Narrow Therapeutic Window Research Articles

Enhancing Therapeutic Drug Monitoring in Indonesia: An Android-Based Pharmacokinetic Calculator for Amikacin

Pharmacokinetics employs complex mathematics to study, model, and predict how drugs are absorbed, distributed, metabolized, and excreted by the body. Amikacin, as a model drug with a narrow therapeutic window, requires Therapeutic Drug Monitoring (TDM) to ensure safety. This study developed an Android-based pharmacokinetic calculator, the "Indonesia Pharmacokinetic Calculator" (KFI), to assist clinical practitioners in quickly and accurately calculating pharmacokinetic parameters using patient weight and Amikacin doses as inputs. The application is designed to provide calculations of pharmacokinetic parameters, a pharmacokinetic simulation graph (plasma concentration-time curve), and predictions of individual patient amikacin plasma concentrations to assess therapeutic effectiveness and minimize toxicity risks. The rigorous testing process has demonstrated that KFI reliably produces expected output data, enhancing clinical pharmacy services in Indonesia through the integration of cutting-edge technology. This tool is expected to improve therapeutic outcomes, particularly for sepsis patients, by facilitating accurate and efficient pharmacokinetic calculations.

CLN-617 Retains IL2 and IL12 in Injected Tumors to Drive Robust and Systemic Immune-Mediated Antitumor Activity.

Despite clinical evidence of antitumor activity, the development of cytokine therapies has been hampered by a narrow therapeutic window and limited response rates. Two cytokines of high interest for clinical development are interleukin 2 (IL2) and interleukin 12 (IL12), which potently synergize to promote the activation and proliferation of T cells and NK cells. However, the only approved human IL2 therapy, Proleukin, is rarely used in the clinic due to systemic toxicities, and no IL12 product has been approved to date due to severe dose-limiting toxicities. Here, we describe CLN-617, a first-in-class therapeutic for intratumoral (IT) injection that co-delivers IL2 and IL12 on a single molecule in a safe and effective manner. CLN-617 is a single-chain fusion protein comprised of IL2, leukocyte-associated immunoglobulin-like receptor 2 (LAIR2), human serum albumin (HSA), and IL12. LAIR2 and HSA function to retain CLN-617 in the treated tumor by binding collagen and increasing molecular weight, respectively. We found that IT administration of a murine surrogate of CLN-617, mCLN-617, eradicated established treated and untreated tumors in syngeneic models, significantly improved response to anti-PD1 checkpoint therapy, and generated a robust abscopal response dependent on cellular immunity and antigen cross-presentation. CLN-617 is being evaluated in a clinical trial in patients with advanced solid tumors (NCT06035744).

Strategies for the development of stimuli-responsive small molecule prodrugs for cancer treatment.

Approved anticancer drugs typically face challenges due to their narrow therapeutic window, primarily because of high systemic toxicity and limited selectivity for tumors. Prodrugs are initially inactive drug molecules designed to undergo specific chemical modifications. These modifications render the drugs inactive until they encounter specific conditions or biomarkers in vivo, at which point they are converted into active drug molecules. This thoughtful design significantly improves the efficacy of anticancer drug delivery by enhancing tumor specificity and minimizing off-target effects. Recent advancements in prodrug design have focused on integrating these strategies with delivery systems like liposomes, micelles, and polymerosomes to further improve targeting and reduce side effects. This review outlines strategies for designing stimuli-responsive small molecule prodrugs focused on cancer treatment, emphasizing their chemical structures and the mechanisms controlling drug release. By providing a comprehensive overview, we aim to highlight the potential of these innovative approaches to revolutionize cancer therapy.

An N-terminal heptad repeat trimer-based peptide fusion inhibitor exhibits potent anti-H1N1 activity

