Safety Studies Research Articles

Sustained release local anesthetics for pain management: relevance and formulation approaches.

This review attempted to ascertain the rationale for the formulation of sustained-release local anesthetics and summarize the various formulation approaches designed to date to achieve sustained and localized local analgesic effects. The incidence of pain, which is the concern of patients as well as health care professionals, is increasing due to accidents, surgical procedures, and other diseases. Local anesthetics can be used for the management of moderate to severe acute and chronic pain. They also allow regional analgesia, in situations where the cause and source of the pain are limited to a particular site or region, without the need for loss of consciousness or systemic administration of other analgesics thereby decreasing the risk of potential toxicities. Though they have an interesting antipain efficacy, the short duration of action of local anesthetics makes the need for their multiple injections or opioid adjuvants mandatory. To overcome this problem, different formulations are being designed that help achieve prolonged analgesia with a single dose of administration. Combination with adjuvants, liposomal formulations, lipid-based nanoparticles, thermo-responsive nanogels, microspheres, microcapsules, complexation with multivalent counterions and HP-β-CD, lipid-based nanoparticles, and bio-adhesive films, and polymeric matrices are among the approaches. Further safety studies are required to ensure the safe and effective utilization of sustained-release local anesthetics. Moreover, the release kinetics of the various formulations should be adequately established.

Abstract LB023: A novel oral Paclitaxel delivery strategy and softgel capsule product for improving cancer therapeutics

Abstract The therapeutic efficacy of a novel oral Paclitaxel formulation was evaluated and compared in Balb/c nude mice bearing PDX NSCLC, gastric cancer, liver cancer, breast cancer, and ovarian cancer treated with Abraxane, Taxol, Lenvatinib and Sorafenib. Therapeutic parameters including tumor volume, tumor growth inhibition (TGI), and treatment-to-control ratio (T/C) were compared among different treatment groups. The drug tolerance, cytotoxicity and safety profile of the oral Paclitaxel formulations were evaluated in Balb/c nude mice and beagle dogs. The tumor distribution of Paclitaxel in NCI-N87 gastric cancer-bearing mice after administration of oral Paclitaxel formulation and Paclitaxel Injection was investigated. The oral Paclitaxel formulation administrated at 100 mg/Kg demonstrated significant better therapeutic efficacy than Albumin-bound Paclitaxel for Injectable Suspension at 30 mg/Kg and Paclitaxel Injection at 15 mg/Kg for NCI-N87 gastric cancer-bearing mice, while the same 100 mg/Kg dose demonstrated noninferior therapeutic efficacy to Abraxane and significant better therapeutic efficacy than Taxol in Hs467T gastric cancer-bearing mice. The oral Paclitaxel formulation administrated at 180 mg/Kg demonstrated noninferior therapeutic efficacy compared with Lenvatinib at 40 mg/Kg, and significant better therapeutic efficacy than Sorafenib at 30 mg/Kg for Hep G2 liver cancer-bearing mice, while the oral paclitaxel at 180 mg/Kg showed inferior therapeutic efficacy than Lenvatinib at 30 mg/Kg but noninferior therapeutic efficacy to Sorafenib at 30 mg/Kg for Huh-7 liver cancer-bearing mice. The oral Paclitaxel formulation administrated at 100 mg/Kg demonstrated significant better therapeutic efficacy than Abraxane for Injectable Suspension at 30 mg/Kg and Taxol at 15 mg/Kg for NCI-H358 NSCLC-bearing mice. The oral Paclitaxel formulation administrated at 100 mg/Kg demonstrated noninferior therapeutic efficacy to Abraxane for Injectable Suspension at 30 mg/Kg and significant better therapeutic efficacy than Taxol at 15 mg/Kg for MDA-MB-231 breast cancer-bearing mice. The oral Paclitaxel formulation administrated at 100 mg/Kg demonstrated noninferior therapeutic efficacy to Abraxane at 30 mg/Kg and significant better therapeutic efficacy than Taxol at 15 mg/Kg for SK-OV-3 ovarian cancer-bearing mice. The gastric tumor distribution of Paclitaxel between 6-24 hour was similar after oral and intravenous administration. The Maximum Tolerated Dose (MTD) of the oral Paclitaxel was determined to be ≥ 200 mg/Kg in mice and ≥ 8.0 mg/Kg in beagle dogs when dosing at Q3DX3Weeks, there were no significant body weight losses, tissue damages and animal death observed during the long-term safety assessment study. The oral Paclitaxel formulation demonstrated better or noninferior therapeutic efficacy in five different PDX tumor-bearing mice compared with standard treatment drugs, good safety and low cytotoxicity at high doses in long-term safety and toxicity studies were observed in both mice and beagle dogs. The oral Paclitaxel formulation showed promising therapeutic potential for various cancer treatment and conducting “chemotherapy at home” with lower medical costs. Citation Format: Hui Yu Huang, Richard Jun Huang. A novel oral Paclitaxel delivery strategy and softgel capsule product for improving cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB023.

