Safety Studies Research Articles

Exploratory functional and quality of life outcomes with daily consumption of the ketone ester bis-octanoyl (R)-1,3-butanediol in healthy older adults: a randomized, parallel arm, double-blind, placebo-controlled study.

Ketone bodies are metabolites produced during fasting or on a ketogenic diet that have pleiotropic effects on the inflammatory and metabolic aging pathways underpinning frailty in in vivo models. Ketone esters (KEs) are compounds that induce hyperketonemia without dietary changes and that may impact physical and cognitive function in young adults. The functional effects of KEs have not been studied in older adults. Our long-term goal is to examine if KEs modulate aging biology mechanisms and clinical outcomes relevant to frailty in older adults. Here, we report the exploratory functional and quality-of-life outcome measures collected during a 12-week safety and tolerability study of KE (NCT05585762). Randomized, placebo-controlled, double-blinded, parallel-group, pilot trial of 12-weeks of daily KE ingestion. The Clinical Research Unit at the Buck Institute for Research on Aging, California. Community-dwelling older adults (≥ 65 years), independent in activities of daily living, with no unstable acute medical conditions (n = 30). Subjects were randomly allocated (1:1) to consume 25 g daily of either KE (bis-octanoyl (R)-1,3-butanediol) or a taste, appearance, and calorie-matched placebo (PLA) containing canola oil. Longitudinal change in physical function, cognitive function and quality of life were assessed as exploratory outcomes in n = 23 completers (n = 11 PLA, n = 12 KE). A composite functional outcome to describe the vigor-frailty continuum was calculated. Heart rate and activity was measured throughout the study using digital wearables. There were no statistically significant longitudinal differences between groups in exploratory functional, activity-based or quality of life outcomes. Daily ingestion of 25 g of KE did not affect exploratory functional or quality-of-life end points in this pilot cohort of healthy older adults. Future work will address these endpoints as primary and secondary outcomes in a larger trial of pre-frail older adults.

A review of the botany, metabolites, pharmacology, toxicity, industrial applications, and processing of Polygalae Radix: the "key medicine for nourishing life".

Polygalae radix (PR) is the dried root of Polygala tenuifolia Willd. and Polygala sibirica L. and enjoys the reputation as the "key medicine for nourishing life." In this study, information about "Polygala tenuifolia Willd.," "Polygala sibirica L.," and "Yuanzhi" was retrieved from scientific databases, including Google Scholar, Baidu Scholar, Web of Science, PubMed, CNKI, and Wan Fang Data. Information from Chinese herbal medicine classics, Yaozhi Data, and the Gaide Chemical Network was also collected. Information related to botany, phytochemistry, pharmacology, toxicity, industrial applications, and processing is summarized in this paper to tap its potentialities and promote its further development and clinical application. More than 320 metabolites have been isolated from PR; saponins, xanthones, and oligosaccharide esters are the main functional metabolites. Pharmacological research shows that its pharmacological action mainly focuses on resisting nervous system diseases, and it also has the functions of anti-oxidation, anti-inflammation, anti-tumor, anti-pathogenic microorganisms and others. The gastrointestinal irritation of its saponins impeded its application, but this irritation can be reduced by controlling the dosage, compatibility with other herbs, or processing. The future progress of PR faces opportunities and challenges. More attention should be paid to the traditional application and processing methods of PR recorded in ancient books. The lack of safety and clinical studies has limited its application and transformation of achievements. Moreover, it is one-sided to take the content of only a few metabolites as the index of processing optimization and quality control, which cannot reflect the full pharmacological and toxicological activities of PR.

Antimicrobial Peptides with Spermicidal Activity as New Contraceptive Agents: Killing Two Birds with One Stone

Abstract: Antimicrobial peptides (AMPs) have emerged as promising candidates for dual-action contraceptive agents, offering both spermicidal and antimicrobial properties. This perspective explores the potential of AMPs in developing novel contraceptive technologies, focusing on their application in condom coatings and vaginal formulations. AMPs exert their effects through membrane disruption mechanisms, targeting both microbial pathogens and sperm cells. Their broad-spectrum activity against various microorganisms, coupled with spermicidal effects, makes them ideal for multipurpose prevention technologies. The incorporation of AMPs into condoms could enhance barrier protection, while vaginal applications offer non-hormonal, on-demand contraceptive options. However, challenges, such as potential vaginal irritation, microbiome disruption, and the need for long-term safety studies, must be addressed. Future research should focus on optimizing AMP selectivity, developing stable formulations, and conducting comprehensive efficacy and safety trials. The dual-action nature of AMPs aligns with the growing demand for integrated approaches to sexual and reproductive health, potentially revolutionizing contraception and STI prevention. By addressing current challenges and leveraging the unique properties of AMPs, researchers can develop a new generation of contraceptive products that offer improved efficacy, safety, and user acceptability.