Influenza viruses are susceptible to seasonal influenza, which has repeatedly caused global pandemics and jeopardized human health. Vaccines are only used as preventive medicine due to the extreme mutability of influenza viruses, and antiviral medication is the most significant clinical treatment to reduce influenza morbidity and mortality. Nevertheless, the clinical application of anti-influenza virus agents is characterized by the narrow therapeutic time window, the susceptibility to drug resistance, and relatively limited effect on severe influenza. Therefore, it is of great significance to develop novel anti-influenza virus drugs to fulfill the urgent clinical needs. Influenza viruses enter host cells through the hemagglutinin (HA) mediated membrane fusion process, and fusion inhibitors function antivirally by blocking hemagglutinin deformation, promising better therapeutic efficacy and resolving drug resistance, with targets different from marketed medicines. Previous studies have shown that unnatural peptides derived from Human Immunodeficiency Virus Type 1 (HIV-1) membrane fusion proteins exhibit anti-HIV-1 activity. Based on the similarity of the membrane fusion protein deformation process between HIV-1 and H1N1, we selected sequences derived from the gp41 subunit in the HIV-1 fusion protein, and then constructed N-trimer spatial structure through inter-helical isopeptide bond modification, to design the novel anti-H1N1 fusion inhibitors. The results showed that the novel peptides could block 6-HB formation during H1N1 membrane fusion procedure, and thus possessed significant anti-H1N1 activity, comparable to the positive control oseltamivir. Our study demonstrates the design viability of peptide fusion inhibitors based on similar membrane fusion processes among viruses, and furthermore provides an important idea for the novel anti-H1N1 inhibitors development.

A validated UPLC-MS/MS method for the quantification of immunosuppressive drugs in peripheral blood mononuclear cells using liquid-liquid extraction with low temperature purification without complex pretreatment steps

Immunosuppressive drugs (ISDs) are given to avoid the allograft rejection after transplantation. The concentrations of ISDs should be closely monitored owing to their wide inter-individual variability in its pharmacokinetics and narrow therapeutic window. Currently, the whole blood concentration measurement is the major approach of therapeutic drug monitoring of clinical ISDs in organ transplantation. Its correlation with the efficacy of ISDs remains elusive. While the acute rejection after transplantation may occur even when whole-blood ISDs concentrations are within the target range. Since the site of action of ISDs are within the lymphocyte, direct measurement of drug exposure in target cells may more accurately reflect the clinical efficacy of ISDs. Although several methods have been developed for the peripheral blood mononuclear cells (PBMCs) extraction and drug concentration measurement, the complex pre-processing has limited the study of the relationship between intracellular ISDs concentrations and the occurrence of rejection. In this study, the extraction of ISDs in PBMCs was carried out by the liquid-liquid extraction with low temperature purification, without centrifugation. The lower limit of quantitation were 0.2 ng/mL for cyclosporine A, tacrolimus and sirolimus, 1.0 ng/mL for mycophenolic acid, and the within-run and between-run coefficient of variations were both less than 12.4 %. The calibration curves of mycophenolic acid had a linear range (ng/mL): 1.0–128.0 (r2 = 0.9992). The calibration curves of other three ISDs had a linear range (ng/mL): 0.2–20.48 (r2 > 0.9956). A total of 157 clinical samples were analyzed by the UPLC-MS/MS for ISDs concentration in blood or plasma ([ISD]blood or plasma) and the concentration within PBMCs ([ISD]PBMC). Although there was strong association between [ISD]PBMC and [ISD]blood or plasma, the large discrepancies between concentration within [ISD]blood or plasma and [ISD]PBMC were observed in a small proportion of clinical samples. The developed method with short analysis time and little amounts of blood sample can be successfully applied to therapeutic drug monitoring of ISDs in PBMCs for analysis of large numbers of clinical samples and is helpful to explore the clinical value of ISDs concentration in PBMCs.

Reshaping tumor microenvironment by regulating local cytokines expression with a portable smart blue-light controlled device

Cytokines have attracted sustained attention due to their multi-functional cellular response in immunotherapy. However, their application was limited to their short half-time, narrow therapeutic window, and undesired side effects. To address this issue, we developed a portable smart blue-light controlled (PSLC) device based on optogenetic technology. By combining this PSLC device with blue-light controlled gene modules, we successfully achieved the targeted regulation of cytokine expression within the tumor microenvironment. To alter the tumor microenvironment of solid tumors, pro-inflammatory cytokines were selected as blue-light controlled molecules. The results show that blue-light effectively regulates the expression of pro-inflammatory cytokines both in vitro and in vivo. This strategy leads to enhanced and activated tumor-infiltrating immune cells, which facilitated to overcome the immunosuppressive microenvironment, resulting in significant tumor shrinkage in tumor-bearing mice. Hence, our study offers a unique strategy for cytokine therapy and a convenient device for animal studies in optogenetic immunotherapy.

Prodrug-inspired adenosine triphosphate-activatable celastrol-Fe(III) chelate for cancer therapy.

