recently, several novel programmed cell death protein 1 (PD-1) inhibitors have been approved for second-line treating advanced or metastatic oesophageal squamous cell carcinoma (OSCC), including camrelizumab, nivolumab, pembrolizumab, sintilimab and tislelizumab. However, the optimal treatment regimen remained ambiguous. The purpose of this study was to investigate the efficacy, safety and economy of available PD-1 inhibitors to determine the optimal treatment from the Chinese healthcare system perspective. A systematic review and economic evaluation. A systematic review was undertaken utilizing PubMed, Web of Science, Cochrane Library, Embase and Scopus databases to identify eligible studies until 31 August 2023. Primary outcomes were progression-free survival (PFS), overall survival (OS) and adverse events (AEs). We also developed a partitioned survival model at 3-week intervals based on five clinical trials to predict long-term costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios for various treatment options. Direct medical costs and utility values were obtained from public drug bidding databases, clinical trials or published literature. The parameter uncertainties within the model were determined via one-way and probabilistic sensitivity analyses. Five randomized controlled trials involving 2837 patients were included in the analysis. Compared with other treatments examined, camrelizumab provided the best PFS benefits [hazard ratio (HR): 0.69, 95% confidence interval (CI): 0.56-0.86], and pembrolizumab provided the best OS benefits (HR: 0.55, 95% CI: 0.37-0.82). Nivolumab caused a relatively lower incidence of treatment-related AEs (HR: 0.10, 95% CI: 0.05-0.20) and grade 3-5 AEs (HR: 0.13, 95% CI: 0.08-0.21) than other immunotherapy regimens. In the economic evaluation, average 10-year costs ranged from $5,433.86 (chemotherapy) to $50,617.95 (nivolumab) and mean QALYs ranged from 0.55 (chemotherapy) to 0.82 (camrelizumab). Pembrolizumab was eliminated because of dominance. Of the remaining strategies, when the willingness-to-pay thresholds were 1, 2 and 3 times GDP per capita in 2022, sintilimab, tislelizumab and camrelizumab were the most cost-effective treatment options, respectively. Sintilimab might be the optimal treatment alternative for second-line therapy of advanced OSCC in China, followed by tislelizumab and camrelizumab. This study has been registered on the PROSPERO database with the registration number CRD42023495204.

Target Attainment and Population Pharmacokinetics of Nirmatrelvir/Ritonavir in Critically Ill Adult Patients.

The population pharmacokinetics of nirmatrelvir/ritonavir (NIR/RIT) has not yet been described for critically ill adult patient. This was a prospective observational population pharmacokinetic study of nirmatrelvir/ritonavir (NIR/RIT) in critically ill adult patients and identify optimal dosing regimens. The prescription of NIR/RIT is determined by the attending physician and ranges from 150mg/100mg to 300mg/100mg twice a day. Two to three serial blood samples were collected for each patient after the second doses. We developed and validated PK model for plasma NIR and plasma RIT. Monte Carlo dosing simulations were performed to assess target attainment. We analyzed 89 plasma samples from 31 adult patients. The data were best described by a one-compartment model. Among the covariates tested on pharmacokinetic parameters, creatinine clearance (CrCL) and area under curve (AUC) of RIT had a significant effect on apparent clearance (CL/F) of NIR. Mean (SD) parameters estimates for the absorption rate constant (Ka), apparent distribution (V/F) and CL/F were 0.42 (0.10) h-1. 36.5 (8.5) L, 3.6 (0.26) L/h, respectively. Dosing simulations showed that the target in vitro 90% effective concentration (EC90) was more likely to be achieved twice a day than once a day at the same daily dose of NIR. High CrCL, low AUC of RIT were associated with a reduced likelihood of NIR reaching the target EC90. Based on our dosing simulations, the initial dosage of NIR/RIT was 300mg/100mg twice a day in critically ill patients with CrCL>45 mL/min; When CrCL in critically ill patients is between 15 and 45 mL/min, NIR/RIT is 150mg/100mg twice a day. The maintenance dose is adjusted according to CrCL and AUC of RIT, with the dosages varying between 75mg/100mg and 300mg/100mg.

