Drug Administration Research Articles

Endpointsfor Pharmacotherapy Trials for AlcoholUse Disorder.

Alcoholuse disorder (AUD) is a debilitating disorder, yet currently approved pharmacotherapies to treat AUD are under-utilized. The three medications approved by the US Food and Drug Administration (FDA) for the indication of AUD are disulfiram, acamprosate, and naltrexone. The current landscape of pharmacotherapies for AUD suggests opportunities for improvement. Clinical trials investigating novel pharmacotherapies for AUD traditionally use abstinence-based drinking outcomes or no heavy drinking days as trial endpoints to determine the efficacy of pharmacotherapies. These outcomes are typically measured through patient self-report endorsements of their drinking. Apart from these traditional outcomes, there have been recent developments in novel endpoints for AUD pharmacotherapies. These novel endpoints include utilizing the World Health Organization (WHO) riskdrinking level reductions to promote a harm-reduction endpoint rather than an abstinence-based endpoint. Additionally, in contrast to patient self-report measurements, biological markers of alcohol use may serve as objective endpoints in AUD pharmacotherapy trials. Lastly, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) definition of recovery from AUD and patient-oriented outcomes offer new frameworks to consider endpoints associated with more than alcohol consumption itself, such as the provider-patient experiences with novel pharmacotherapies. These recent developments in new endpoints for AUD pharmacotherapies offer promising future opportunities for pharmacotherapy development, so long as validity and reliability measures are demonstrated for the endpoints. A greater breadth of endpoint utilization may better capture the complexity of AUD symptomatology.

A randomized phase III double-blind placebo-controlled trial of first-line chemotherapy and trastuzumab with or without bevacizumab for patients with HER2/neu-positive metastatic breast cancer: a trial of the ECOG-ACRIN Cancer Research Group (E1105).

In 2008, bevacizumab received accelerated Food and Drug Administration (FDA) approval for use in human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Based on the pre-clinical and preliminary clinical activity of the trastuzumab and bevacizumab combination, ECOG-ACRIN E1105 trial was developed to determine if the addition of bevacizumab to a chemotherapy and trastuzumab combination for first-line therapy would improve progression-free survival (PFS) in patients with HER2-positive MBC. 96 patients were randomized to receive standard first-line chemotherapy and trastuzumab with or without bevacizumab between November 2007 and October 2009, and 93 began protocol therapy. Induction therapy was given for 24weeks, followed by maintenance trastuzumab with or without bevacizumab. 60% (56/93) began carboplatin and 74% (69/93) completed 6 cycles of induction therapy. Primary endpoint was PFS. Median PFS was 11.1 and 13.8months for placebo and bevacizumab arms, respectively (hazard ratio [HR] 95%, Confidence Interval [Cl] for bevacizumab vs. placebo: 0.73 [0.43-1.23], p = 0.24), and at a median follow-up of 70.7months, median survival was 49.1 and 63months (HR [95% Cl] for OS: 1.09 [0.61-1.97], p = 0.75). The most common toxicities across both arms were neutropenia and hypertension, with left ventricular systolic dysfunction, fatigue, and sensory neuropathy reported more frequently with bevacizumab. In this trial, the addition of bevacizumab did not improve outcomes in patients with metastatic HER2-positive breast cancer. Although the trial was underpowered due to smaller than anticipated sample size, these findings corroborated other clinical trials during this time. NCT00520975.

Diabetic Neuropathy: A Guide to Pain Management.

Diabetic neuropathy is a common complication of diabetes mellitus (DM) and can affect up to 50% of DM patients during their lifetime. Patients typically present with numbness, tingling, pain, and loss of sensation in the extremities. Since there is no treatment targeting the underlying mechanism of neuropathy, strategies focus on preventative care and pain management. Up to 69% of patients with diabetic neuropathy receive pharmacological treatment for neuropathic pain. The United States Food and Drug Administration (FDA) confirmed four drugs for painful diabetic neuropathy (PDN): pregabalin, duloxetine, tapentadol, and the 8% capsaicin patch. Nonpharmacological treatments such as spinal cord stimulation (SCS) and transcutaneous electrical nerve stimulation (TENS) both show promise in reducing pain in DM patients. Despite the high burden associated with PDN, effective management remains challenging. This update covers the background and management of diabetic neuropathy, including its epidemiology, pathogenesis, preventative care, and current therapeutic strategies.