FSCIG 10% in pediatric primary immunodeficiency diseases: a European post-authorization safety study

BackgroundThe safety, tolerability, and immunogenicity of hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) 10% (dual-vial unit of human immunoglobulin 10% and recombinant human hyaluronidase [rHuPH20]) were assessed in children with primary immunodeficiency diseases (PIDs).MethodsThis phase 4, post-authorization, prospective, interventional, multicenter study (NCT03116347) conducted in the European Economic Area, enrolled patients aged 2 to < 18 years with a documented PID diagnosis who had received immunoglobulin therapy for ≥ 3 months before enrollment. New fSCIG 10% starters underwent fSCIG 10% dose ramp-up for ≤ 6 weeks (epoch 1) before receiving fSCIG 10% for ≤ 3 years (epoch 2); patients pretreated with fSCIG 10% entered epoch 2 directly. The primary outcome was the number and rate (per infusion) of all noninfectious treatment-related serious and severe adverse events (AEs).ResultsIn total, 42 patients were enrolled and dosed (median [range] age: 11.5 [3–17] years; 81% male; 23 new starters; 19 pretreated). Overall, 49 related noninfectious, treatment-emergent AEs (TEAEs) were reported in 15 patients; most were mild in severity (87.8%). No treatment-related serious TEAEs were reported. Two TEAEs (infusion site pain and emotional distress) were reported as severe and treatment-related in a single new fSCIG 10% starter. The rate of local TEAEs was lower in pretreated patients (0.1 event/patient-year) versus new starters (1.3 events/patient-year). No patients tested positive for binding anti-rHuPH20 antibodies (titer of ≥ 1:160).ConclusionsNo safety signals were identified, and the incidence of local AEs declined over the duration of fSCIG 10% treatment. This study supports fSCIG 10% long-term safety in children with PIDs.Trial registration number (ClinicalTrials.gov)NCT03116347.

A Suicide Prevention Digital Technology for Individuals Experiencing an Acute Suicide Crisis in Emergency Departments: Naturalistic Observational Study of Real-World Acceptability, Feasibility, and Safety.

Emergency departments (EDs) are the front line in providing suicide care. Expert consensus recommends the delivery of several suicide prevention evidence-based interventions for individuals with acute suicidal ideation in the ED. ED personnel demands and staff shortages compromise delivery and contribute to long wait times and unnecessary hospitalization. Digital technologies can play an important role in helping EDs deliver suicide care without placing further demands on the care team if their use is safe to patients in a routine care context. This study evaluates the safety and effectiveness of an evidence-based digital technology (Jaspr Health) designed for persons with acute suicidal ideation seeking psychiatric crisis ED services when used as part of routine ED-based suicide care. This study deployed Jaspr Health for real-world use in 2 large health care systems in the United States and aimed to evaluate (1) how and whether Jaspr Health could be safely and effectively used outside the context of a researcher-facilitated clinical trial, and (2) that Jaspr's use would be associated with improved patient agitation and distress. Under the auspices of a nonsignificant risk device study, ED patients with acute suicidal ideation (N=962) from 2 health care systems representing 10 EDs received access to Jaspr Health as part of their routine suicide care. Primary outcome measures included how many eligible patients were assigned Jaspr Health, which modules were assigned and completed, and finally, the number of adverse events reported by patients or by medical staff. Secondary outcome measures were patient agitation, distress, and satisfaction. The most frequent modules assigned were Comfort and Skills (98% of users; n=942) and lethal means assessment (90% of patient users; n=870). Patient task completion rates for all modules ranged from 51% to 79%. No adverse events were reported, suggesting that digital technologies can be safely used for people seeking ED-based psychiatric services. Statistically significant (P<.001) reductions in agitation and distress were reported after using the app. Average patient satisfaction ratings by site were 7.81 (SD 2.22) and 7.10 (SD 2.65), with 88.8% (n=325) and 84% (n=90) of patients recommending the app to others. Digital technologies such as Jaspr Health may be safely and effectively integrated into existing workflows to help deliver evidence-based suicide care in EDs. These findings hold promise for the use of digital technologies in delivering evidence-based care to other vulnerable populations in complex environments.