A study of qualitative correlations between crucial bio-markers and the optimal drug regimen of Type I lepra reaction: A deterministic approach

Abstract Mycobacterium leprae is a bacterium that causes the disease leprosy (Hansen’s disease), which is a neglected tropical disease. More than 2,00,000 cases are being reported per year worldwide. This disease leads to a chronic stage known as lepra reaction that majorly causes nerve damage of the peripheral nervous system leading to loss of organs. The early detection of this lepra reaction through the level of bio-markers can prevent this reaction occurring and the further disabilities. Motivated by this, we frame a mathematical model considering the pathogenesis of leprosy and the chemical pathways involved in lepra reactions. The model incorporates the dynamics of the susceptible Schwann cells, infected Schwann cells, and the bacterial load and the concentration levels of the bio-markers interferon- γ \hspace{0.1em}\text{interferon-}\hspace{0.1em}\gamma , tumor necrosis factor- α \hspace{0.1em}\text{tumor necrosis factor-}\hspace{0.1em}\alpha , IL (interleukin)- 10 \hspace{0.1em}\text{IL (interleukin)-}\hspace{0.1em}10 , IL- 12 \hspace{0.1em}\text{IL-}\hspace{0.1em}12 , IL- 15 \hspace{0.1em}\text{IL-}\hspace{0.1em}15 , and IL- 17 \hspace{0.1em}\text{IL-}\hspace{0.1em}17 . We consider a nine-compartment optimal control problem considering the drugs used in multi drug therapy (MDT) as controls. We validate the model using 2D heat plots. We study the correlation between the bio-markers levels and drugs in MDT and propose an optimal drug regimen through these optimal control studies. We use the Newton’s gradient method for the optimal control studies.

Population pharmacokinetics and individualized dosing of vancomycin for critically ill patients receiving continuous renal replacement therapy: the role of residual diuresis.

Background: Vancomycin dosing is difficult in critically ill patients receiving continuous renal replacement therapy (CRRT). Previous population pharmacokinetic (PopPK) models seldom consider the effect of residual diuresis, a significant factor of elimination, and thus have poor external utility. This study aimed to build a PopPK model of vancomycin that incorporates daily urine volume to better describe the elimination of vancomycin in these patients. Methods: We performed a multicenter retrospective study that included critically ill patients who received intermittent intravenous vancomycin and CRRT. The PopPK model was developed using the NONMEM program. Goodness-of-fit plots and bootstrap analysis were employed to evaluate the final model. Monte Carlo simulation was performed to explore the optimal dosage regimen with a target area under the curve of ≥400mg/Lh and 400-600mg/L h. Results: Overall, 113 observations available from 71 patients were included in the PopPK model. The pharmacokinetics could be well illustrated by a one-compartment model with first-order elimination, with the 24-h urine volume as a significant covariate of clearance. The final typical clearance was 1.05L/h, and the mean volume of distribution was 69.0L. For patients with anuria or oliguria, a maintenance dosage regimen of 750mg q12h is recommended. Conclusion: Vancomycin pharmacokinetics in critically ill patients receiving CRRT were well described by the developed PopPK model, which incorporates 24-h urine volume as a covariate. This study will help to better understand vancomycin elimination and benefit precision dosing in these patients.

Advancements in Bullous Pemphigoid Treatment: A Comprehensive Pipeline Update.