A simple Cox approach to estimating risk ratios without sharing individual-level data in multi-site studies.

Epidemiologic studies frequently use risk ratios to quantify associations between exposures and binary outcomes. When the data are physically stored at multiple data partners, it can be challenging to perform individual-level analysis if data cannot be pooled centrally due to privacy constraints. Existing methods either require multiple file transfers between each data partner and an analysis center (e.g., distributed regression) or only provide approximate estimation of the risk ratio (e.g., meta-analysis). Here we develop a practical method that requires a single transfer of eight summary-level quantities from each data partner. Our approach leverages an existing risk-set method and software originally developed for Cox regression. Sharing only summary-level information, the proposed method provides risk ratio estimates and confidence intervals identical to those that would be provided - if individual-level data were pooled - by the modified Poisson regression. We justify the method theoretically, confirm its performance using simulated data, and implement it in a distributed analysis of COVID-19 data from the U.S. Food and Drug Administration's Sentinel System.

Gamete and embryo donation guidance

This document provides the latest recommendations for the evaluation of potential sperm, oocyte, and embryo donors, as well as their recipients, incorporating recent information about optimal screening and testing for sexually transmitted infections, genetic diseases, and psychological assessments. This revised document incorporates recent information from the US Centers for Disease Control and Prevention, the US Food and Drug Administration, and the American Association of Tissue Banks, with which all programs offering gamete and embryo donation services must be thoroughly familiar, and replaces the document titled "Recommendations for gamete and embryo donation: a committee opinion," last published in2013.

The effect of anthelmintic treatment and efficacy on the faecal microbiota of healthy adult horses

Changes to the faecal microbiota of horses associated with administration of anthelmintic drugs is poorly defined. This study included horses with cyathostomin infection where susceptibility and resistance to oxfendazole and abamectin was known. This study assessed the changes to the faecal microbiota associated with administration of two different anthelmintics in this population. Twenty-four adult horses were included. Faecal egg counts were performed on all horses prior to random allocation into abamectin (n=8), oxfendazole (n=8) or Control groups (n=8) and at Day 14 post treatment. Faecal samples were collected for microbiota analysis prior to anthelmintic administration and on Day 3 and Day 14. From each faecal sample, DNA was extracted prior to PCR amplification, next generation sequencing and analysis using QIIME2. Anthelmintic treatment was associated with changes in alpha diversity (p <0.05), with increased evenness and diversity at Day 14 and increased richness at Day 3 within the abamectin group. Differences in relative abundance of bacteria at the phyla, family and genus taxonomic levels occurred after treatment; indicating that the microbiota was altered with anthelmintic administration. The results support that anthelmintic administration and removal of cyathostomins from the large intestine of horses is associated with changes in the faecal microbiota. The results suggest that removal of cyathostomins is associated with greater differences in microbiota, compared to anthelmintic drug administration that is ineffective in reducing cyathostomin infection. Cyathostomin removal was supported by adequate reduction of faecal egg counts, determined by faecal egg count reduction testing.

Seasonal increase in syphilis screening reactivity rates in whole blood donors, United States, 2011-2023.

In December 2021, the U.S. Food and Drug Administration published a letter to clinical laboratory staff and healthcare providers detailing a risk of false Rapid Plasma Reagin (RPR) when using the Bio-Rad Laboratories BioPlex 2200 Syphilis Total & RPR kit in people who had received COVID-19 vaccination; Treponema pallidum particle agglutination assays did not appear to be impacted by this issue. We evaluated reactivity rates of syphilis screening with negative confirmatory testing at our institution by year and seasonality. We performed a retrospective study of routine syphilis testing of whole blood (WB) collections at an academic hospital-based donor center in the eastern United States. All WB donations from 2011 to 2023 which demonstrated reactive syphilis screening (Beckman Coulter PK TP Microhemagglutination) with negative confirmatory testing (CAPTIA Syphilis (T. pallidum)-G) were evaluated. Reactivity rates by year and season of donation were compared using unpaired t-tests. A total of 109 WB donations from 86 unique donors who donated from 2011 to 2023 screened reactive for syphilis with negative confirmatory testing. The unconfirmed syphilis reactivity rate increased from 2018 to 2023 (mean: 0.360%) compared to 2011-2017 (mean: 0.071%, p < .05). An autumnal peak in unconfirmed reactives was observed. The unconfirmed syphilis reactivity rate among WB donors at our institution increased markedly since 2017 compared to the 7 years prior and doubled from 2020 to 2021. No testing assay changes explain these results. The autumnal peak in unconfirmed reactives suggests a possible environmental trigger such as viral infection or vaccination.