Cannabinoids Used for Medical Purposes in Children and Adolescents

Cannabinoids are increasingly used for medical purposes in children. Evidence of the safety of cannabinoids in this context is sparse, creating a need for reliable information to close this knowledge gap. To study the adverse event profile of cannabinoids used for medical purposes in children and adolescents. For this systematic review and meta-analysis, MEDLINE, Embase, PsycINFO, and the Cochrane Library were searched for randomized clinical trials published from database inception to March 1, 2024, for subject terms and keywords focused on cannabis and children and adolescents. Search results were restricted to human studies in French or English. Two reviewers independently performed the title, abstract, and full-text review, data extraction, and quality assessment. Included studies enrolled at least 1 individual 18 years or younger, had a natural or pharmaceutical cannabinoid used as an intervention to manage any medical condition, and had an active comparator or placebo. Two reviewers performed data extraction and quality assessment independently. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline and PRISMA-S guideline were used. Data were pooled using a random-effects model. The primary outcome was the incidence of withdrawals, withdrawals due to adverse events, overall adverse events, and serious adverse events in the cannabinoid and control arms. Secondary outcomes were the incidence of specific serious adverse events and adverse events based on organ system involvement. Of 39 175 citations, 23 RCTs with 3612 participants were included (635 [17.6%] female and 2071 [57.3%] male; data not available from 2 trials); 11 trials (47.8%) included children and adolescents only, and the other 12 trials (52.2%) included children, adolescents, and adults. Interventions included purified cannabidiol (11 [47.8%]), nabilone (4 [17.4%]), tetrahydrocannabinol (3 [13.0%]), cannabis herbal extract (3 [13.0%]), and dexanabinol (2 [8.7%]). The most common indications were epilepsy (9 [39.1%]) and chemotherapy-induced nausea and vomiting (7 [30.4%]). Compared with the control, cannabinoids were associated with an overall increased risk of adverse events (risk ratio [RR], 1.09; 95% CI, 1.02-1.16; I2 = 54%; 12 trials), withdrawals due to adverse events (RR, 3.07; 95% CI, 1.73-5.43; I2 = 0%; 14 trials), and serious adverse events (RR, 1.81; 95% CI, 1.21-2.71; I2 = 59%; 11 trials). Cannabinoid-associated adverse events with higher RRs were diarrhea (RR, 1.82; 95% CI, 1.30-2.54; I2 = 35%; 10 trials), increased serum levels of aspartate aminotransferase (RR, 5.69; 95% CI, 1.74-18.64; I2 = 0%; 5 trials) and alanine aminotransferase (RR, 5.67; 95% CI, 2.23-14.39; I2 = 0%; 6 trials), and somnolence (RR, 2.28; 95% CI, 1.83-2.85; I2 = 8%; 14 trials). In this systematic review and meta-analysis, cannabinoids used for medical purposes in children and adolescents in RCTs were associated with an increased risk of adverse events. The findings suggest that long-term safety studies, including those exploring cannabinoid-related drug interactions and tools that improve adverse event reporting, are needed.

Safety and efficacy evaluation of plain OTC-HCL in acute and subacute toxicity tests and infected mice

The study aimed to evaluate the safety and efficacy of plain Oxytetracycline hydrochloride (OTC-HCL) in mice experimentally infected with 544 strain. The safety of plain OTC-HCL was assessed through acute and subacute toxicity testing. The LD value was determined, and hematologic, biochemical, and histopathological analyses were performed. For efficacy evaluation, mice were intraperitoneally injected with 3 × 10^6 CFU of 544 in 0.5 ml. Following infection, the mice received 25 mg/kg of plain OTC-HCL intravenously either daily or on alternate days for 21 days, starting from day 14 post-infection. Efficacy was assessed by measuring the logarithmic decrease in counts in the liver, lymph nodes, and spleen on days 1, 7, and 14 after treatment. Plain OTC-HCL has an LD of greater than 250 mg/kg. In both acute and subacute toxicity evaluations, the hematologic and biochemical data of the drug were within the normal range. Histopathology studies revealed no significant changes in the safety studies. In the subacute toxicity study, the drug was administered to mice received plain OTC-HCl @ 25 mg/kg intravenously for 21 days. Efficacy was measured by the decrease of counts in the liver, lymph nodes, and spleen. Plain OTC-HCL was found to be safe in both acute and subacute toxicity tests and effectively reduced the infection load of in mice. Our findings and novelties are 1) LDis more than 250 mg/kg for plain OTC-HCL by intravenously as a single dose. 2) Histopathology indicates that there is no organ toxicity for plain OTC-HCL in safety studies. 3) Plain OTC-HCL was found to be effective in reducing the infection load in -infected mice.