Bullous pemphigoid (BP) is a common autoimmune bullous disease affecting mainly the elderly, with rising incidence due to increased life expectancy. This disease is characterized by tense bullous lesions on normal or erythematous skin, accompanied by pruritus. BP pathogenesis involves autoantibodies against hemidesmosomal proteins BP180 and BP230, leading to detachment at the dermo-epidermal junction as well as blister formation. BP is associated with coexisting comorbidities and drug exposure, and its management often requires high doses or chronic use of systemic glucocorticoids, posing risks of adverse effects. This review focuses on novel treatment options for BP, exploring therapies targeting different immune pathways. Rituximab, a CD20 monoclonal antibody, depletes B-lymphocytes and has shown efficacy in severe cases. Dupilumab, targeting interleukin (IL)-4 receptor α and thus blocking IL-4 and IL-13, downregulates type 2 helper (Th2) responses and has demonstrated promising results. Targeting eosinophil-related molecules using bertilimumab and AKST4290 has yielded positive results in clinical trials. Omalizumab, an immunoglobulin (Ig)E antibody, can reduce disease severity and allows corticosteroid tapering in a number of cases. Complement inhibitors such as nomacopan and avdoralimab are being investigated. IL-17 and IL-23 inhibitors such as secukinumab and tildrakizumab have shown potential in a limited number of case reports. Neonatal Fc receptor antagonists such as efgartigimod are under investigation. Additionally, topical therapies and Janus kinase inhibitors are being explored as potential treatments for BP. These novel therapies offer promising alternatives for managing BP, with potential to improve outcomes and reduce high cumulative doses of systemic corticosteroids and related toxicities. Further research, including controlled clinical trials, is needed to establish their efficacy, safety, and optimal dosing regimens for BP management.

Potential for intramyocardial fibrosis detection based on estimation of extracellular volume using dual-energy computed tomography

An increase in left ventricular (LV) extracellular volume (ECV) is an important parameter of LV morphology and is considered synonymous with myocardial fibrosis, as well as a reliable marker of myocardial injury and impaired cardiac function. Accurate methods for detecting and assessing myocardial fibrosis are very important for clinical practice. The current standard for myocardial fibrosis imaging is delayed gadolinium enhanced cardiac magnetic resonance imaging (MRI) or T1 mapping, but these techniques have limitations. They can be avoided by using dual-energy computed tomography (DECT), which makes it possible to identify myocardial fibrosis, including small-focal fibrosis, in two different ways (subtraction technique and iodine density measurement technique). The literature analysis carried out by the authors showed good comparability of MRI and DECT results in determining ECV in patients with various heart diseases of both ischemic and non-ischemic nature, including cardiomyopathies, aortic stenosis, pulmonary hypertension, sarcoidosis, and amyloidosis. In addition, the use of DECT to identify myocardial fibrosis is also possible if cardiac inflammation is suspected. In addition to evaluating the effectiveness of DECT compared with MRI, different scanning protocols were analyzed, since there is currently no consensus on the optimal contrast administration regimen. The issue of radiation exposure in modern DECT scanners is also separately considered. The authors showed that DECT is an important tool for determining ECV, which is of interest for clinical practice.

Initial Chemotherapy for Locally Advanced and Metastatic NUT Carcinoma

IntroductionNUT carcinoma (NC) is an underdiagnosed and aggressive poorly differentiated or squamous cell cancer. A subset of NC is sensitive to chemotherapy, but the optimal regimen is unknown. Experts have recommended platinum- and ifosfamide-based therapy based on case reports. MethodsPatients with pathologically confirmed NC with known survival outcomes after chemotherapy and consented to participate in a worldwide registry were studied. Results were summarized using descriptive methods. ResultsThe study included 118 patients with NC. Median age was 34 (range: 1–82) years, 39% were women, and 61% harbored a BRD4::NUTM1 fusion. Patients received platinum (74%) or ifosfamide (26%, including regimens with both, 13%).Of 62 patients with nonmetastatic disease, 40% had a thoracic primary. Compared with platinum-based chemotherapy, patients who received ifosfamide-based chemotherapy had nominally higher progression-free survival (12 mo: 59% [95% CI: 32–87] versus 37% [95% CI: 22–52], hazard ratio = 0.68 [0.32, 1.42], p = 0.3) but not overall survival (OS). Among the 56 patients with metastatic disease, 80% had a thoracic primary. Ifosfamide had an objective response rate (ORR) of 75% (six of eight) and platinum had an ORR of 31% (11 of 36). Nevertheless, there was no difference in progression-free survival or OS.The 3-year OS of the entire cohort was 19% (95% CI: 10%–28%). Of the 11 patients alive greater than 3 years, all presented with nonmetastatic and operable or resectable disease. ConclusionThere is a numerically higher ORR for ifosfamide-based therapy compared with platinum-based therapy, with limited durability. OS at 3 years is only 19%, and development of effective therapies is an urgent unmet need for this patient population.