Abstract LB040: MACO-355, a unique pan-LILR monoclonal antibody for cancer therapy, re-programs and stimulates immuno-suppressive macrophages in a novel ligand-binding blocking independent manner

Abstract Macrophages populate most solid tumors in large numbers and limit effective anti-tumoral immune responses. The leukocyte immunoglobulin-like receptors (LILR) such as e.g. LILRB1, LILRB2, and others are expressed on tumor associated macrophages. Despite sharing multiple ligands such as major histocompatibility complex class I G (HLA-G), these receptors regulate different macrophage functions such as phagocytosis or cytokine release. To date, therapeutic approaches to targeting LILRs have concentrated on blocking receptor-ligand interactions to relieve ligand-mediated immune suppression. MACO-355 is a fully human antibody binding multiple LILRA (activating) and LILRB (inhibiting) family members including LILRB1, LILRB2, LILRB3, LILRA4 and LILRA6, that does not neutralize ligand (HLA-G, HLA-A, HLA-E) binding to either LILRB1 or to LILRB2. Nevertheless, MACO-355 mediates macrophage reprogramming even under strong immune suppressive conditions, as measured e.g. by stimulation of the TLR agonist induced pro-inflammatory cytokine release in CSF1, TGFβ, IL-10, and IL-4 treated cells. Concordantly, stimulation of immuno-suppressive macrophages with MACO-355 also resulted in significantly higher levels of T cell expansion, proliferation, and INFγ release in a co-culture suppression assay compared to ligand blocking antibodies. Additionally, MACO-355 enhances macrophage phagocytosis irrespective of tumor cell HLA-G ligand status and NK tumor cell killing. All these in vitro activities translate into in vivo activity in A375 melanoma CDX tumor model comparable to that of anti-PD-1 and anti-PD-L1 Abs in humanized mice. Safety studies showed that despite its potent immune stimulatory activity, MACO-355 does not lead to spurious pro-inflammatory cytokine production in in vitro cytokine storm assays. Molecular studies showed MACO-355 binds a novel epitope distant from a ligand binding pocket on LILRs and requires both bi-valent binding and Fc effector function for full activity. This results in pronounced modulation of intracellular kinase signaling. MACO-355 is a unique receptor-ligand non-blocking pan-LILR antibody highly potent in pro-inflammatory reprogramming of immuno-suppressive macrophages, both in vitro and in vivo. This appears to occur via a novel mode of action in which MACO-355 clusters multiple LILRs with Fc-receptors into unconventional signaling hubs. Altogether the data support the future clinical evaluation of MACO-355 as a cancer therapeutic. Citation Format: Krzysztof B. Wicher, Moritz Haneklaus, Martha Lopez-Yrigoyen, Alicia Poindron, Carmen Rodriguez-Seoane, Maikel Fransen, Chantell Payton, Stephane M. Guillame, Luca Cassetta, Stephen Myatt, Carola Ries. MACO-355, a unique pan-LILR monoclonal antibody for cancer therapy, re-programs and stimulates immuno-suppressive macrophages in a novel ligand-binding blocking independent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB040.

Citizens protein project: A self-funded, transparent, and concerning report on analysis of popular protein supplements sold in the Indian market.

Protein powders, including those containing herbal and dietary supplements such as vitamins, minerals, and other natural or synthetic ingredients, can be associated with hepatotoxicity. Protein supplements are often mislabeled and deceptive in their contents. In this self-funded transparent study, we extensively analyzed popular protein supplements in India to identify potential hepatotoxic substances based on industrial standards. All products underwent extensive analysis, including total protein content, fungal aflatoxin detection, pesticide residue estimation, heavy metal quantification, steroid detection, and complete organic and inorganic profiling, according to industry standards. Most protein supplements did not meet the labeled and advertised protein content, while certain brands surpassed the stated levels, raising concerns about potential "protein/amino-spiking." In addition, the major brands contained detectable fungal toxins and pesticide residues. Furthermore, many major formulations contained harmful heavy metals such as lead and arsenic, and some featured hepatoxic herbal extracts, particularly green tea extract, turmeric, Garcinia cambogia, and Ashwagandha. Indian-made products were inferior to those manufactured by multinational companies. The presence of various potentially toxic compounds, such as cycloheptatriene, benzene derivatives, toluene, and isopropyl alcohol, within a nonstandardized and unregulated diverse ingredient mix added to the overall concern. We demonstrate that the protein-based herbal and dietary supplement industry requires stringent scrutiny, regulation, and basic safety studies before being marketed. Manufacturers must consider reducing "ingredient complexities" of their protein powders to prevent adverse interactions between herbal and nonherbal components in consumers. Manufacturers must avoid using known toxic ingredients to reduce the avoidable disease burden within the public community.