Efficient vehicle lateral safety analysis based on Multi-Kriging metamodels: Autonomous trucks under different lateral control modes during being overtaken

Different lateral control modes for autonomous trucks have been proposed in the past to improve road sustainability. To evaluate the lateral reliability and risk of autonomous trucks under different lateral control modes, especially in windy conditions and during overtaking, this study proposes a high-precision, efficient method based on Multi-Kriging (MK) metamodeling. Compared to Support Vector Regression (SVR), widely used in vehicle safety studies, the MK method builds Kriging metamodels for all potential deviation crashes of autonomous trucks, significantly reducing computational costs while ensuring accuracy. Additionally, instead of using the maximum lateral deviation as a dynamic risk indicator, this study innovatively suggests using the distance between the autonomous truck and the lane line after the maximum lateral deviation occurs. Considering the vehicle and environmental characteristics, the MK method is used to calculate the probability of a crash and the associated risk at various lateral positions of the autonomous truck, quantifying the crash probability and risk values under different lateral control modes. Furthermore, the study investigates the influence of the standard deviation of the normal distribution on the crash probability and risk values of autonomous trucks, providing valuable insights for future research on road sustainability and safety under autonomous driving conditions.

Using Vaccine Safety Data to Demonstrate the Potential of Pooled Data Analysis.

In Canada, vaccine safety studies are often conducted at the provincial/territorial level where the primary data on vaccination reside. Combining health services data from multiple jurisdictions using a pooled data analytic approach would reduce the amount of time needed to detect vaccine safety signals. To determine the difference in the time it would take to identify safety signals using different proportions of the Canadian population, we conducted power and sample size calculations for a hypothetical self-controlled case series-based surveillance analysis. We used scenarios modeled after the real-world examples of myocarditis and vaccine-induced immune thrombotic thrombocytopenia (VITT) following COVID-19 vaccination as our base cases. Our calculations demonstrated that in the case of a myocarditis-type event, a pooled analysis would reduce the time needed to detect a safety signal by over 60% compared to using Ontario data alone. In the case of a VITT-type event, a pooled analysis could detect a safety signal 49 days sooner than using Ontario data alone, potentially averting as many as 30 events. Our analysis demonstrates that there is substantial value in using pan-Canadian health services data to evaluate the safety of vaccines. Efforts should be made to develop a pan-Canadian vaccine data source to allow for an earlier evaluation of suspected adverse events following immunization.

Sacituzumab-govitecan in metastatic triple-negative breast cancer: a multicenter effectiveness and safety study.

Aim: Sacituzumab-govitecan (Sgov) is a new antibody-drug conjugate recently approved for metastatic triple negative breast cancer (mTNBC), so there are still few data published in the real-world setting.Materials & methods: This study was to analyze the effectiveness and safety of Sgov in mTNBC of patients from the three main hospitals of a city and to compare with the pivotal ASCENT-trial. A total of46 patients were included, all women diagnosed with mTNBC, with a median age of 52years and Eastern Cooperative Oncology Group performance status 0-1 71.8% of patients.Results: Sgov effectiveness data seem to be slightly inferior than expected. Furthermore, it is observed that patients with an Eastern Cooperative Oncology Group of twoor higher benefit significantly less from treatment with the drug. Safety profile of Sgov is acceptable.

High-risk powered two-wheelers scenarios generation for autonomous vehicle testing using WGAN