Approaches to Selection of Optimal Chemotherapy Regimens in Tuberculosis Patients with Concurrent Diabetes Mellitus

The objective: to develop approaches to selection of optimal chemotherapy regimens in tuberculosis patients with concurrent diabetes mellitus (DM), by studying complications of diabetes mellitus and adverse drug reactions to anti-tuberculosis drugs.Subjects and Methods. 235 adult pulmonary tuberculosis patients with concurrent diabetes were enrolled in the study. Of them, 123 were men (52.3%) and 112 were women (47.7%), and the age of the patients varied from 19 to 78 years old.Results. Complications of diabetes mellitus (DM) were reported in 190/235 (80.8%) patients. Encephalopathy occurred most often – in 147/190 (77.3%) patients, diabetic macroangiopathy developed less often - in 41 (21.6%), followed by diabetic retinopathy – in 20 (10.5%), diabetic nephropathy - in 11 (5.8%), ketoacidosis – in 4 (2.1%), and diabetic foot – in 4 (2.1%). Diabetic macroangiopathy was significantly more often observed in men (66.7%) versus women (31.7%); p<0.01, and diabetic nephropathy was more common in women (81.8%) than men (18.2%); p<0.01. As the age of patients and duration of diabetes increased, the incidence of complications of diabetes also increased. Adverse drug reactions (ADRs) to anti-tuberculosis drugs (TB drugs) occurred in 168/235 (71.4%) patients. ADRs to two or more TB drugs were registered in 140/168 (83.3%) patients. The most frequent irreversible ADRs were caused by the following drugs (of the number of patients taking them): aminoglycosides (58.8%), capreomycin (54.5%), PAS (50.0%), ethambutol (100.0%), cycloserine (40.0%), levofloxacin (33.3%), pyrazinamide (23.3%), terizidone (28.6%), prothionamide (26.3%), linezolid (21.4% ), and moxifloxacin (20.0%).Conclusion. When treating pulmonary tuberculosis in patients with diabetes mellitus, chemotherapy regimens containing aminoglycosides, capreomycin, prothionamide, and pyrazinamide should be avoided. If there is even an initial stage of retinopathy, ethambutol should be avoided. Patients with encephalopathy should be switched from cycloserine to terizidone.

Physicochemical and Organoleptic Characteristics of Velva Guava Crystal with the Addition of Combrang Juice and CMC

This research aims to ascertain the impact of CMC and kecombrang fruit juice addition on crystal guava Velva's organoleptic and physicochemical properties and the optimal treatment regimen to yield velva with the best properties. The two-factor factorial pattern utilized in this study's fully randomized design (CRD) has three repetitions. Factor I include 5%, 10%, and 15% of kecombrang fruit juice (v/v). Factor II, namely the addition of 0.5%, 0.75%, and 1% CMC. The conclusion in this study was 15% kecombrang fruit juice and 1% CMC concentration, which produced crystal guava velva with an antioxidant activity value of 41.543%; crude fiber content 6.270%; melting time 17.37 minutes/20gr; viscosity 4203 mPas; overrun 22.03 %; total solids 39.06 %; and the hedonic organoleptic test includes color 3.63; aroma 3.10; texture 3.73 and taste 3.27. The conclusion of this study shows that velva guava crystal has met the quality standards of velva.

Machine Learning-Led Optimization of Combination Therapy: Confronting the Public Health Threat of Extensively Drug Resistant Gram-Negative Bacteria.