Celastrol (CEL), an active compound isolated from the root of Tripterygium wilfordii, exhibits broad anticancer activities. However, its poor stability, narrow therapeutic window and numerous adverse effects limit its applications in vivo. In this study, an adenosine triphosphate (ATP) activatable CEL-Fe(III) chelate was designed, synthesized, and then encapsulated with a reactive oxygen species (ROS)-responsive polymer to obtain CEL-Fe nanoparticles (CEL-Fe NPs). In normal tissues, CEL-Fe NPs maintain structural stability and exhibit reduced systemic toxicity, while at the tumor site, an ATP-ROS-rich tumor microenvironment, drug release is triggered by ROS, and antitumor potency is restored by competitive binding of ATP. This intelligent CEL delivery system improves the biosafety and bioavailability of CEL for cancer therapy. Such a CEL-metal chelate strategy not only mitigates the challenges associated with CEL but also opens avenues for the generation of CEL derivatives, thereby expanding the therapeutic potential of CEL in clinical settings.

Model-Informed Reinforcement Learning for Enabling Precision Dosing Via Adaptive Dosing.

Precision dosing, the tailoring of drug doses to optimize therapeutic benefits andminimize risks in each patient, is essential for drugs with a narrow therapeutic window and severe adverse effects. Adaptive dosing strategies extend the precision dosing concept to time-varying treatments which require sequential dose adjustments based on evolving patient conditions. Reinforcement learning (RL) naturally fits this paradigm: it perfectly mimics the sequential decision-making process where clinicians adapt dose administration based on patient response and evolution monitoring. This paper aims to investigate the potentiality of coupling RL with population PK/PD models to develop precision dosing algorithms, reviewing the most relevant works in the field. Case studies in which PK/PD models were integrated within RL algorithms as simulation engine to predict consequences of any dosing action have been considered and discussed. They mainly concern propofol-induced anesthesia, anticoagulant therapy with warfarin and a variety of anticancer treatments differing for administered agents and/or monitored biomarkers. The resulted picture highlights a certain heterogeneity in terms of precision dosing approaches, applied methodologies, and degree of adherence to the clinical domain. In addition, a tutorial on how a precision dosing problem should be formulated in terms of the key elements composing the RL framework (i.e., system state, agent actions and reward function), and on how PK/PD models could enhance RL approaches is proposed for readers interested in delving in this field. Overall, the integration of PK/PD models into a RL-framework holds great promise for precision dosing, but further investigations and advancements are still needed to address current limitations and extend the applicability of this methodology to drugs requiring adaptive dosing strategies.

Effect of early post-hematopoietic stem cell transplant tacrolimus concentration on transplant outcomes in pediatric recipients: One facility’s ten-year experience of immunosuppression with tacrolimus

Acute graft-versus-host disease (GVHD) is a common life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), ranking as the second leading cause of death among recipients, surpassed only by disease relapse. Tacrolimus is commonly used for GVHD prophylaxis, but achieving therapeutic blood levels is challenging, particularly in pediatrics, due to the narrow therapeutic window and the high interindividual variability. The retrospective study conducted at IRCCS “Burlo Garofolo” in Italy aimed to assess the impact of early post-HSCT tacrolimus levels on transplant-related outcomes in pediatric recipients. The population pharmacokinetic model (POP/PK) was set up to describe tacrolimus pharmacokinetics. Elevated tacrolimus (>12–15 ng/ml) levels within the initial weeks post-HSCT are associated with reduced post-transplant infections (p < 0.0001) and decreased incidence of early transplant-related events (p < 0.01), including a lower incidence of acute GVHD (p < 0.05 on day 0). High tacrolimus exposure can lead to an increased risk of chronic GVHD (p < 0.0001) and reduced overall survival (p < 0.01). Personalized dosing and therapeutic monitoring of tacrolimus are crucial to ensure optimal outcomes. POP/PK could help achieve this goal, giving us a model by which we can balance immunosuppression while looking at the patient’s general well-being and providing the necessary treatment.

New Predictive Equation for the Estimation of Plasma Concentrations of Formed Colistin in Patients Treated With Colistimethate Sodium for Multidrug-Resistant Gram-Negative Bacterial Infections.