Safety and Efficacy of Pegcetacoplan in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria over 48Weeks: 307 Open-Label Extension Study.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening disease characterized by complement-mediated hemolysis and thrombosis. Pegcetacoplan, the first targeted complement component3 (C3) PNH therapy, was safe and efficacious in treatment-naive and pre-treated patients with PNH in five clinical trials. The 307 open-label extension (OLE) study (NCT03531255) is a non-randomized, multicenter extension study of long-term safety and efficacy of pegcetacoplan in adult patients with PNH who completed a pegcetacoplan parent study. All patients received pegcetacoplan. Outcomes at the 48-week data cutoff (week48 of 307-OLE or August 27, 2021, whichever was earlier) are reported. Hemoglobin concentrations, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores, and transfusion avoidance were measured. Hemoglobin > 12g/dL and sex-specific hemoglobin normalization (i.e., male, ≥ 13.6g/dL; female, ≥ 12g/dL) were assessed as percentage of patients with data available and no transfusions 60days before data cutoff. Treatment-emergent adverse events, including hemolysis, were reported. Data from 137 patients with at least one pegcetacoplan dose at data cutoff were analyzed. Mean (standard deviation [SD]) hemoglobin increased from 8.9 (1.22) g/dL at parent study baseline to 11.6 (2.17) g/dL at 307-OLE entry and 11.6 (1.94) g/dL at data cutoff. At parent study baseline, mean (SD) FACIT-Fatigue score of 34.1 (11.08) was below the general population norm of 43.6; scores improved to 42.8 (8.79) at 307-OLE entry and 42.4 (9.84) at data cutoff. In evaluable patients, hemoglobin > 12g/dL occurred in 40.2% (43 of 107) and sex-specific hemoglobin normalization occurred in 31.8% (34 of 107) at data cutoff. Transfusion was not required for 114 of 137 patients (83.2%). Hemolysis was reported in 23 patients (16.8%). No thrombotic events or meningococcal infections occurred. Pegcetacoplan sustained long-term improvements in hemoglobin concentrations, fatigue reduction, and transfusion burden. Long-term safety findings corroborate the favorable profile established for pegcetacoplan. ClinicalTrials.gov identifier, NCT03531255.

Outpatient hysteroscopy: Suitable for all? A retrospective cohort study of safety, success and acceptability in Australia.

In Australia, gynaecologists continue to assess and investigate abnormal uterine bleeding with inpatient hysteroscopy despite evidence validating outpatient hysteroscopy services. This retrospective cohort study assessed the safety, success and acceptability of office hysteroscopy in a gynae-oncology rapid-access clinic over six years in Sydney, Australia, and included all women without an age or body mass index (BMI) cut-off using a 'see and treat' concept. A database was created and analysed retrospectively for patients who attended office hysteroscopy service between January 2016 and March 2021 (63 months, 481 eligible). An anonymous modified PAT-32 patient satisfaction questionnaire was also offered to an initial cohort after their procedure to gauge insightful feedback about acceptability. A total of 92% of patients had successful outpatient hysteroscopic access; 24% of cases required hysteroscopy under general anaesthesia (GA) despite pathology in over 50% of cases; 68% of the total were able to be managed with outpatient hysteroscopy and did not require a follow-up GA hysteroscopy. This paper is also the first of its kind to our knowledge to incorporate patients >65 years, those with a BMI >35 and those with a history of cervical stenosis. This study suggests that age and BMI do not impact the success rate of the procedure. This study demonstrates that outpatient hysteroscopy is an acceptable, safe procedure that is well tolerated by patients. Considering our rapid-access hysteroscopy service allowed 68% of the patient cohort to avoid hysteroscopy under GA, we estimate conservatively ~$63 million per year in Australia could be saved by performing office hysteroscopies.

