Preclinical Program Research Articles

A Systematic Review of the State of Preclinical Mentorship Programs in Plastic and Reconstructive Surgery.

Plastic and reconstructive surgery is consistently one of the most competitive medical specialties in the match. The recent United States Medical Licensing Examination score reporting switch to pass-fail led to a change in metrics by which applicants are evaluated by plastic surgery programs. Applicant research productivity and the demand for plastic surgery mentorship will continue to rise. Given the competitive nature of the residency match and shift in metrics emphasis after the change in STEP 1 scoring, early exposure to plastic surgery and mentoring relationships are paramount to applicant success. However, most medical students are not exposed to plastic surgery until they begin clinical rotations. A literature review of plastic surgery mentorship programs available during preclinical years was conducted to identify preclinical mentorship opportunities in plastic surgery. Sixty-eight references were identified, but only two studies met the inclusion criteria of addressing mentorship programs in preclinical years. Examination of the included studies indicated that preclinical medical students achieve self-identified goals and generate longitudinal benefits in plastic surgery by participating in early and focused mentorship programs. The limited number of studies in this review highlights a lack of available, studied preclinical mentorship programs in plastic surgery and reveals a knowledge gap concerning the creation of successful preclinical mentorship programs. Early exposure to plastic surgery, combined with the development of structured preclinical mentorship programs, can potentially replicate successful outcomes seen in other surgical subspecialties' mentorship programs while addressing the lack of formalized mentorship opportunities for preclinical students in plastic surgery.

Design and Preclinical Characterization Program toward Asundexian (BAY 2433334), an Oral Factor XIa Inhibitor for the Prevention and Treatment of Thromboembolic Disorders.

Activated coagulation factor XI (FXIa) is a highly attractive antithrombotic target as it contributes to the development and progression of thrombosis but is thought to play only a minor role in hemostasis so that its inhibition may allow for decoupling of antithrombotic efficacy and bleeding time prolongation. Herein, we report our major efforts to identify an orally bioavailable, reversible FXIa inhibitor. Using a protein structure-based de novo design approach, we identified a novel micromolar hit with attractive physicochemical properties. During lead modification, a critical problem was balancing potency and absorption by focusing on the most important interactions of the lead series with FXIa while simultaneously seeking to improve metabolic stability and the cytochrome P450 interaction profile. In clinical trials, the resulting compound from our extensive research program, asundexian (BAY 2433334), proved to possess the desired DMPK properties for once-daily oral dosing, and even more importantly, the initial pharmacological hypothesis was confirmed.

Preclinical simulation integrated into a nurse practitioner disease management course: Student perceptions and learning outcomes

ABSTRACT Nurse practitioner (NP) educators have been tasked with incorporating simulation into preclinical curricula while pivoting to competency-based education. Despite evidence supporting simulation's role in preclinical health care education, limited scholarship has evaluated this educational method among NP students. We sought to evaluate student perceptions, learning satisfaction, and confidence after participation in an experientially designed, preclinical, simulation program and to compare levels of clinical communication self-efficacy and self-rated, clinical rotation preparedness before and after participation. The preclinical simulation program was designed, implemented, and evaluated within a disease management course. Students reported high levels of satisfaction and confidence with learning. Clinical communication self-efficacy (t[17] = 3.73, p < .01) and self-rated levels of clinical rotation preparedness (t[17] = −2.97, p < .01) were significantly higher after program participation. Simulation may be successfully implemented in preclinical disease management courses. Positive program evaluations create a foundation for further competency-based NP educational design using simulation. Faculty should consider implementing experientially designed preclinical simulation in NP programs to promote progression toward competency within the NP role and to encourage clinical readiness.

A small animal model of NASH with progressive steatohepatitis -induced by fast food diet and alcohol in C57BL/6J mouse with high human pathophysiological proximity.