Objective Autonomous vehicles (AVs) have the potential to revolutionize the future of mobility by significantly improving traffic safety. This study presents a novel method for validating the safety performance of AVs in high-risk scenarios involving powered 2-wheelers (PTWs). By generating high-risk scenarios using in-depth crash data, this study is devoted to addressing the challenge of public road scenarios in testing, which often lack the necessary complexity and risk to effectively evaluate the capabilities of AVs in high-risk situations. Method Our approach employs a Wasserstein generative adversarial network (WGAN) to generate high-risk scenes, particularly focusing on PTW scenarios. By extracting 314 car-to-PTW crashes from the China In-depth Mobility Safety Study–Traffic Accident database, we simulate outcomes using PC-Crash software. The data are divided into scenes at 0.1-s intervals, with WGAN generating numerous high-risk scenes. By using a cumulative distribution function (CDF), we sampled and analyzed the vehicle’s dynamic information to generate complete scenarios applicable to the test. The validation process involves using the SVL Simulator and the Baidu Apollo joint simulation platform to evaluate the AV’s driving behavior and interactions with PTWs. Results This study evaluates model generation results by comparing distributions using Wasserstein distance as an indicator. The generator converges after approximately 200 epochs, with the iterator converging quickly. Subsequently, 10,000 new scenes are then generated. The distribution of several key parameters in the generated scenes can be found to approximate that of the original scenes. After sampling, the usability of generated scenarios is 64.76%. Virtual simulations confirm the effectiveness of the scenario generation method, with a generated scenario crash rate of 16.50% closely reflecting the original rate of 15.0%, showcasing the method’s capacity to produce realistic and hazardous scenarios. Conclusions The experimental results suggest that these scenarios exhibit a level of risk similar to the original crashes and are effective for testing AVs. Consequently, the generated scenarios enhance the diversity of the scenario library and accelerate the overall testing process of AVs.

Multicenter randomized controlled trial to assess the effectiveness of PASSEO-LUX DCB® drug coated balloon compared to plain balloon angioplasty of arteriovenous fistulae for hemodialysis: Two-years results.

To compare primary patency after angioplasty with drug-coated balloon (DCB)-Passeo-18Lux, BIOTRONIK versus uncoated balloon in dysfunctional peripheral vascular access (PVA) for hemodialysis. A total of 133 patients from four hospitals were randomized to receive DCB or plain old balloon angioplasty (POBA) after satisfactory treatment (residual stenosis <30%) with high pressure balloon (HPB). The primary endpoint was clinical patency of PVA 2 years after angioplasty. Secondary endpoints included the relationship between the location of stenosis and patency and also, other covariates. Mortality at 2 years was compared between both groups. Patency measured in days after angioplasty was higher in fistulae dilated with DCB than HPB. Kaplan-Meier survival curves showed the next percent of success (free time restenosis) after DCB versus POBA at 6 months-77.1% versus 58.2% (160.41-143.72 days until restenosis), 12 months-51.4% versus 44.3% (274.1-237.23), 18 months-38.6% versus 38% (350.74-305.18), and 24 months-37.1% versus 30.4% (419.04-369.1). At 6 months, this difference was statistically significant (p = 0.018), but not at 12 (p = 0.225), 18 (p = 0.471), or 24 months (p = 0.236). Mortality was similar in both groups. DCB angioplasty resulted in superior target lesion primary patency (TLPP)-free survival at 6 months of follow-up. No significant improvements in TLPP-free survival long term were observed. Mortality observed at 1 and 2 years was similar in DCB and POBA: there was no significant difference, and a safety study demonstrated no difference between the two groups (complications and mortality): DCB is safe to use in stenosis treatment in patients who are PVA carriers. Level Ia, therapeutic study, RCT. EBM ratings will be based on a scale of 1-5.

A Review of the Therapeutical Perspective of Phytochemicals in the Treatment of HIV

Abstract: HIV/AIDS is one of the most widespread global diseases. It is caused by the human immunodeficiency virus (HIV), which leads to the development of acquired immunodeficiency syndrome (AIDS). In AIDS patients, the immune system progressively weakens, making them vulnerable to various infections and cancers. The virus can be transmitted through the exchange of bodily fluids such as blood, semen, vaginal fluid, and breast milk, where HIV can be found in both free virus particles and infected immune cells. Although drug resistance remains a challenge for HIV/AIDS treatment, researchers are exploring the use of natural substances in the development of anti-HIV drugs. Clinical trials based on plant-derived compounds are currently being conducted. Experimental research suggests that plants may have the potential to treat HIV. However, the identification of active compounds, testing of extracts, and creation of suitable bioassays are all complex processes. Natural product scientists face the challenge of separating these complicated extracts into their active components. Various phytochemicals found in Astragalus membranaceus Bunge, Chelidonium majus L, Combretum molle (R. Br. ex. G. Don.) Engl&amp; Diels, Dittrichiaviscosa (L.) Greuter, Helichrysum populifolium, Hoodia gordonii (Masson) Sweet ex Decne, and Hypericumperf, have been investigated pharmacologically and pharmacokinetically. Further research is needed to optimize formulations and production in accordance with preclinical safety and efficacy studies.