Developing optimized regimens for combination antibiotic therapy is challenging and often performed empirically over many clinical studies. Novel implementation of a hybrid machine-learning pharmacokinetic/pharmacodynamic/toxicodynamic (ML-PK/PD/TD) approach optimizes combination therapy using human PK/TD data along with in vitro PD data. This study utilized human population PK (PopPK) of aztreonam, ceftazidime/avibactam, and polymyxin B along with in vitro PDs from the Hollow Fiber Infection Model (HFIM) to derive optimal multi-drug regimens de novo through implementation of a genetic algorithm (GA). The mechanism-based PD model was constructed based on 7-day HFIM experiments across 4 clinical, extensively drug resistant Klebsiella pneumoniae isolates. GA-led optimization was performed using 13 different fitness functions to compare the effects of different efficacy (60%, 70%, 80%, or 90% of simulated subjects achieving bacterial counts of 102 CFU/mL) and toxicity (66% of simulated subjects having a target polymyxin B area under the concentration-time curve [AUC] of 100 mg·h/L and aztreonam AUC of 1,332 mg·h/L) on the optimized regimen. All regimens, except those most heavily weighted for toxicity prevention, were able to achieve the target efficacy threshold (102 CFU/mL). Overall, GA-based regimen optimization using preclinical data from animal-sparing in vitro studies and human PopPK produced clinically relevant dosage regimens similar to those developed empirically over many years for all three antibiotics. Taken together, these data provide significant insight into new therapeutic approaches incorporating ML to regimen design and treatment of resistant bacterial infections.

Efficacy and safety of glucocorticoids use in patients with COVID-19: a systematic review and network meta‑analysis

BackgroundCurrently, some meta-analyses on COVID-19 have suggested that glucocorticoids use can reduce the mortality rate of COVID-19 patients, utilization rate of invasive ventilation, and improve the prognosis of patients. However, optimal regimen and dosages of glucocorticoid remain unclear. Therefore, the purpose of this network meta-analysis is to analyze the efficacy and safety of glucocorticoids in treating COVID-19 at regimens.MethodsThis meta-analysis retrieved randomized controlled trials from the earliest records to December 30, 2022, published in PubMed, Embase, Cochrane Library, CNKI Database and Wanfang Database, which compared glucocorticoids with placebos for their efficacy and safety in the treatment of COVID-19, Effects of different treatment regimens, types and dosages (high-dose methylprednisolone, very high-dose methylprednisolone, Pulse therapy methylprednisolone, medium-dose hydrocortisone, high-dose hydrocortisone, high-dose dexamethasone, very high-dose dexamethasone and placebo) on 28-day all-caused hospitalization mortality, hospitalization duration, mechanical ventilation requirement, ICU admission and safety outcome were compared.ResultsIn this network meta-analysis, a total of 10,544 patients from 19 randomized controlled trials were finally included, involving a total of 9 glucocorticoid treatment regimens of different types and dosages. According to the analysis results, the 28-day all-cause mortality rate was the lowest in the treatment with pulse therapy methylprednisolone (OR 0.08, 95% CI 0.02, 0.42), but the use of high-dose methylprednisolone (OR 0.85, 95% CI 0.59, 1.22), very high-dose dexamethasone (OR 0.95, 95% CI 0.67, 1.35), high-dose hydrocortisone (OR 0.64, 95% CI 0.34, 1.22), medium-dose hydrocortisone (OR 0.80, 95% CI 0.49, 1.31) showed no benefit in prolonging the 28-day survival of patient. Compared with placebo, the treatment with very high-dose methylprednisolone (MD = -3.09;95%CI: -4.10, -2.08) had the shortest length of hospital stay, while high-dose dexamethasone (MD = -1.55;95%CI: -3.13,0.03) and very high-dose dexamethasone (MD = -1.06;95%CI: -2.78,0.67) did not benefit patients in terms of length of stay.ConclusionsConsidering the available evidence, this network meta‑analysis suggests that the prognostic impact of glucocorticoids in patients with COVID-19 may depend on the regimens of glucocorticoids. It is suggested that pulse therapy methylprednisolone is associated with lower 28-day all-cause mortality, very high-dose methylprednisolone had the shortest length of hospital stay in patients with COVID-19.Trial registrationPROSPERO CRD42022350407 (22/08/2022).