The clinical use of colistin methanesulphonate (CMS) is limited by potential nephrotoxicity. The selection of an efficient and safe CMS dose for individual patients is complicated by the narrow therapeutic window and high interpatient pharmacokinetic variability. In this study, a simple predictive equation for estimating the plasma concentration of formed colistin in patients with multidrug and extremely drug-resistant gram-negative bacterial infections was developed. The equation was derived from the largest clinical cohort of patients undergoing therapeutic drug monitoring (TDM) of colistin for over 8 years in a tertiary Spanish hospital. All variables associated with C ss,avg were selected in a multiple linear regression model that was validated in a second cohort of 40 patients. Measured C ss,avg values were compared with those predicted by our model and a previous published algorithm for critically ill patients. In total, 276 patients were enrolled [the mean age was 67.2 (13.7) years, 203 (73.6%)] were male, and the mean (SD) C ss,avg was 1.12 (0.98) mg/L. Age, gender, estimated glomerular filtration rate, CMS dose and frequency, and concomitant drugs were included in the model. In the external validation, the previous algorithm appeared to yield more optimized colistin plasma concentrations when all types of C ss,avg values (high and low) were considered, while our equation yielded a more optimized prediction in the subgroup of patients with low colistin plasma concentrations (C ss,avg <1.5 mg/L). The proposed equation may help clinicians to better use CMS among a wide variety of patients, to maximize efficacy and prevent nephrotoxicity. A further prospective PK study is warranted to externally validate this algorithm.

Tumor-Localized Interleukin-2 and Interleukin-12 Combine with Radiation Therapy to Safely Potentiate Regression of Advanced Malignant Melanoma in Pet Dogs.

Cytokines IL2 and IL12 exhibit potent anticancer activity but suffer a narrow therapeutic window due to off-tumor immune cell activation. Engineering cytokines with the ability to bind and associate with tumor collagen after intratumoral injection potentiated response without toxicity in mice and was previously safe in pet dogs with sarcoma. Here, we sought to test the efficacy of this approach in dogs with advanced melanoma. This study examined 15 client-owned dogs with histologically or cytologically confirmed malignant melanoma that received a single 9-Gy fraction of radiotherapy, followed by six cycles of combined collagen-anchored IL2 and IL12 therapy every 2 weeks. Cytokine dosing followed a 3 + 3 dose escalation design, with the initial cytokine dose chosen from prior evaluation in canine sarcomas. No exclusion criteria for tumor stage or metastatic burden, age, weight, or neuter status were applied for this trial. Median survival regardless of the tumor stage or dose level was 256 days, and 10/13 (76.9%) dogs that completed treatment had CT-measured tumor regression at the treated lesion. In dogs with metastatic disease, 8/13 (61.5%) had partial responses across their combined lesions, which is evidence of locoregional response. Profiling by NanoString of treatment-resistant dogs revealed that B2m loss was predictive of poor response to this therapy. Collectively, these results confirm the ability of locally administered tumor-anchored cytokines to potentiate responses at regional disease sites when combined with radiation. This evidence supports the clinical translation of this approach and highlights the utility of comparative investigation in canine cancers.

Effects of Sex Differences and Combined Use of Clozapine on Initial Dosage Optimization of Valproic Acid in Patients with Bipolar Disorder.

Due to the narrow therapeutic window and large pharmacokinetic variation of valproic acid (VPA), it is difficult to make an optimal dosage regimen. The present study aims to optimize the initial dosage of VPA in patients with bipolar disorder. A total of 126 patients with bipolar disorder treated by VPA were included to construct the VPA population pharmacokinetic model retrospectively. Sex differences and combined use of clozapine were found to significantly affect VPA clearance in patients with bipolar disorder. The initial dosage of VPA was further optimized in male patients without the combined use of clozapine, female patients without the combined use of clozapine, male patients with the combined use of clozapine, and female patients with the combined use of clozapine, respectively. The CL/F and V/F of VPA in patients with bipolar disorder were 11.3 L/h and 36.4 L, respectively. It was found that sex differences and combined use of clozapine significantly affected VPA clearance in patients with bipolar disorder. At the same weight, the VPA clearance rates were 1.134, 1, 1.276884, and 1.126 in male patients without the combined use of clozapine, female patients without the combined use of clozapine, male patients with the combined use of clozapine, and female patients with the combined use of clozapine, respectively. This study further optimized the initial dosage of VPA in male patients without the combined use of clozapine, female patients without the combined use of clozapine, male patients with the combined use of clozapine, and female patients with the combined use of clozapine, respectively. This study is the first to investigate the initial dosage optimization of VPA in patients with bipolar disorder based on sex differences and the combined use of clozapine. Male patients had higher clearance, and the recommended initial dose decreased with increasing weight, providing a reference for the precision drug use of VPA in clinical patients with bipolar disorder.