Comparative assessment of plate count and PMA-qPCR methods for modeling the growth of lactic acid bacteria in smoked Turkey ham

This study compared the quantitative polymerase chain reaction (qPCR) method combined with propidium monoazide (PMA) and the plate count (PC) method, both combined with predictive modeling, to describe the behavior of lactic acid bacteria (LAB) in vacuum-packaged sliced smoked turkey ham (STH). The PMA-qPCR method does not allow the DNA amplification of died cells but allow the amplification of viable cells, including the non-culturable. The standard curves relating quantification cycle (Cq) and log10 CFU/g demonstrated good linearity (R2 > 0.95), evidencing its accuracy and reproducibility. These curves were used to quantify Leuconostoc mesenteroides and Weissella viridescens in artificially inoculated STH samples stored at different isothermal temperatures (8, 10, 12, 16 and 20 °C). Firstly, the PMA-qPCR and PC methods were compared, and the analysis demonstrated a good correlation (R2 = 0.99) and agreement between the results. However, the PC method underestimated the quantification of W. viridescens cells by 0.76 log10 CFU/g at 8 °C, suggesting bacterial stress at this temperature, which was not observed for L. mesenteroides. In terms of growth, the maximum specific growth rate increased with rising temperature for both LAB. Predictive modeling indicated that the growth of L. mesenteroides and W. viridescens at 8 °C suggests a shelf life of approximately 4.25 days for STH based on PC data, and 4.13 days based on PMA-qPCR data. In conclusion, the PMA-qPCR method presented an advantage in terms of accuracy, especially under bacterial stress conditions, and proved to be a promising alternative for the quantification of LAB in refrigerated ready-to-eat meat products. The predictive models used were suitable for describing microbial growth, reinforcing the importance of the PMA-qPCR method in shelf life and food safety studies.

Limb Perfusion Delivery of a rAAV1 Alpha-1 Antitrypsin Vector in Non-Human Primates Is Safe but Insufficient for Therapy.

α-1 antitrypsin (AAT) deficiency is an inherited, genetic condition characterized by reduced serum levels of AAT and increased risk of developing emphysema and liver disease. AAT is normally synthesized primarily in the liver, but muscle-targeting with a recombinant adeno-associated virus (rAAV) vector for α-1 antitrypsin (AAT) gene therapy has been used to minimize liver exposure to the virus and hepatotoxicity. Clinical trials of direct intramuscular (IM) administration of rAAV1-hAAT have demonstrated its overall safety and transgene expression for 5 years. However, the failure to reach the therapeutic target level after 100 large-volume (1.5 mL) IM injections of maximally concentrated vector led us to pursue a muscle-targeting approach using isolated limb perfusion. This targets the rAAV to a greater muscle mass and allows for a higher total volume (and thereby a higher dose) than is tolerable by multiple direct IM injections. Limb perfusion has been shown to be feasible in non-human primates using the rAAV1 serotype and a ubiquitous promoter expressing an epitope-tagged AAT matched to the host species. In this study, we performed a biodistribution and preclinical safety study in non-human primates with a clinical candidate rAAV1-human AAT (hAAT) vector at doses ranging from 3.0 × 1012 to 1.3 × 1013 vg/kg, bracketing those used in our clinical trials. We found that limb perfusion delivery of rAAV1-hAAT was safe and showed a biodistribution pattern similar to previous studies. However, serum levels of AAT obtained with high-dose limb perfusion still reached only ~50% of the target serum levels. Our results suggest that clinically effective AAT gene therapy may ultimately require delivery at doses between 3.5 × 1013-1 × 1014 vg/kg, which is within the dose range used for approved rAAV gene therapies. Muscle-targeting strategies could be incorporated when delivering systemic administration of high-dose rAAV gene therapies to increase transduction of muscle tissues and reduce the burden on the liver, especially in diseases that can present with hepatotoxicity such as AAT deficiency.

Phase I study of safety and efficacy of allogeneic natural killer cell therapy in relapsed/refractory neuroblastomas post autologous hematopoietic stem cell transplantation