Implementation and early outcomes with Pathogen Reduced Cryoprecipitated Fibrinogen Complex.

Cryoprecipitated antihemophilic factor (cryo) has been used for fibrinogen replacement in actively bleeding patients, dysfibrinogenemia, and hypofibrinogenemia. Cryo has a shelf life of 4 to 6 hours after thawing and a long turnaround time in issuing the product, posing a major limitation of its use. Recently, the US Food and Drug Administration approved Pathogen Reduced Cryoprecipitated Fibrinogen Complex (INTERCEPT Fibrinogen Complex [IFC]) for the treatment of bleeding associated with fibrinogen deficiency, which can be stored at room temperature and has a shelf life of 5 days after thawing. We identified locations and specific end users with high cryoprecipitate utilization and waste. We partnered with our blood supplier to use IFC in these locations. We analyzed waste and turnaround time before and after implementation. Operative locations had a waste rate that exceeded nonoperative locations (16.7% vs 3%) and were targeted for IFC implementation. IFC was added to our inventory to replace all cryo orders from adult operating rooms, and waste decreased to 2.2% in these locations. Overall waste of cryoprecipitated products across all locations was reduced from 8.8% to 2.4%. The turnaround time for cryoprecipitated products was reduced by 58% from 30.4 minutes to 14.6 minutes. There has been a substantial decrease in waste with improved turnaround time after IFC implementation. This has improved blood bank logistics, improved efficiency of patient care, and reduced costly waste.

Design of point-of-care electrochemical sensor for therapeutic drug monitoring of ofloxacin in biological fluids

A disposable screen-printed sensor has been crafted specifically for therapeutic drug monitoring purposes, particularly for detecting ofloxacin in biological fluids. To enhance selectivity toward ofloxacin, a supramolecular calix [6] arene serves as the ionophore of choice. The sensor incorporates a graphene nanocomposite as an ion-to-electron transducer layer, which not only boosts potential stability but also mitigates potential drift. The developed ofloxacin sensor underwent rigorous characterization following IUPAC guidelines. The linearity range spans from 1 × 10–6 to 1 × 10–2 M, with a measured slope of 59.0 mV/decade. Impressively, it boasts a percentage recovery of 100.18 ± 1.60 and a low detection limit (LOD) of 6 × 10–7 M. Stability assessments indicate reliable performance over an extended period of 8 weeks. The versatility of this sensor extends to various applications, including the determination of ofloxacin in pharmaceutical formulations, bulk powder, and biological fluids. Notably, it has demonstrated efficacy post-bioanalysis validation, adhering to Food and Drug Administration regulations. This advancement holds promise for personalized therapeutic drug monitoring in clinical pharmacy studies and quality control laboratories, thereby optimizing patient care at the point-of-care.Graphical abstract

Development and validation of stability-indicating method of etrasimod by HPLC/DAD/MS/MS technique with greenness profiling

Etrasimod, a novel selective sphingosine-1-phosphate receptor modulator, was recently approved by the U.S. Food and Drug Administration and the European Medicinal Agency for the treatment of moderately to severely active ulcerative colitis in adults. In this research, the forced degradation study as an integral part of drug product and packaging development, which generates data on degradation mechanisms, is published. The development and validation of the stability-indicating method using a superior high-performance liquid chromatography technique coupled with a diode array detector and tandem mass spectrometer was performed to support the forced degradation study and monitor the formation of degradation products. Etrasimod demonstrated good stability under elevated temperature and basic stress conditions, while acidic hydrolysis, oxidative, and photolytic degradation produced eight degradation products. The knowledge of degradation products will be useful in the long-term stability study for establishing the acceptance criteria of etrasimod as a drug substance and dosage form during quality control and stability assessment. The eco-friendliness of the developed forced degradation procedure was evaluated using various greenness appraisal tools. The green metric tools showed that the forced degradation procedure obeys eco-friendly conditions.