Non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis (ASH) both can progress to end-stage liver disease (ESLD). No relevant animal models are available for studying the toxic consequences of concurrent fast food diet and alcohol usage in fibrosing NASH. As a result, dependable and short-term in-vivo models capable of recapitulating human disease pathophysiology are required for deciphering mechanistic insights and preclinical drug discovery programs. The current study aims to develop a mouse model for progressive steatohepatitis employing a fast food (FF) diet with intermittent oral alcohol (EtOH) administration. For eight (8) weeks, C57BL/6J mice were fed standard chow (SC) diet±EtOH or FF±EtOH. EtOH uses enhanced the histological characteristics of FF -induced steatohepatitis and fibrosis. A dysregulated molecular signaling cascade related to oxidative stress, steatosis, fibrosis, DNA damage, and apoptosis was evident at protein and gene expression levels in the FF+EtOH. The results from the in-vivo model were replicated in mouse hepatocyte cultures (AML-12) subjected to palmitic acid (PA)±EtOH exposures. The results of the present study indicate that the clinical hallmarks of human progressive steatohepatitis and fibrosis were achieved in our mice model, showing its suitability for preclinical research.

The pharmacokinetic profile of brensocatib and its effect on pharmacodynamic biomarkers including NE, PR3, and CatG in various rodent species.

Brensocatib is a novel, oral, selective, reversible inhibitor of dipeptidyl peptidase 1 (DPP1), which activates several neutrophil serine proteases (NSPs), including neutrophil elastase (NE), proteinase 3 (PR3), and cathepsin G (CatG) in the bone marrow during the early stage of neutrophil maturation. These NSPs are associated with pathogen destruction and inflammatory mediation; their dysregulated activation can result in excess secretion of active NSPs causing damaging inflammation and contributing to neutrophil-mediated inflammatory and autoimmune diseases. Pharmacological inhibition of DPP1 in the bone marrow could therefore represent an attractive strategy for these neutrophil-driven diseases. A completed Phase 2 trial in non-cystic fibrosis bronchiectasis patients (ClinicalTrials.gov number NCT03218917; EudraCT number: 2017-002533-32) indeed demonstrated that administration of brensocatib attenuated the damaging effects of chronic inflammation by inhibiting the downstream activation of NSPs. To support a range of preclinical programs and further understand how rodent species and strains may affect brensocatib's pharmacokinetic (PK) profile and its pharmacodynamic (PD) effects on NE, PR3, and CatG, an extensive naïve dosing study with brensocatib at different dosing levels, frequencies, and durations was undertaken. Dose-dependent PK exposure responses (AUC and Cmax) were observed regardless of the rodent species and strain. Overall, mice showed greater reduction in NSP activities compared to rats. Both mice and rats dosed once daily (QD) had equivalent NSP activity reduction compared to BID (twice a day) dosing when the QD dose was 1.5-times the BID daily dose. For both mouse strains, CatG activity was reduced the most, followed by NE, then PR3; whereas, for both rat strains, PR3 activity was reduced the most, followed by CatG, and then NE. Maximum reduction in NSP activities was observed after ∼7 days and recoveries were nearly symmetrical. These results may facilitate future in vivo brensocatib study dosing considerations, such as the timing of prophylactic or therapeutic administration, choice of species, dosage and dosing frequency.

BMaps: A Web Application for Fragment-Based Drug Design and Compound Binding Evaluation.

Fragment-based drug design uses data about where, and how strongly, small chemical fragments bind to proteins, to assemble new drug molecules. Over the past decade, we have been successfully using fragment data, derived from thermodynamically rigorous Monte Carlo fragment-protein binding simulations, in dozens of preclinical drug programs. However, this approach has not been available to the broader research community because of the cost and complexity of doing simulations and using design tools. We have developed a web application, called BMaps, to make fragment-based drug design widely available with greatly simplified user interfaces. BMaps provides access to a large repository (>550) of proteins with 100s of precomputed fragment maps, druggable hot spots, and high-quality water maps. Users can also employ their own structures or those from the Protein Data Bank and AlphaFold DB. Multigigabyte data sets are searched to find fragments in bondable orientations, ranked by a binding-free energy metric. The designers use this to select modifications that improve affinity and other properties. BMaps is unique in combining conventional tools such as docking and energy minimization with fragment-based design, in a very easy to use and automated web application. The service is available at https://www.boltzmannmaps.com.

The use of simulators to acquire ERCP skills: a systematic review.