Despite low incidence, neuroblastoma, an immunologically cold tumor, is the most common extracranial solid neoplasm in pediatrics. In relapsed/refractory cases, the benefits of autologous hematopoietic stem cell transplantation (auto-HSCT) and other therapies are limited. Natural killer (NK) cells apply cytotoxicity against tumor cells independently of antigen-presenting cells and the adaptive immune system. The primary endpoint of this trial was to assess the safety of the injection of allogenic, ex vivo-expanded and primed NK cells in relapsed/refractory neuroblastoma patients after auto-HSCT. The secondary endpoint included the efficacy of this intervention in controlling tumors. NK cells were isolated and primed ex vivo (by adding interleukin [IL]-2, IL-15, and IL-21) in a GMP-compliant CliniMACS system and administered to four patients with relapsed/refractory MYCN-positive neuroblastoma. NK cell injections (1 and 5 × 107 cells/kg in the first and second injections, respectively) were safe, and no acute or sub-acute adverse events were observed. During the follow-up period, one complete response (CR) and one partial response (PR) were observed, while two cases exhibited progressive disease (PD). In follow-up evaluations, two died due to disease progression, including the case with a PR. The patient with CR had regular growth at the 31-month follow-up, and another patient with PD is still alive and receiving chemotherapies 20 months after therapy. This therapy is an appealing and feasible approach for managing refractory neuroblastomas post-HSCT. Further studies are needed to explore its efficacy with higher doses and more frequent administrations for high-risk neuroblastomas and other immunologically cold tumors.Trial registration number: irct.behdasht.gov.ir (Iranian Registry of Clinical Trials, No. IRCT20201202049568N1).

A Randomized Comparative study of efficacy and safety between %20 and %30 Hydrogen peroxide in the Treatment of Actinic keratosis

Background and objectives: Actinic keratosis is a premalignant skin lesion that presents clinically as a sand-like macule or papule on an erythematous base with a superficial scale due to atypical proliferation of keratinocytes and may progress to squamous cell carcinoma. The aim of this study was to compare the efficacy of hydrogen peroxide in treatment of actinic keratosis between two different concentrations (%20 and %30). Methods: This is a randomized open label therapeutic trial of twenty patients with actinic keratosis has been enrolled, it was conducted from April 2022 to August 2022 at Sulaimaniah dermatology teaching center. Patients were divided to two treatment groups. Hydrogen peroxide %20 applied to the actinic lesions of group A, while group B applied 30% Hydrogen peroxide to the lesions. The solution was applied to the lesions in a circular motion for 20 seconds, for four rounds per session Patients were seen after a first session in two weeks. Maximum four sessions spaced out by 15 days are given until clearance. Result: we conducted a randomized open label therapeutic trial. It was conducted from April 2022 to August 2022 at Sulaimaniah dermatology teaching center. Regarding response in Group A out of twenty actinic lesions, marked and moderate improvement was recorded in %40, %30 of the lesions respectively while the remaining lesions %30 of them showed slight improvement and no clinically clearance has been recorded. In comparsison, Group B out of twenty lesions %60 of them clinically cleared and slight improvement was recorded only in %20 of lesions. There were statistically significant differences between (20% &amp; 30% Hydrogen peroxide ) in response (p-value=0.000). Regarding side effects; majority of patients (85%) in both groups had recorded burning sensation, irritation and transient erythema, while no scarring, pigmentation, atrophy has been recorded. There were no statically significant differences between two groups. Conclusion: Hydrogen peroxide can be used as safe, alternative method to other modalities in treatment of actinic keratosis lesions, results would be better if higher concentration %30 used

Phase 1 Trials of Gatralimab, a Next-Generation Humanized Anti-CD52 Monoclonal Antibody, in Participants with Progressive Multiple Sclerosis.

Lymphocyte depletion via anti-CD52 monoclonal antibody (mAb) therapy is an effective treatment strategy for relapsing-remitting multiple sclerosis (MS) but is associated with infusion/injection-associated reactions (IARs) and autoimmune-related adverse events (AEs). Gatralimab is a next-generation humanized anti-CD52 mAb. Two first-in-human trials were conducted in participants with progressive MS to assess the pharmacodynamics, pharmacokinetics, and safety of gatralimab administered via subcutaneous (SC) and intravenous (IV) routes, and to determine the effect of different comedication regimes on IARs to SC gatralimab. A Phase 1 trial (NCT02282826) included double-blind, placebo-controlled sequential ascending single IV (1, 3.5, and 12mg) and SC (12, 36, and 60mg) dose groups. A Phase 1b trial (NCT02977533) involved five groups who received SC gatralimab (36, 48, or 60mg) and different comedications. A long-term safety (LTS) study (NCT02313285) examined safety and pharmacodynamics over 4years. Gatralimab produced depletion of lymphocytes (dose-dependently) and CD4+ regulatory T cells, with partial repopulation to normal values by approximately 12months. Peak serum gatralimab concentrations followed dose-proportionality and were delayed by 6.0-7.5days following SC administration. Treatment-emergent AEs, including IARs, were reported for most participants but were generally of mild or moderate severity, and treatment-emergent serious AEs were mostly MS-related. Methylprednisolone and antihistamine comedications were associated with reduced incidence of fevers and skin and subcutaneous tissue AEs, respectively. During the LTS study, one participant (3.0%) experienced an autoimmune-related AE (Basedow's disease), and subsequently died from pulmonary sepsis deemed unrelated to gatralimab by the investigator. These data show that gatralimab achieves the desired pharmacodynamic effect of lymphocyte depletion followed by repopulation, and has an acceptable safety profile, including low risk of non-MS autoimmunity. Although gatralimab is no longer in development for MS, insights from these trials may inform the development of comedication regimes of future anti-CD52 mAbs and subcutaneous formulations of other lymphocyte-depleting mAbs. NCT02282826, NCT02977533, NCT02313285.