Exploring the Relationship Between Atorvastatin and Memory Loss: A Comprehensive Analysis Integrating Real-World Pharmacovigilance and Mendelian Randomization.

Atorvastatin is a drug widely used to prevent cardiovascular and cerebrovascular diseases. Current observational studies suggest that atorvastatin may be associated with cognitive dysfunction (especially memory loss). However, some studies have suggested that dyslipidemia may be an important factor in cognitive dysfunction. The purpose of this study was to perform a pharmacovigilance analysis using real-world data from the US Food and Drug Administration's Adverse Event Reporting System (FAERS) to assess whether memory loss is an adverse effect of atorvastatin and to further clarify its causality through Mendelian randomization (MR). We extracted real-world data from the FAERS database (Quarter 1 2004 to Quarter 1 2023). Disproportionality analysis methods and measures of association such as the reporting odds ratio (OR), proportional reporting ratio, Bayesian confidence interval progressive neural network, and polynomial Gamma Poisson distribution reduction were used to assess whether memory loss was an adverse effect of atorvastatin. In addition, we used MR to evaluate causality in depth. In the pharmacovigilance analysis of atorvastatin, we extracted four datasets of clinical symptoms associated with memory loss from the FAERS database [Amnesia (n = 1196), Memory impairment (n = 840), Transient global amnesia (n = 38), and Retrograde amnesia (n = 9)]. The reporting OR, proportional reporting ratio, Bayesian confidence interval progressive neural network, and Gamma Poisson distribution reduction all showed positive results for amnesia, transient global amnesia, and retrograde amnesia, while the reporting OR and Bayesian confidence interval progressive neural network also showed positive results for memory disorders. Thus, memory loss was a frequent side effect of atorvastatin. The MR analyses were used to further evaluate the association between statins and memory loss. The results of the MR analysis (statins and memory loss) are as follows: Ivw (mre) (β = 0.11 [OR = 1.11], P = 0.01 < 0.05) and the OR and β directions of MR-Egger and weighted mode were the same. The results of the MR analysis (statins and mitochondrial DNA copy number) are as follows: Ivw(mre) (β = -0.03 [OR = 0.96], P < 0.01) and the OR and β direction of MR-Egger and weighted mode are the same. The results of the MR analysis (DNA copy number and memory loss) are as follows: Ivw(β = - 0.06 [OR = 0.94], P = 0.04 < 0.05) and the OR and β direction of MR-Egger and weighted mode were the same. The pleiotropy test did not find horizontal diversity in our results. This study suggests that memory loss is a notable adverse event associated with atorvastatin and provides evidence indicating a potential causal relationship between atorvastatin and memory loss. We also found that statins may further affect memory by affecting mitochondrial function. Therefore, in the clinical use of atorvastatin, it is important to carefully monitor the changes in cognitive function of patients. Second, a pharmacovigilance analysis combined with MR was used in this study to provide a new approach for the study of adverse drug reactions. This comprehensive analysis method helps to evaluate the safety of drugs and the risk of adverse reactions more comprehensively and provides doctors with a more accurate clinical decision-making basis.

Optimizing early phase clinical trial washout periods: a report from the therapeutic advances in childhood leukemia and lymphoma (TACL) consortium.