A Phase 0/I Pharmacokinetic and Pharmacodynamics and Safety and Tolerability Study of Letrozole in Combination with Standard Therapy in Recurrent High-Grade Gliomas.

High-grade gliomas (HGG) carry a poor prognosis, with glioblastoma accounting for almost 50% of primary brain malignancies in the elderly. Unfortunately, despite the use of multiple treatment modalities, the prognosis remains poor in this population. Our preclinical studies suggest that the presence of aromatase expression, encoded by CYP19A1, is significantly upregulated in HGGs. Remarkably, we find that letrozole (LTZ), an FDA-approved aromatase inhibitor, has marked activity against HGGs. We conducted a phase 0/I single-center clinical trial (NCT03122197) to assess the tumoral availability, pharmacokinetics (PK), safety, and tolerability of LTZ in recurrent patients with HGG. Planned dose cohorts included 2.5, 5, 10, 12.5, 15, 17.5, and 20 mg of LTZ administered daily pre- and postsurgery or biopsy. Tumor samples were assayed for LTZ content and relevant biomarkers. The recommended phase 2 dose (R2PD) was determined as the dose that resulted in predicted steady-state tumoral extracellular fluid (ECF; Css,ecf) >2 μmol/L and did not result in ≥33% dose-limiting adverse events (AE) assessed using CTCAE v5.0. Twenty-one patients were enrolled. Common LTZ-related AEs included fatigue, nausea, musculoskeletal, anxiety, and dysphoric mood. No DLTs were observed. The 15 mg dose achieved a Css,ecf of 3.6 ± 0.59 μmol/L. LTZ caused dose-dependent inhibition of estradiol synthesis and modulated DNA damage pathways in tumor tissues as evident using RNA-sequencing analysis. On the basis of safety, brain tumoral PK, and mechanistic data, 15 mg daily is identified as the RP2D for future trials.

Efficacy and safety of oral factor Xa inhibitors versus vitamin-K antagonists in the early phase after acute ischemic stroke or TIA in the real-world setting: The PRODAST study.

Factor Xa (FXa) inhibitors are superior to vitamin K antagonists (VKAs) in terms of avoiding hemorrhagic complications. However, no robust data are available to date as to whether this also applies to the early phase after stroke. In this prospective registry study, we aimed to investigate whether anticoagulation with FXa inhibitors in the early phase after acute ischemic stroke or transient ischemic attack (TIA) is associated with a lower risk of major bleeding events compared with VKAs. The Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA (PRODAST) study is a prospective, multicenter, observational, post-authorization safety study at 86 German stroke units between July 2015 and November 2020. Primary outcome was a major bleeding event during hospital stay. Secondary endpoints were recurrent strokes, recurrent ischemic strokes, TIA, systemic/pulmonary embolism, myocardial infarction, death and the composite endpoint of stroke, systemic embolism, life-threatening bleeding and death. In total, 10,039 patients have been recruited. 5,874 patients were treated with FXa inhibitors and 1,050 patients received VKAs and were eligible for this analysis. Overall, event rates were low. We observed 49 major bleeding complications during 33,297 treatment days with FXa-inhibitors (rate of 14.7 cases per 10,000 treatment days) and 16 cases during 7,714 treatment days with VKAs (rate of 20.7 events per 10,000 treatment days), translating into an adjusted hazard ratio (aHR) of 0.70 (95% confidence interval (95% CI): 0.37-1.32) in favor of FXa inhibitors. Hazards for ischemic endpoints (63 vs 17 strokes, aHR: 0.96 (95% CI: 0.53-1.74), mortality (33 vs 6 deaths, aHR: 0.87 (95% CI: 0.33-2.34)) and the combined endpoint (154 vs 39 events, aHR: 0.99 (95% CI: 0.65-1.41) were not substantially different. This large real-world study shows that FXa inhibitors appear to be similarly effective in terms of bleeding events and ischemic endpoints compared to VKAs in the early post-stroke phase of hospitalization. However, the results need to be interpreted with caution due to the low precision of the estimates.