The effect of transcutaneous auricular vagus nerve stimulation on cardiovascular function in subarachnoid hemorrhage patients: a safety study.

Subarachnoid hemorrhage (SAH) is characterized by intense central inflammation, leading to substantial post-hemorrhagic complications such as vasospasm and delayed cerebral ischemia. Given the anti-inflammatory effect of transcutaneous auricular vagus nerve stimulation (taVNS) and its ability to promote brain plasticity, taVNS has emerged as a promising therapeutic option for SAH patients. However, the effects of taVNS on cardiovascular dynamics in critically ill patients, like those with SAH, have not yet been investigated. Given the association between cardiac complications and elevated risk of poor clinical outcomes after SAH, it is essential to characterize the cardiovascular effects of taVNS to ensure this approach is safe in this fragile population. Therefore, we assessed the impact of both acute taVNS and repetitive taVNS on cardiovascular function in this study. In this randomized clinical trial, 24 SAH patients were assigned to either a taVNS treatment or a Sham treatment group. During their stay in the intensive care unit, we monitored patient electrocardiogram (ECG) readings and vital signs. We compared long-term changes in heart rate, heart rate variability, QT interval, and blood pressure between the two groups. Additionally, we assessed the effects of acute taVNS by comparing cardiovascular metrics before, during, and after the intervention. We also explored acute cardiovascular biomarkers in patients exhibiting clinical improvement. We found that repetitive taVNS did not significantly alter heart rate, QT interval, blood pressure, or intracranial pressure. However, taVNS increased overall heart rate variability and parasympathetic activity compared to the sham treatment. The increase in parasympathetic activity was most pronounced from 2-4 days after initial treatment (Cohen's d = 0.50). Acutely, taVNS increased heart rate, blood pressure, and peripheral perfusion index without affecting the corrected QT interval, intracranial pressure, or heart rate variability. The acute post-treatment elevation in heart rate was more pronounced in patients who experienced a decrease of more than one point in their Modified Rankin Score at the time of discharge. Our study found that taVNS treatment did not induce adverse cardiovascular effects, such as bradycardia or QT prolongation, supporting its development as a safe immunomodulatory treatment approach for SAH patients. The observed acute increase in heart rate after taVNS treatment may serve as a biomarker for SAH patients who could derive greater benefit from this treatment. NCT04557618.

Pharmacokinetic and preclinical safety studies of endolysin-based therapeutic for intravenous administration

Pharmacokinetics and safety studies of innovative drugs is an essential part of drug development process. Previously we have developed a novel drug for intravenous administration (lyophilizate) containing modified endolysin LysECD7-SMAP that showed notable antibacterial effect in different animal models of systemic infections. Here we present data on pharmacokinetics of endolysin in mice after single and multiple injections. Time-concentration curves were obtained, and pharmacokinetic parameters for preparation (C0, kel t1/2, AUC0-∞, MRT, ClT, Vss) were calculated. It was shown that although endolysin is rather short-lived in blood serum (t1/2 = 12.5 min), the therapeutic concentrations of LysECD7-SMAP (in degraded and non-degraded form) were detected for 60 minutes after injection that is sufficient for antibacterial effect. Based on the obtained data, it was proposed that endolysin distributes presumably in murine blood, degrades in blood and liver, and is eliminated via glomerular filtration. Safety profile of the preparation relating to general toxicity, immunotoxicity and allergenicity was assessed in rodents. It was demonstrated that LysECD7-SMAP in potential therapeutic (12.5 mg/kg), 10-fold (125 mg/kg) and 40-fold (500 mg/kg) doses showed no signs of intoxication and significant abnormalities after single and repeated i.v. administrations, preparation was non-immunogenic and induced minor and reversible allergic reaction in animals.