Mitochondrion-targeted carboxymethyl chitosan hybrid nanoparticles loaded with Coenzyme Q10 protect cardiac grafts against cold ischaemia‒reperfusion injury in heart transplantation

BackgroundHeart transplantation (HT) has been approved as an optimal therapeutic regimen for patients with terminal-stage cardiac failure. However, cold ischaemia‒reperfusion (I/R) injury remains an unavoidable and outstanding challenge, which is a major factor in early graft dysfunction and an obstacle to long-term survival in HT. Cold I/R injury induces cardiac graft injury by promoting mitochondrial dysfunction and augmenting free radical production and inflammatory responses. We therefore designed a mitochondrion-targeted nanocarrier loaded with Coenzyme Q10 (CoQ10) (CoQ10@TNPs) for treatment of cold I/R injury after cardiac graft in a murine heterotopic cardiac transplantation model.MethodsHybrid nanoparticles composed of CaCO3/CaP/biotinylated-carboxymethylchitosan (CaCO3/CaP/BCMC) were synthesized using the coprecipitation method, and the mitochondria-targeting tetrapeptide SS31 was incorporated onto the surface of the hybrid nanoparticles through biotin-avidin interactions. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) analysis were used for characterisation. In vitro, the hypoxia-reoxygenation model of H9c2 cells was employed to replicate in vivo cold I/R injury and treated with CoQ10@TNPs. The impact of CoQ10@TNPs on H9c2 cell injury was assessed by analysis of oxidative damage and apoptosis. In vivo, donor hearts (DHs) were perfused with preservation solution containing CoQ10@TNPs and stored in vitro at 4 °C for 12 h. The DHs were heterotopically transplanted and analysed for graft function, oxidative damage, apoptosis, and inflammatory markers 1 day post-transplantation.ResultsCoQ10@TNPs were successfully synthesized and delivered CoQ10 to the mitochondria of the cold ischaemic myocardium. In vitro experiments demonstrated that CoQ10@TNPs was taken up by H9c2 cells at 4 °C and localized within the mitochondria, thus ameliorating oxidative stress damage and mitochondrial injury in cold I/R injury. In vivo experiments showed that CoQ10@TNPs accumulated in DH tissue at 4 °C, localized within the mitochondria during cold storage and improved cardiac graft function by attenuating mitochondrial oxidative injury and inflammation.ConclusionsCoQ10@TNPs can precisely deliver CoQ10 to the mitochondria of cold I/R-injured cardiomyocytes to effectively eliminate mitochondrial reactive oxygen species (mtROS), thus reducing oxidative injury and inflammatory reactions in cold I/R-injured graft tissues and finally improving heart graft function. Thus, CoQ10@TNPs offer an effective approach for safeguarding cardiac grafts against extended periods of cold ischaemia, emphasizing the therapeutic potential in mitigating cold I/R injury during HT. These findings present an opportunity to enhance existing results following HT and broaden the range of viable grafts for transplantation.

The Impact of 131I-Metaiodobenzylguanidine as a Conditioning Regimen of Tandem High-Dose Chemotherapy and Autologous Stem Cell Transplantation for High-Risk Neuroblastoma.

The optimal conditioning regimen of tandem high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) for high-risk neuroblastoma (HR-NBL) has not been established. The efficacy of 131I-MIBG therapy is under exploration in newly diagnosed HR-NBL patients. Here, we compared the outcomes of tandem HDC/ASCT between the 131I-MIBG combination and non-MIBG groups. We retrospectively analyzed the clinical data of 33 HR-NBL patients who underwent tandem HDC/ASCT between 2007 and 2021 at the Seoul National University Children's Hospital. The median age at diagnosis was 3.6 years. 131I-MIBG was administered to 13 (39.4%) of the patients. Thirty patients (90.9%) received maintenance therapy after tandem HDC/ASCT, twenty-two were treated with isotretinoin ± interleukin-2, and eight received salvage chemotherapy. The five-year overall survival (OS) and event-free survival (EFS) rates of all patients were 80.4% and 69.4%, respectively. Comparing the 131I-MIBG combined group and other groups, the five-year OS rates were 82.1% and 79.7% (p = 0.655), and the five-year EFS rates were 69.2% and 69.6% (p = 0.922), respectively. Among the adverse effects of grade 3 or 4, the incidence of liver enzyme elevation was significantly higher in the non-131I-MIBG group. Although tandem HDC/ASCT showed promising outcomes, the 131I-MIBG combination did not improve survival rates.