The National Cancer Institute (NCI) issued a 2021 memorandum adopting the American Society of Clinical Oncology (ASCO) and Friends of Cancer Research (Friends) task force recommendations to broaden clinical study eligibility criteria. They recommended that washout periods be eliminated for most prior cancer therapy and when required, to utilize evidence/rationale-based criteria. The Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) consortium responded to this guidance. A TACL task force reviewed the consortium's research portfolio, the relevant literature and guidance documents from ASCO-Friends, NCI, and US Food and Drug Administration (FDA) to make expert consensus and evidence-based recommendations for modernizing, broadening and codifying TACL-study washout periods while ensuring consistency with pediatric ethics and federal regulations. TACL's screening log was reviewed to estimate the impact that updated washout periods would have on patient inclusivity and recruitment. Over a 19-year period, 42 patients (14.6% of all screened ineligible (n = 287) patients), were identified as excluded from TACL early-phase studies exclusively due to not meeting washout criteria. An additional six (2.1%) did not meet washout and at least one other exclusion criterion. A new TACL washout guidance document was developed/adopted for use. Where washout criteria were not eliminated, rationale/evidenced-based criteria were established with citation. In an effort to reduce unnecessary exclusion from clinical trials, TACL created rationale/evidenced-based washout period standards largely following guidance from the NCI/ASCO-Friends recommendations. These new, expanded eligibility criteria are expected to increase access to TACL clinical trials while maintaining safety and scientific excellence.

Chronic pyogenic spondylitis in patients with spinal gout: a case series and literature review

Background. Spinal gout is a rare and poorly described group of noninfectious inflammatory spinal lesions characterized by the deposition of monosodium urate crystals in the epidural space, paravertebral soft tissues, and by facet joints damage. There is no systematized data on the course of infectious spondylitis and spinal gout in the literature. The aim of the study — to present long-term outcomes of surgical treatment of chronic pyogenic spondylitis in patients with spinal gout and systematize the literature data on the issue. Methods. The clinical part of the study included 6 consecutively operated patients in the period from 2018 to 2021. The diagnosis of spinal gout and chronic pyogenic spondylitis was verified according to the results of histologic and bacteriologic studies of surgical material. Catamnesis accounted for at least 12 months. We studied the peculiarities of clinical and laboratory, radiological and histologic manifestations of the disease. Literature data systematization was carried out in the databases PubMed, Google Scholar, eLIBRARY from 2013 to 2023. Inclusion criteria: level of evidence II B-IV, catamnesis more or equal to 6 months, information on diagnostic and treatment measures. Results. The average age of the patients was 55±9 years. The duration of the diagnostic pause was 8±5 years. Multisegmented lesions of the lumbar (n = 6) spine prevailed. According to the classification of Pola E. et al. (2017) the following types of spondylitis were identified: B.3 (n = 1), C.1 (n = 1), C.3 (n = 2) and C.4 (n = 2). The clinical manifestation was dominated by chronic back pain with an intensity of 6,1±1,4 VAS scores. Neurologic disorders of the lower extremities and pelvic (ASIA scale) corresponded to types B (n = 1) and C (n = 4). The type of surgery: three-column reconstruction through combined approach in 2 cases and isolated anterior column reconstruction in 2 cases, 360° fusion in 1 case, and debridement of the epidural space and anterior column through posterior approach in 1 case. The follow-up results show the absence of recurrence of spondylitis in 4 cases, in 2 patients there were postoperative complications that required revision, after which no recurrence of spondylitis was noted. We selected 17 publications for literature review. Conclusion. The combination of chronic pyogenic spondylitis and spinal gout is a rare and poorly described pathology in the literature. Long therapeutic pause, chronic character of vertebrogenic pain syndrome in combination with increased uric acid level and formation of tophi of vertebral localization are distinctive features of the disease. Neurologic disorders with the combination of spondylitis and gout result from stenosis of the spinal canal due to two factors — epidural abscesses and tophi. Achieving local control of the combined pathology is possible with a combination of surgical intervention and long-term administration of hypouricemic drugs.

Ionic Polymerization-Based Synthesis of Bioinspired Adhesive Hydrogel Microparticles with Tunable Morphologies from Microfluidics.