Immunogenicity and safety of SARS-CoV-2 recombinant protein subunit vaccine (IndoVac) adjuvanted with alum and CpG 1018 in Indonesian adults: A phase 3, randomized, active-controlled, multicenter trial

BackgroundBio Farma has developed a recombinant protein subunit vaccine (IndoVac) that is indicated for active immunization in population of all ages. This article reported the results of the phase 3 immunogenicity and safety study in Indonesian adults aged 18 years and above. MethodsWe conducted a randomized, active-controlled, multicenter, prospective intervention study to evaluate the immunogenicity and safety of IndoVac in adults aged 18 years and above. Participants who were SARS-CoV-2 vaccine-naïve received two doses of either IndoVac or control (Covovax) with 28 days interval between doses and were followed up until 12 months after complete vaccination. ResultsA total of 4050 participants were enrolled from June to August 2022 and received at least one dose of vaccine. The geometric mean ratio (GMR) of neutralizing antibody at 14 days after the second dose was 1.01 (95 % confidence interval (CI) 0.89–1.16), which met the WHO non-inferiority criteria for immunobridging (95 % CI lower bound > 0.67). The antibody levels were maintained through 12 months after the second dose. The incidence rate of adverse events (AEs) were 27.95 % in IndoVac group and 32.15 % in Covovax group with mostly mild intensity (27.70 %). The most reported solicited AEs were pain (14.69 %) followed by myalgia (7.48 %) and fatigue (6.77 %). Unsolicited AEs varied, with each of the incidence rate under 5 %. There were no serious AEs assessed as possibly, probably, or likely related to vaccine. ConclusionsIndoVac in adults showed favourable safety profile and elicited non-inferior immune response to Covovax. (ClinicalTrials.gov: NCT05433285, Indonesian Clinical Research Registry: INA-R5752S9).

A multicenter, open-label long-term safety study of rimegepant for the acute treatment of migraine.

The present study evaluated the long-term safety and tolerability of rimegepant, an orally administered small molecule calcitonin gene-related peptide receptor antagonist, in people with migraine. This multicenter, long-term, open-label safety study included adults (≥18 years) with ≥1 year history of migraine who were sequentially enrolled into three groups: participants in the first two groups had either 2-8 or 9-14 moderate to severe migraine attacks per month by history and treated as needed (pro re nata [PRN]) with one rimegepant 75 mg oral tablet up to once per calendar day for 52 weeks (PRN 2-8 and PRN 9-14); a third group, included to collect safety data during higher-frequency dosing, had 4-14 moderate to severe migraine attacks per month by history and who took one rimegepant tablet every other day as scheduled dosing plus PRN dosing of one rimegepant tablet for migraine attacks of any severity on nonscheduled dosing days for 12 weeks (every other day (EOD) + PRN). Overall, 1800 participants self-administered rimegepant (PRN 2-8: n = 1033; PRN 9-14: n = 481; EOD + PRN: n = 286). The most common on-treatment adverse events (AEs) were upper respiratory tract infection (8.8%), nasopharyngitis (6.8%) and sinusitis (5.1%). Most AEs were mild or moderate and considered unrelated to rimegepant. Serious AEs considered possibly (n = 1) or unlikely (n = 9) related to rimegepant were reported in ten (0.6%) participants. No signal of drug-induced liver injury because of rimegepant was identified. Rimegepant 75 mg up to once per day as EOD + PRN for 12 weeks or PRN for up to 52 weeks was safe and well tolerated. No signal of hepatotoxicity, potential drug abuse, or medication-overuse headache was identified.Trial registration: Clinicaltrials.gov: NCT03266588.

Effect of PCI on Health Status in Ischemic Left Ventricular Dysfunction: Insights From REVIVED-BCIS2

BackgroundIn the REVIVED-BCIS2 (Revascularization for Ischemic Ventricular Dysfunction) trial, percutaneous coronary intervention (PCI) did not reduce the incidence of death or hospitalization for heart failure (HHF). ObjectivesThis prespecified secondary analysis investigated the effect of PCI on health status measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ) combined with the primary outcome in a win ratio. MethodsParticipants with severe ischemic left ventricular dysfunction were randomized to either PCI in addition to optimal medical therapy (OMT) (PCI) or OMT alone (OMT). The primary outcome was a hierarchical composite of all-cause death, HHF, and KCCQ–Overall Summary Score (OSS) at 24 months analyzed using the unmatched win ratio. The key secondary endpoint was a KCCQ-OSS responder analysis. ResultsA total of 347 participants were randomized to PCI and 353 to OMT. Median age was 70.0 years (Q1-Q3: 63.3-76.1 years). Mean left ventricular ejection fraction was 27.0 ± 6.7%. PCI did not improve the primary endpoint (win ratio for PCI vs OMT: 1.05; 95% CI: 0.88-1.26; P = 0.58). PCI resulted in more KCCQ-OSS responders than OMT at 6 months (54.1% vs 40.7%; OR: 1.96; 95% CI: 1.41-2.71; P < 0.001) and fewer deteriorators (25.2% vs 31.4%; OR: 0.69; 95% CI: 0.47-1.00; P = 0.048). PCI did not impact KCCQ-OSS responders or deteriorators at 12 or 24 months. ConclusionsPCI did not improve the hierarchical composite of death, HHF, and health status at 2 years. PCI improved KCCQ-OSS at 6 months, but this benefit was not sustained to 1- or 2-year follow-up. (Revacularization for Ischemic Ventricular Dysfunction [REVIVED-BCIS2]; NCT01920048)