Pharmacokinetics, Tissue Residues, and Withdrawal Times of Oxytetracycline in Rainbow Trout (Oncorhynchus mykiss) after Single- and Multiple-Dose Oral Administration.

The aim of this study was to compare the pharmacokinetics of oxytetracycline (OTC) following single- (60 mg/kg) and multiple-dose oral administrations (60 mg/kg, every 24 h for 7 days) in rainbow trout. It also aimed to determine bioavailability after a single dose and tissue residues and withdrawal times after multiple doses. This study was carried out on 420 rainbow trout at 9 ± 0.8 °C. This study was carried out in two stages: single-dose (intravascular and oral) and multiple-dose treatment. The OTC concentrations in plasma and tissues were measured by high-performance liquid chromatography and analyzed by a non-compartmental method. The withdrawal time (WT) was estimated using the WT 1.4 software. OTC exhibited a long terminal elimination half-life (t1/2ʎz) after IV and oral administration. The oral bioavailability of OTC was very low (2.80%). In multiple-dose treatment, t1/2ʎz, the area under the plasma concentration-time curve and peak plasma concentration increased significantly after the last day compared to the first day. OTC showed strong accumulation after multiple doses with a value of 5.33. OTC concentrations were obtained in the order liver > kidney > muscle+skin > plasma. At 9 ± 0.8 °C, the WT calculated for muscle+skin was 56 days for Europe and 50 days for China, respectively. The t1/2ʎz (68.94 h) and time (68 h) above the 1 µg/mL MIC following a single OTC dose may support the extension of the 24 h dosing interval following multiple dosing. However, further studies are required to determine the optimal dosage regimen in multiple-dose OTC treatment in the treatment of infections caused by susceptible pathogens.

Dose optimization of meropenem for critically ill patients by pharmacokinetic/ pharmacodynamic simulation

Recent pharmacokinetic/pharmacodynamic (PK/PD) studies revealed that prolonged infusion, especially continuous infusion could improve probability of target attainment (PTA) of meropenem. However, the implementation of continuous meropenem infusion in the clinical environment can be limited due to the solution’s instability, which results in a diminished effectiveness of the drug. The two-step infusion approach has been expected as a promising novel approach to address this issue. The aim of this study was to assess the probability of target attainment for finding the optimal dosage regimens of meropenem in critically ill patients. Monte Carlo simulation using Ehmann population pharmacokinetic model was performed to evaluate the following different intravenous infusion regimens including extended infusion (EI), continuous infusion (CI) and two-step infusion (TS) with three total daily doses (3g, 4.5g and 6g). The PK/PD target was defined as the probability of achieving a fractional time above the MIC of ≥ 98% on the first day of therapy. Subsequently, dosing regimens were suggested based on renal function which was estimated by the Cockcroft & Gault creatinine clearance (Clcr =10-30, 31-50, 51-70, 71-90, 91-130, and over 130 mL/min). Simulations also revealed that the 1000mg q8h EI regimen is suitable to reach MICs of 1 mg/L, regardless of the patient’s renal function. For higher MICs and up to 16 mg/L, continuous infusion therapy with a loading dose of 0.5 g and a maintenance dose of 3 g to 6 g per day should be considered in clinical practice. The two-step infusion approach did not demonstrate superior PTA compared to extended infusion therapy and was significantly lower than that of continuous infusion at the same dosage level.

A population pharmacokinetic model of methotrexate in Korean patients with haematologic malignancy.