Shape-anisotropic hydrogel microparticles have attracted considerable attention for drug-delivery applications. Particularly, nonspherical hydrogel microcarriers with enhanced adhesive and circulatory abilities have demonstrated value in gastrointestinal drug administration. Herein, inspired by the structures of natural suckers, we demonstrate an ionic polymerization-based production of calcium (Ca)-alginate microparticles with tunable shapes from Janus emulsion for the first time. Monodispersed Janus droplets composed of sodium alginate and nongelable segments were generated using a coflow droplet generator. The interfacial curvatures, sizes, and production frequencies of Janus droplets can be flexibly controlled by varying the flow conditions and surfactant concentrations in the multiphase system. Janus droplets were ionically solidified on a chip, and hydrogel beads of different shapes were obtained. The in vitro and in vivo adhesion abilities of the hydrogel beads to the mouse colon were investigated. The anisotropic beads showed prominent adhesive properties compared with the spherical particles owing to their sticky hydrogel components and unique shapes. Finally, a novel computational fluid dynamics and discrete element method (CFD-DEM) coupling simulation was used to evaluate particle migration and contact forces theoretically. This review presents a simple strategy to synthesize Ca-alginate particles with tunable structures that could be ideal materials for constructing gastrointestinal drug delivery systems.

Lathyrol reduces the RCC invasion and incidence of EMT via affecting the expression of AR and SPHK2 in RCC mice

ObjectiveTo investigate the effects of Lathyrol on the expression of androgen receptor (AR) and sphingosine kinase 2 (SPHK2) in renal cell carcinoma (RCC) mice and to further explore the mechanism by which Lathyrol inhibits the invasion and incidence of epithelial-mesenchymal transition (EMT).MethodsAn RCC xenograft mouse model was constructed, and the mice were randomly divided into a model group, an experiment group and a negative control group. The experiment group was intragastrically gavaged with Lathyrol solution (20 mg/kg), the model group was intragastrically gavaged with 0.9% NaCl (same volume as that used in the experiment group), and the negative control group was injected intraperitoneally with 2 mg/kg cisplatin aqueous solution. Changes in the body weight and tumor volume of the mice were recorded. Western blot (WB) was used to assess the protein expression levels of AR, p-AR, CYP17A1, PARP1, E-cadherin, N-cadherin, vimentin, α-SMA, β-catenin, and ZO-1. Protein expression levels of SPHK2, metal matrix protease 2 (MMP2), MMP9 and urokinase-type plasminogen activator (uPA) in tumor tissues were assessed by immunohistochemistry (IHC). AR expression in tumor tissues was assessed after immunofluorescence (IF) staining.ResultsAfter 14 days of drug administration, compared with that in the model group, the tumor volumes in the negative control and experiment groups were lower; the difference in tumor volume among the model, control and experiment groups was statistically significant (P < 0.05). The differences in body weight among the three groups were not statistically significant (P > 0.05). In the model group, the protein expression levels of AR, p-AR, CYP17A1, SPHK2, and PARP1 were relatively increased, the protein expression levels of E-cadherin and ZO-1 were relatively reduced (P < 0.05), and the protein expression levels of N-cadherin, β-catenin, vimentin, and α-SMA were relatively increased (P < 0.05). In the negative control and experiment groups, the protein expression levels of AR, p-AR, CYP17A1, SPHK2, and PARP1 were relatively decreased (P < 0.05), the protein expression levels of E-cadherin and ZO-1 were relatively increased (P < 0.05), and the protein expression levels of N-cadherin, β-catenin, vimentin and α-SMA were relatively decreased (P < 0.05).ConclusionLathyrol and cisplatin inhibit the proliferation of RCC xenografts, reduce the protein expression levels of AR, CYP17A1, SPHK2, PARP1, E-cadherin, and ZO-1 in tumor tissues (P < 0.05), and promote the protein expression levels of N-cadherin, β-catenin, vimentin and α-SMA (P < 0.05). Therefore, Lathyrol reduces RCC invasion and EMT by affecting the expression of AR and SPHK2 in RCC mice.

Effect of impeller rotational phase on the FDA blood pump velocity fields.