Risk of extended major adverse cardiovascular event endpoints with tofacitinib versus TNF inhibitors in patients with rheumatoid arthritis: a post hoc analysis of a phase 3b/4 randomised safety study

ObjectivesCompare the risk of extended major adverse cardiovascular (CV) event (MACE) composite outcomes and component events in patients with rheumatoid arthritis (RA) treated with tofacitinib versus tumour necrosis factor inhibitors...

Big Multiple Sclerosis Data network: an international registry research network.

The Big Multiple Sclerosis Data (BMSD) network ( https://bigmsdata.org ) was initiated in 2014 and includes the national multiple sclerosis (MS) registries of the Czech Republic, Denmark, France, Italy, and Sweden as well as the international MSBase registry. BMSD has addressed the ethical, legal, technical, and governance-related challenges for data sharing and so far, published three scientific papers on pooled datasets as proof of concept for its collaborative design. Although BMSD registries operate independently on different platforms, similarities in variables, definitions and data structure allow joint analysis of data. Certain coordinated modifications in how the registries collect adverse event data have been implemented after BMSD consensus decisions, showing the ability to develop together. Scientific projects can be proposed by external sponsors via the coordinating centre and each registry decides independently on participation, respecting its governance structure. Research datasets are established in a project-to-project fashion and a project-specific data model is developed, based on a unifying core data model. To overcome challenges in data sharing, BMSD has developed procedures for federated data analysis. Presently, BMSD is seeking a qualification opinion from the European Medicines Agency (EMA) to conduct post-authorization safety studies (PASS) and aims to pursue a qualification opinion also for post-authorization effectiveness studies (PAES). BMSD aspires to promote the advancement of real-world evidence research in the MS field.

Development of a pharmaceutical database as an aid to the nonclinical detection of drug-induced cardiac toxicity

The Health and Environmental Sciences Institute (HESI) Cardiac Safety Committee designed and created a publicly accessible database with an initial set of 128 pharmacologically defined pharmaceutical agents, many with known cardiotoxic properties. The database includes specific information about each compound that could be useful in evaluating hypotheses around mechanisms of drug-induced cardiac toxicity or for development of novel cardiovascular safety assays. Data on each of the compounds was obtained from published literature and online sources (e.g., DrugBank.ca and International Union of Basic and Clinical Pharmacology (IUPHAR) / British Pharmacological Society (BPS) Guide to PHARMACOLOGY) and was curated by 10 subject matter experts. The database includes information such as compound name, pharmacological mode of action, characterized cardiac mode of action, type of cardiac toxicity, known clinical cardiac toxicity profile, animal models used to evaluate the cardiotoxicity profile, routes of administration, and toxicokinetic parameters (i.e., Cmax). Data from both nonclinical and clinical studies are included for each compound. The user-friendly web interface allows for multiple approaches to search the database and is also intended to provide a means for the submission of new data/compounds from relevant users. This will ensure that the database is constantly updated and remains current. Such a data repository will not only aid the HESI working groups in defining drugs for use in any future studies, but safety scientists can also use the database as a vehicle of support for broader cardiovascular safety studies or exploring mechanisms of toxicity associated with certain pharmacological modes of action.

Pharmacokinetics and Preclinical Safety Studies of Modified Endolysin-based Gel for Topical Application

Antibacterial therapy with phage-encoded endolysins or their modified derivatives with improved antibacterial, biochemical and pharmacokinetic properties is one of the most promising strategies that can supply existing antibacterial drugs array. Gram-negative bacteria-induced infections treatment is especially challenging because of rapidly spreading bacterial resistance. We have developed modified endolysin LysECD7-SMAP with a significant antibacterial activity and broad spectra of action against gram-negative bacteria. Endolysin was formulated in a bactericidal gel for topical application with pronounced effectivity in local animal infectious models. Here we present preclinical safety studies and pharmacokinetics of LysECD7-SMAP-based gel. We have detected LysECD7-SMAP in the skin and underlying muscle at therapeutic concentrations when the gel is applied topically to intact or injured skin. Moreover, the protein does not enter the bloodstream, and has no systemic bioavailability, assuming no systemic adverse effects. In studies of general toxicology, local tolerance, and immunotoxicology it was approved that LysECD7-SMAP gel local application results in the absence of toxic effects after single and multiple administration. Thus, LysECD7-SMAP-containing gel has appropriate pharmacokinetics and can be considered as safe that supports the initiation of the phase I clinical trials of novel antibacterial drug intending to treat acute wound infections caused by resistant gram-negative bacteria.