Therapeutic Efficacy of Selenium Pre-treatment in Mitigating Cadmium-Induced Cardiotoxicity in Zebrafish (Danio rerio).

Cardiovascular diseases are a rampant public health threat. Environmental contaminants, such as Cadmium (Cd), a toxic metal, have been linked to increased risk for cardiovascular diseases. Given that human exposure to Cd is increasing overtime, there is a need to develop new therapies to ameliorate Cd toxicity. Selenium (Se), an essential trace element, has been proposed to rescue the effects of Cd toxicity, with mixed effects. Se's narrow therapeutic window necessitates precise dosing to avoid toxicity. Here, we assessed the effects of various waterborne Cd and Se concentrations and sequences on cardiac function using zebrafish (Danio rerio). We showed that Cd induced pericardial edemas and modified heart rates in a concentration-dependent manner. To identify the therapeutic range of Se for Cd-induced cardiotoxicity, zebrafish embryos were treated with 0, 10, 50, 100, 150, or 200 μg/L Se for 1-4 days prior to exposure to Cd at 2.5, and 5 μg/L. We found that a 50 μg/L Se pre-treatment prior to Cd at 2.5 μg/L, but not at 5 μg/L, reduced the prevalence of pericardial edemas and ameliorated Cd-induced bradycardia in zebrafish. Embryos exposed to 10 and 50 μg/L of Se showed typical heart morphology, whereas other Se-exposed and Se-deficient fish presented pericardial edemas. Longer Se pre-treatment durations led to fewer incidences of pericardial edemas. Overall, this study highlights the importance of optimizing Se concentration and pre-treatment periods to harness its protective effects against Cd-induced cardiotoxicity. These findings provide insights into potential therapeutic strategies for reducing Cd-related cardiovascular damage in humans.

Model-Informed individualized dosage regimen of sirolimus in pediatric patients with intractable lymphatic malformations

Intractable lymphatic malformations (iLM) pose a significant threat to affected children, demonstrating limited responses to conventional treatments. Sirolimus, effectively inhibiting endothelial cell proliferation in lymphatic vessels, plays a crucial role in iLM treatment. However, the drug's narrow therapeutic window and substantial interindividual variability necessitate customized dosing strategies. This study aims to establish a Population Pharmacokinetic Model (PopPK model) for sirolimus in pediatric iLM patients, identifying quantitative relationships between covariates and sirolimus clearance and volume of distribution. Initial dosages are recommended based on a target concentration range of 5–15 ng/mL. Retrospective data from our institution, encompassing 53 pediatric patients with 275 blood concentration results over the past five years (average age: 4.64 ± 4.19 years), constituted the foundation of this analysis. The final model, adopting a first-order absorption and elimination single-compartment model, retained age as the sole covariate. Results indicated a robust correlation between apparent clearance (CL/F) at 5.56 L/h, apparent volume of distribution (V/F) at 292.57 L, and age. Monte Carlo simulation guided initial dosages for patients aged 0–18 years within the target concentration range. This study presents the first PopPK model using a large Therapeutic Drug Monitoring (TDM) database to describe personalized sirolimus dosing for pediatric iLM patients, contributing to pharmacokinetic guidance and potentially improving long-term clinical outcomes.

Research Progress of Disulfide Bond Based Tumor Microenvironment Targeted Drug Delivery System.

Cancer poses a significant threat to human life and health. Chemotherapy is currently one of the effective cancer treatments, but many chemotherapy drugs have cell toxicity, low solubility, poor stability, a narrow therapeutic window, and unfavorable pharmacokinetic properties. To solve the above problems, target drug delivery to tumor cells, and reduce the side effects of drugs, an anti-tumor drug delivery system based on tumor microenvironment has become a focus of research in recent years. The construction of a reduction-sensitive nanomedicine delivery system based on disulfide bonds has attracted much attention. Disulfide bonds have good reductive responsiveness and can effectively target the high glutathione (GSH) levels in the tumor environment, enabling precise drug delivery. To further enhance targeting and accelerate drug release, disulfide bonds are often combined with pH-responsive nanocarriers and highly expressed ligands in tumor cells to construct drug delivery systems. Disulfide bonds can connect drug molecules and polymer molecules in the drug delivery system, as well as between different drug molecules and carrier molecules. This article summarized the drug delivery systems (DDS) that researchers have constructed in recent years based on disulfide bond drug delivery systems targeting the tumor microenvironment, disulfide bond cleavage-triggering conditions, various drug loading strategies, and carrier design. In this review, we also discuss the controlled release mechanisms and effects of these DDS and further discuss the clinical applicability of delivery systems based on disulfide bonds and the challenges faced in clinical translation.