The Food and Drug Administration (FDA) blood pump is an open-source benchmark cardiovascular device introduced for validating computational and experimental performance analysis tools. The time-resolved velocity field for the whole impeller has not been established, as is undertaken in this particle image velocimetry (PIV) study. The level of instantaneous velocity fluctuations is important, to assess the flow-induced rotor vibrations which may contribute to the total blood damage. To document these factors, time-resolved two-dimensional PIV experiments were performed that were precisely phase-locked with the impeller rotation angle. The velocity fields in the impeller and in the volute conformed with the previous single blade passage experiments of literature. Depending on the impeller orientation, present experiments showed that volute outlet nozzle flow can fluctuate up to 34% during impeller rotation, with a maximum standard experimental uncertainty of 2.2%. Likewise, the flow fields in each impeller passage also altered in average 33.5%. Considerably different vortex patterns were observed for different blade passages, with the largest vortical structures reaching an average core radii of 7 mm. The constant volute area employed in the FDA pump design contributes to the observed velocity imbalance, as illustrated in our velocity measurements. By introducing the impeller orientation parameter for the nozzle flow, this study considers the possible uncertainties influencing pump flow. Expanding the available literature data, analysis of inter-blade relative velocity fields is provided here for the first-time to the best of our knowledge. Consequently, our research fills a critical knowledge gap in the understanding of the flow dynamics of an important benchmark cardiovascular device. This study prompts the need for improved hydrodynamic designs and optimized devices to be used as benchmark test devices, to build more confidence and safety in future ventricular assist device performance assessment studies.

Nuclear-Based Labeling of Cellular Immunotherapies: A Simple Protocol for Preclinical Use.

Labeling and tracking existing and emerging cell-based immunotherapies using nuclear imaging is widely used to guide the preclinical phases of development and testing of existing and new emerging off-the-shelf cell-based immunotherapies. In fact, advancing our knowledge about their mechanism of action and limitations could provide preclinical support and justification for moving towards clinical experimentation of newly generated products and expedite their approval by the Food and Drug Administration (FDA).Here we provide the reader with a ready to use protocol describing the labeling methodologies and practical procedures to render different candidate cell therapies in vivo traceable by nuclear-based imaging. The protocol includes sufficient practical details to aid researchers at all career stages and from different fields in familiarizing with the described concepts and incorporating them into their work.

Hyaluronic acid modified indocyanine green nanoparticles: a novel targeted strategy for NIR-II fluorescence lymphatic imaging

The lymphatic system, alongside blood circulation, is crucial for maintaining bodily equilibrium and immune surveillance. Despite its importance, lymphatic imaging techniques lag behind those for blood circulation. Fluorescence imaging, particularly in the near-infrared-II (NIR-II) region, offers promising capabilities with centimeter-scale tissue penetration and micron-scale spatial resolution, sparking interest in visualizing the lymphatic system. Although indocyanine green (ICG) has been approved by the Food and Drug Administration (FDA) for use as a near-infrared-I (NIR-I) region fluorescent dye, its limitations include shallow penetration depth and low signal-to-noise ratio. Research suggests that ICG’s fluorescence emission tail in the second near-infrared window holds potential for high-quality NIR-II imaging. However, challenges like short circulation half-life and concentration-dependent aggregation hinder its wider application. Here we developed HA@ICG nanoparticles (NPs), a superior ICG-based NIR-II fluorescent probe with excellent biocompatibility, prolonging in vivo imaging, and enhancing photostability compared to ICG alone. Leveraging LYVE-1, a prominent lymphatic endothelial cell receptor that binds specifically to hyaluronic acid (HA), our nanoprobes exhibit exceptional performance in targeting lymphatic system imaging. Moreover, our findings demonstrate the capability of HA@ICG NPs for capillary imaging, offering a means to assess local microcirculatory blood supply. These compelling results underscore the promising potential of HA@ICG NPs for achieving high-resolution bioimaging of nanomedicines in the NIR-II window.

Pharmacokinetics of Trazodone in Hispaniolan Parrots (Amazona ventralis).