A Study of Safety and Effectiveness of Evicel Fibrin Sealant as an Adjunctive Hemostat in Pediatric Surgery.

Data on the use of fibrin sealants to control intraoperative bleeding in children are scarce. Evicel Fibrin Sealant (Ethicon Inc., Raritan, New Jersey, United States) was found safe and effective in clinical trials of adults undergoing various surgery types. We evaluated the safety and efficacy of Evicel versus Surgicel Absorbable Hemostat (Ethicon Inc.) as adjunctive topical hemostats for mild/moderate raw-surface bleeding in pediatric surgery. A phase III randomized clinical trial was designed as required by the European Medicines Agency's Evicel Pediatric Investigation Plan: 40 pediatric subjects undergoing abdominal, retroperitoneal, pelvic, or thoracic surgery were randomized to Evicel or Surgicel, to treat intraoperative mild-to-moderate bleeding. Descriptive analyses included time-to-hemostasis and rates of treatment success (4, 7, 10 minutes), intraoperative treatment failure, rebleeding, and thromboembolic events. Forty of 130 screened subjects aged 0.9 to 17 years were randomized 1:1 to Evicel or Surgicel. Surgeries were predominantly open abdominal procedures. The median bleeding area was 4.0 cm2 for Evicel and 1.0 cm2 for Surgicel. The median time-to-hemostasis was 4.0 minutes for both groups. The 4-, 7-, and 10-minute treatment success rates were 80.0% versus 65.0%, 100.0% versus 80.0%, and 95.0% versus 90.0%, whereas treatment failure rates were 5.0% versus 25.0%, for Evicel and Surgicel, respectively. No deaths or thrombotic events occurred. Re-bleeding occurred in 5.0% of Evicel and 10.0% of Surgicel subjects. In accordance with adult clinical trials, this randomized study supports the safety and efficacy of Evicel for controlling mild-to-moderate surgical bleeding in a broad range of pediatric surgical procedures.

Inhalable porous particles as dual micro-nano carriers demonstrating efficient lung drug delivery for treatment of tuberculosis

Inhalation therapy treating severe infectious disease is among the more complex and emerging topics in controlled drug release. Micron-sized carriers are needed to deposit drugs into the lower airways, while nano-sized carriers are of preference for cell targeting. Here, we present a novel and versatile strategy using micron-sized spherical particles with an excellent aerodynamic profile that dissolve in the lung fluid to ultimately generate nanoparticles enabling to enhance both extra- and intra-cellular drug delivery (i.e., dual micro-nano inhalation strategy). The spherical particles are synthesised through the condensation of nano-sized amorphous silicon dioxide resulting in high surface area, disordered mesoporous silica particles (MSPs) with monodispersed size of 2.43 μm. Clofazimine (CLZ), a drug shown to be effective against multidrug-resistant tuberculosis, was encapsulated in the MSPs obtaining a dry powder formulation with high respirable fraction (F.P.F. <5 μm of 50%) without the need of additional excipients. DSC, XRPD, and Nitrogen adsorption-desorption indicate that the drug was fully amorphous when confined in the nano-sized pores (9–10 nm) of the MSPs (shelf-life of 20 months at 4 °C). Once deposited in the lung, the CLZ-MSPs exhibited a dual action. Firstly, the nanoconfinement within the MSPs enabled a drastic dissolution enhancement of CLZ in simulated lung fluid (i.e., 16-fold higher than the free drug), increasing mycobacterial killing than CLZ alone (p = 0.0262) and reaching concentrations above the minimum bactericidal concentration (MBC) against biofilms of M. tuberculosis (i.e., targeting extracellular bacteria). The released CLZ permeated but was highly retained in a Calu-3 respiratory epithelium model, suggesting a high local drug concentration within the lung tissue minimizing risk for systemic side effects. Secondly, the micron-sized drug carriers spontaneously dissolve in simulated lung fluid into nano-sized drug carriers (shown by Nano-FTIR), delivering high CLZ cargo inside macrophages and drastically decreasing the mycobacterial burden inside macrophages (i.e., targeting intracellular bacteria). Safety studies showed neither measurable toxicity on macrophages nor Calu-3 cells, nor impaired epithelial integrity. The dissolved MSPs also did not show haemolytic effect on human erythrocytes. In a nutshell, this study presents a low-cost, stable and non-invasive dried powder formulation based on a dual micro-nano carrier to efficiently deliver drug to the lungs overcoming technological and practical challenges for global healthcare.