The Influence of Genetic Polymorphisms on Warfarin Dosage Requirements in Cardiac Valve Surgery Patients

Aim: Warfarin, a widely prescribed anticoagulant, exhibits considerable variability in patient response, making its clinical use challenging due to a narrow therapeutic window. This study aimed to evaluate the prevalence of CYP2C9 and VKORC1 gene polymorphisms in a cohort of 87 Turkish patients who underwent cardiac valve surgery and received warfarin therapy, as well as to assess their impact on warfarin dosage requirements. Methods: The frequencies of CYP2C9 and VKORC1 polymorphisms were analyzed, and patients were stratified based on the presence or absence of mutations affecting warfarin dosing. Results: Revealed that patients carrying at least one CYP2C9 or VKORC1 polymorphism required a significantly lower weekly warfarin dose to achieve the optimal international normalized ratio (INR). Conclusion: This study highlights the critical role of genetic factors in determining warfarin dosage and supports the integration of pharmacogenetic testing into clinical practice to personalize warfarin therapy. Such an approach has the potential to enhance treatment outcomes and minimize the risk of adverse events. Further research involving larger sample sizes and diverse patient populations is warranted to validate these findings and refine the current understanding of the genetic determinants of warfarin dosing.

Assessment of the Functional Status of Patients after Ischemic Stroke Treated with Thrombolytic Therapy

Introduction. One of the most effective methods for treating acute ischemic stroke is thrombolytic therapy, which involves intravenous administration of recombinant tissue plasminogen activator (rtPA) within a narrow therapeutic window of up to 4.5 hours from symptom onset. Aim. The aim of this study was to assess the functional status of patients with ischemic stroke treated with thrombolytic therapy. Material and Methods. The study was conducted in the Neurological Department with a Stroke Subunit on a group of 90 patients hospitalized due to ischemic stroke and eligible for thrombolytic treatment. Functional status was assessed using the modified Rankin Scale, the National Institutes of Health Stroke Scale (NIHSS), and the Barthel Index on admission and at discharge from the hospital. Results. The mean scores on the modified Rankin Scale, NIHSS, and Barthel Index on admission were 4.3, 13.1, and 14.2, respectively. At discharge, the scores were 2.4, 6.0, and 59.5, respectively. Conclusions. Based on the conducted research, it was observed that thrombolytic therapy contributed to the improvement of functional status. (JNNN 2024;13(2):47–53)

Evaluation of the use and efficacy of prothrombin complex concentrates in patients presenting to the emergency department with warfarin

Aims: Warfarin administration has been a standard treatment for preventing thromboembolism in patients with atrial fibrillation prosthetic heart valves for many years. It is one of the leading drugs implicated in emergency room visits for adverse drug reactions. Because of a narrow therapeutic window, as many as 3% to 7% of patients taking warfarin are at risk of significant, life-threatening bleeding, and it is generally considered that this requires rapid and complete warfarin reversal. Although there are treatments such as vitamin K and fresh frozen plasma to reverse the effects of warfarin, the most effective method involves using prothrombin complex concentrates (PCC). This study aims to evaluate the use and efficacy of PCC in patients with warfarin-induced bleeding in the emergency department. Methods: The patients receiving PCC for warfarin reversal in the emergency department between January 1, 2019 – April 1, 2021, were identified from the hospital's electronic database. Demographic data, reasons for warfarin use, PCC indications, INR values before and after PCC, and mortality of the patients were evaluated. The four-factor PCC dose was determined according to the patient's body weight, admission INR level, and target INR level. The study was conducted with 73 patients. Results: The mean age of the patients was 69.3 ± 15.5 years. The female/male ratio was 1/1.5. The most common PCC indications were gastrointestinal bleeding (32.9%), urogenital bleeding (23.3%), epistaxis (12.3%), and urgent surgical need (12.3%), respectively. The median international normalized ratio (INR) before and after treatment with PCC was 9.2 (min-max 2.1-11.8) and 1.8 (min-max 1.0-4.6). The mean dose of PCC was 1500 IU (min-max 750-3250 IU). In addition to PCC, all patients received vitamin K; 17.8% received erythrocyte suspension, and 10.9% received fresh frozen plasma. There were no PCC-related complications in the emergency department. While 38.4% of the patients consulted the inpatient services after the emergency department, 5.5% were referred to an external center, and 56.2% were discharged from the emergency department after successful treatment. 26% of the patients were followed in the intensive care unit. No patient died in the emergency department. However, in-hospital mortality was 5.5%. Conclusion: Four-factor PCC is an effective and safe treatment for reversing warfarin-associated bleeding.