The objective of this study was to establish the pharmacokinetics of a single oral dose of trazodone in the Hispaniolan Amazon parrot (Amazona ventralis). Trazodone is a selective serotonin antagonist and reuptake inhibitor used commonly in both human and veterinary medicine as an antidepressant behavioral modification medicine. A single oral dose of compounded trazodone hydrochloride solution (20 mg/mL) at 50 mg/kg was administered to a total of 7 healthy adult Hispaniolan Amazon parrots. The 7 healthy adult parrots ranged in age from 10 to 15 years and weighed 228 to 323g. Blood was collected at baseline (2 weeks before study) and at 1, 2, 4, 6, 10, and 14 hours post-drug administration. Plasma concentrations of both trazodone and its active metabolite m-chlorophenylpiperazine (mCPP) were measured via liquid chromatography tandem mass spectrometry. Noncompartmental pharmacokinetic analysis was completed. The half-life (t1/2) ± SD of trazodone for the Hispaniolan parrots was 1.89 ± 0.49 hours, and the t1/2 ± SD of mCPP metabolite was 1.9 ± 0.55 hours. Maximum serum drug concentrations, or Cmax (ng/mL), were 738.3 ± 285.3 for trazodone. Times to achieve Cmax (hours) for trazadone and the mCPP metabolite were 1 hour and 2 hours postdosing, respectively. While this study did not establish the behavioral effects of trazodone, no adverse side effects were observed throughout the 48-hour period following drug administration and blood collection. Our results indicate that the oral administration of a 50-mg/kg single dose of trazodone to Hispaniolan parrots may be considered a safe dose. Plasma concentrations are comparable to previously published values in humans, dogs, horses, and pigeons (Columba livia domestica) for up to 14 hours following dosing. This study indicates that further studies are needed to establish the pharmacodynamics and the efficacy of trazodone in the medical management of behavioral problems in psittacine species.

Demonstration of Physicochemical and Functional Similarity of Biosimilar Pegfilgrastim-cbqv to Pegfilgrastim.

Pegfilgrastim-cbqv/CHS-1701 (UDENYCA®) (hereafter referred to as pegfilgrastim-cbqv) was approved in 2018 by the US Food and Drug Administration as a biosimilar for pegfilgrastim (Neulasta®) (hereafter referred to as pegfilgrastim). Both pegfilgrastim-cbqv and pegfilgrastim are conjugates of recombinant human granulocyte colony stimulating factor (r-metHuG-CSF) with a 20kDa polyethylene glycol (PEG) indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients receiving myelosuppressive anticancer drugs. The demonstration of analytical similarity for PEG-protein conjugates presents unique challenges since both the protein and PEG attributes must be characterized. The current study demonstrates the analytical similarity of pegfilgrastim-cbqv and the reference product, pegfilgrastim. In addition to the physicochemical and functional characterization of the protein, the study assessed attributes specific to PEGylation including PEG size and polydispersity, site of attachment, linker composition, and PEGylation process-related variants. The structural, functional, and stability attributes of pegfilgrastim-cbqv and pegfilgrastim were compared using state-of-the-art analytical methods. For the protein, the primary structure, disulfide structure, and secondary and tertiary structures were assessed using traditional protein characterization techniques such as mass spectrometry (MS), circular dichroism (CD), intrinsic fluorescence, and differential scanning calorimetry (DSC), as well as more advanced techniques such as two-dimensional (2D) nuclear magnetic resonance (NMR) and hydrogen deuterium exchange (HDX). For the PEG moiety, the site of attachment, occupancy, linker composition, size and polydispersity were compared using mass spectrometry (both intact and after endoprotease digestion), multiangle light scattering detection (MALS), and Edman degradation. Purity assessments included the assessment of both protein variants and PEGylation variants using chromatographic and electrophoretic analytical separation techniques. The functional similarity between pegfilgrastim-cbqv and pegfilgrastim was compared using both a cell-based bioassay and surface plasmon resonance (SPR). The degradation rates and stability profiles were compared under accelerated and stressed conditions. Biosimilarity was demonstrated by a thorough assessment of physiochemical and functional attributes, as well as comparative stability, of pegfilgrastim-cbqv relative to pegfilgrastim. These studies demonstrated identical primary structure and disulfide structure, highly similar secondary and tertiary structure, as well as functional similarity. The impurity profile of pegfilgrastim-cbqv was comparable to that of pegfilgrastim with only minor differences in PEGylation variants and a slight offset in the PEG molar mass. These differences were not clinically relevant. The degradation profiles were qualitatively and quantitatively similar under accelerated and stress conditions. The structural, functional, and stability data demonstrate that pegfilgrastim-cbqv is highly similar to the reference product, pegfilgrastim.