Role of biologics in severe food allergy.

This review examine the dynamic landscape of food allergy treatment within the context of emerging biologics. Our purpose is to comprehensively evaluate the potential benefits, challenges, and transformative impact associated with the utilization of biologics in comparison to conventional therapeutic modalities. This document synthesizes recent scientific investigations to various biologics, such as omalizumab, ligelizumab, dupilumab, and tezepelumab, providing a nuanced understanding of their roles in oral immunotherapy, rapid desensitization, and overall food allergy management. Recent studies and clinical trials highlight the impact of anti-IgE treatment on food allergies, revealing critical findings such as dose-related efficacy, facilitation of rapid desensitization in peanut allergies, and the sustained positive outcomes observed in individuals with multifood allergies. The use of biologics presents a groundbreaking approach in the treatment of food allergies. The multifaceted action of these agents, along with their potential to overcome the challenges associated with traditional therapies, marks a significant advancement. Despite the persisting challenges of economic constraints and the need for further safety studies, biologics offer a promising avenue for improving the quality of life for individuals with food allergies. Ongoing research and collaborative efforts are imperative to fully realize the transformative potential inherent in these emerging therapeutic frontiers.

Development of radiation sources based on CAD models for the nuclear analysis of IFMIF-DONES lithium loop

IFMIF-DONES is a neutron source designed to irradiate materials to be used in future fusion power reactors such as DEMO. The facility is based on a deuteron beam impinging onto a liquid lithium jet to generate the neutron flux. Lithium and Corrosion Products will get activated and produce Be-7 and Activated Corrosion Products (ACP). These products will be distributed along the lithium loop, both dissolved in lithium and deposited locally. This complex gamma source should be properly represented to perform radiological safety studies. A new tool, called CAD2CDGS, was created to represent these sources. This tool creates decay gamma sources based on CAD geometries and codifies them into CDGS format. Sources are specified in the CAD model, allowing a user-friendly approach. The tool is based on Open-Source tools (FreeCAD) and EUROfusion codes (cR2S European SDDR tool). In this article the CAD2CDGS tool methodology, inputs and workflow are explained. Two verification tests have been done to check the correctness. Finally, it is demonstrated the applicability of the tool to IFMIF-DONES, with the radiological zoning analysis of the rooms surrounding the Lithium Loop Cell impact by the Be-7 and ACP.

A Phase 1, Double-blinded, Placebo-Controlled Clinical Trial to Evaluate the Safety and Immunogenicity of HEV-239 (Hecolin®) Vaccine in Healthy US Adults.

Establishing the safety and immunogenicity of a hepatitis E virus vaccine in multiple populations could facilitate broader access and prevent maternal and infant mortality. We conducted a phase 1, randomized, double-blinded, placebo-controlled (4:1 vaccine: placebo) trial of 30 µg HEV-239 (Hecolin®, Xiamen Innovax Biotech Company Limited, China) administered intramuscularly in healthy US adults aged 18-45 years. Participants were vaccinated on days 1, 29, and 180. Participants reported solicited local and systemic reactions for 7 days following vaccination and were followed through 12 months after enrollment for safety and immunogenicity (IgG, IgM). Solicited local and systemic reactions between treatment and placebo group were similar and overall mild. No participants experienced serious adverse events related to HEV-239. All participants receiving HEV-239 seroconverted at one month following the first dose and remained seropositive throughout the study. HEV-239 elicited a robust hepatitis E IgG response that peaked one month following the second dose (Geometric Mean Concentration (GMC) 6.16; 95% CI 4.40-8.63), was boosted with the third dose (GMC 11.50; 95% CI 7.90-16.75) and persisted through 6 months. HEV-239 is safe and elicits a durable immune response through at least 6 months after the third dose in healthy US adults. NCT03827395. Safety Study of Hepatitis E Vaccine (HEV239) - Full Text View - ClinicalTrials.gov.