This study was conducted to develop a population pharmacokinetic (PK) model of methotrexate in Korean patients with haematologic malignancy, identify factors affecting methotrexate PK, and propose an optimal dosage regimen for the Korean population. Data were retrospectively collected from 188 patients with acute leukaemia or non-Hodgkin's lymphoma who were admitted to Severance Hospital during the period from November 2005 to January 2016. Using demographic factors and laboratory results as potential covariates for PK parameters, model development was performed using NONMEM and optimal dosing regimens were developed using the final PK model. A two-compartment model incorporating body weight via allometry best described the data, yielding typical parameter values of 25.09 L for central volume of distribution ( ), 17.65 L for peripheral volume of distribution ( ), 12.89 L/h for clearance (CL) and 0.655 L/h for inter-compartmental clearance in a 50 kg patient. Covariate analyses showed that, at the weight of 50 kg, CL decreased by 0.11 L/h for each 1-year increase in age above 14 years old and decreased 0.8-fold when serum creatinine level doubled, indicating the importance of age-specific dose individualization in methotrexate treatment. Volume of distribution at steady state derived from PK parameters (= + ) was 0.85 L/kg, which was similar to those in the Western or Chinese populations. Optimal doses simulated from the final model successfully produced the PK measures close to the target chosen. The population PK model and optimal dosage regimens developed in this study can be used as a basis to achieve precision dosing in Korean patients with haematologic malignancy.

Antithrombotic Management for Transcatheter Aortic Valve Implantation.

There have been significant changes in the optimal antithrombotic regimen post transcatheter aortic valve implantation (TAVI) after the results of major clinical trials in the past few years. Given the clinical importance of the optimal antithrombotic therapy post TAVI, we performed a narrative description of the major clinical trials behind the scientific evidence supporting these changes, as well the current guideline recommendations and knowledge gaps. We performed a narrative description of the major clinical trials behind the scientific evidence supporting these changes. We used PubMed as a major source to collect the major clinical trials including the following key words: "transcatheter aortic valve replacement", "transcatheter aortic valve implantation", "antithrombotic", "antiplatelet" and "anticoagulation". We selected the major clinical trials on this topic. This is not a systematic review or meta-analysis. We describe the results of the major clinical trials on antithrombotic therapy post TAVI: POPULAR-TAVI A, POPULAR-TAVI B, ENVISAGE-TAVI AF, GALILEO, ATLANTIS and ADAPT-TAVR trials. Based on the results of these trials, single antiplatelet therapy is recommended post TAVI in patients without concomitant indication for oral anticoagulation or dual antiplatelet therapy, especially in elderly patients. In younger patients, it is advised to evaluate the patient's bleeding and thrombotic risk, and dual antiplatelet therapy may be reasonable in patients with a high thrombotic risk and low bleeding risk. In patients with a concurrent indication for oral anticoagulation or dual antiplatelet therapy, it is recommended to continue oral anticoagulation or dual antiplatelet therapy post TAVI. In most patients without concomitant indication for oral anticoagulation, single antiplatelet therapy is recommended post TAVI.

Antithrombotic Therapy after Percutaneous Left Atrial Appendage Closure: Evidence, Challenges and Future Directions.

Percutaneous left atrial appendage closure (LAAC) has been established in clinical practice as an attractive alternative to oral anticoagulation for preventing stroke in patients with atrial fibrillation and high bleeding risk. The devices approved in Europe and United States (US) for percutaneous LAAC contain metal and antithrombotic therapy is strongly recommended after their implantation to prevent apposition of thrombus on the atrial surface of the device during endothelialization. However, there is still uncertainty regarding the optimal antithrombotic drug regimen following device implantation in view of the incomplete understanding of the LAAC device healing process, the lack of randomized clinical trials comparing different antithrombotic agents after LAAC and the heterogeneous bleeding risk of patients undergoing LAAC. Thus, this review aims to evaluate the available evidence and the remaining challenges related to the post-LAAC antithrombotic regimens. Furthermore, common clinical scenarios associated with challenging management of antithrombotic therapy after LAAC and potential future directions, will be discussed.