A Co-MOF encapsulated microneedle patch activates hypoxia induction factor-1 to pre-protect transplanted flaps from distal ischemic necrosis

Avoiding ischemic necrosis after flap transplantation remains a significant clinical challenge. Developing an effective pretreatment method to promote flap survival postoperatively is crucial. Cobalt chloride (CoCl2) can increase cell tolerance to ischemia and hypoxia condition by stimulating hypoxia-inducible factor-1 (HIF-1) expression. However, the considerable toxic effects severely limit the clinical application of CoCl2. In this study, cobalt-based metal-organic frameworks (Co-MOF) encapsulated in a microneedle patch (Co-MOF@MN) was developed to facilitate the transdermal sustained release of Co2+ for rapid, minimally invasive rapid pretreatment of flap transplantation. The MN patch was composed of a fully methanol-based two-component cross-linked polymer formula, with a pyramid structure and high mechanical strength, which satisfied the purpose of penetrating the skin stratum corneum of rat back to achieve subcutaneous vascular area administration. Benefiting from the water-triggered disintegration of Co-MOF and the transdermal delivery via the MN patch, preoperative damage and side effects were effectively mitigated. Moreover, in both the oxygen-glucose deprivation/recovery (OGD/R) cell model and the rat dorsal perforator flap model, Co-MOF@MN activated the HIF-1α pathway and its associated downstream proteins, which reduced reperfusion oxidative damage, improved blood supply in choke areas, and increased flap survival rates post-transplantation. This preprotection strategy, combining MOF nanoparticles and the MN patch, meets the clinical demands for trauma minimization and uniform administration in flap transplantation. Statement of significanceCobalt chloride (CoCl2) can stimulate the expression of hypoxia-inducible factor (HIF-1) and improve the tolerance of cells to ischemia and hypoxia conditions. However, the toxicity and narrow therapeutic window of CoCl2 severely limit its clinical application. Herein, we explored the role of Co-MOF as a biocompatible nanocage for sustained release of Co2+, showing the protective effect on vascular endothelial cells in the stress model of oxygen-glucose deprivation. To fit the clinical needs of minimal trauma in flap transplantation, a Co-MOF@MN system was developed to achieve local transdermal delivery at the choke area, significantly improving blood supply opening and flap survival rate. This strategy of two-step delivery of Co2+ realized the enhancement of biological functions while ensuring the biosafety.

The Clinical and Mutational Spectrum of Bardet-Biedl Syndrome in Saudi Arabia.

The retinal features of Bardet-Biedl syndrome (BBS) are insufficiently characterized in Arab populations. This retrospective study investigated the retinal features and genotypes of BBS in Saudi patients managed at a single tertiary eye care center. Data analysis of the identified 46 individuals from 31 families included visual acuity (VA), systemic manifestations, multimodal retinal imaging, electroretinography (ERG), family pedigrees, and genotypes. Patients were classified to have cone-rod, rod-cone, or generalized photoreceptor dystrophy based on the pattern of macular involvement on the retinal imaging. Results showed that nyctalopia and subnormal VA were the most common symptoms with 76% having VA ≤ 20/200 at the last visit (age: 5-35). Systemic features included obesity 91%, polydactyly 56.5%, and severe cognitive impairment 33%. The predominant retinal phenotype was cone-rod dystrophy 75%, 10% had rod-cone dystrophy and 15% had generalized photoreceptor dystrophy. ERGs were undetectable in 95% of patients. Among the 31 probands, 61% had biallelic variants in BBSome complex genes, 32% in chaperonin complex genes, and 6% had biallelic variants in ARL6; including six previously unreported variants. Interfamilial and intrafamilial variabilities were noted, without a clear genotype-phenotype correlation. Most BBS patients had advanced retinopathy and were legally blind by early adulthood, indicating a narrow therapeutic window for rescue strategies.