In 2022, a systematic search of the literature was conducted on MEDLINE and SCOPUS under the guidance of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020 protocol seeking articles with the MeSH terms 'Endoscopic Retrograde Cholangiopancreatography' OR 'ERCP' in combination with 'simulation' OR 'simulator'. The search resulted in 41 references. A total of 19 articles met the inclusion criteria and were included in the qualitative analysis. Only one of the articles fulfilled the criteria of a robust validation study. Since only one of the 19 articles met the requirements for a thorough and correct validation, further studies with sufficient numbers of subjects, that evaluate complete preclinical training programs based on validated ERCP simulators are warranted.

Manual dexterity in dentistry: Development and evaluation of a preclinical training program.

The aim of this study was to develop and evaluate the effect of a manual dexterity training program on manual dexterity, perception of self-confidence, quality of cavity preparations, and ergonomic work posture of dental students prior to preclinical training. Students in the first year of the undergraduate dentistry program (N = 63) participated in this study. The program consisted of eight phases in which students performed different types of activities. The dependent variables were: manual dexterity assessed by the modified Dental Manual Dexterity Assessment; self-confidence to perform a preclinical procedure using the VAS scale; quality of Class I cavity preparation; angular deviation from the neutral position of the neck, trunk, wrist and distance between the student's eyes and the mannequin's tooth. These variables were evaluated at two different times: before and after the application of the program. The independent variable was the preclinical manual dexterity training program. After meeting the assumption of normality, the paired t-Student test was performed, the significance level was 5%. The results showed a statistically significant difference in relation to manual dexterity (p < 0.001), self-confidence (p < 0.001), quality of cavity preparations (p < 0.001), distance from the eyes of the student/mannequin (p < 0.001), deviation angle of the neutral position of the trunk (p = 0.007) and wrists (p < 0.001), with better results in posttraining. It was possible to conclude that, in general, the proposed training positively influenced the self-confidence, dexterity, quality of work, and ergonomics of the evaluated students.

Использование приматов в доклинических исследованиях препаратов моноклональных антител

The emergence of new biopharmaceuticals, including therapeutic monoclonal antibodies (MABs), required a revision of the preclinical development strategy. To provide human risk assessment data, preclinical in vivo efficacy and safety studies of biotechnology-derived pharmaceuticals should be conducted in pharmacologically relevant species. A relevant species is one in which the test material is pharmacologically active due to the expression of the epitope and is one which demonstrate a similar tissue cross-reactivity profile as for human tissues. Often, the only relevant species for preclinical safety assessment of therapeutic MABs are non-human primates (NHPs). If there are no other alternatives (homologous proteins, genetically modified animals), all measures should be taken to reduce the number of animals involved in preclinical studies in accordance with the 3Rs principle. There is not a single solution for therapeutic MABs preclinical development program. When planning research, a scientifically-based approach should always be applied, taking into account all available data. While NHPs are currently necessary to provide risk assessment data for many therapeutic MABs, the very characteristics of MABs biology such as high target specificity, predictable metabolic pathways, and low toxicity, also provide opportunities to minimize the use of NHPs in safety testing and to increase the efficiency of MABs development. The opportunities to adapt development program for MAB at low risk of toxicity include reducing the number of chronic studies, dose groups and recovery group animals. If rodents are also a pharmacologically relevant species, the use of NSPs may be reduced. The paper discusses examples of preclinical programs for therapeutic MABs and possible strategies aimed to minimize the number of NHPs during preclinical safety studies without compromising human safety.

Endocrine Disorders Associated with Medicinal Products: Approaches to Preclinical Safety Assessment

The endocrine system coordinates almost all organs and other systems in vertebrates. In particular, it regulates such important biological functions as metabolism, development, reproduction, and behaviour. To date, a significant amount of information has accumulated on endocrine disorders associated with chemical compounds (endocrine disruptors) used in various fields of human activity. The aim of this study was to evaluate the possibility of preclinical risk assessment for the endocrine function disorders attributable to new medicinal products. Endocrine disruptors are associated with a wide range of adverse events, including developmental problems arising from functional abnormalities of the endocrine system. Endocrine disorders caused by endocrine-disrupting chemicals are characterised by a long latency period between exposure and manifestation of a dysfunction; a nonlinear dose–response relationship; and a linear correlation of damage severity to exposure timing and duration. The chemicals influence the endocrine system through multiple mechanisms, the main of which being the interaction with cellular receptors sensitive to certain hormones and the influence on gene expression, intracellular signalling, and hormone transport, etc. This paper discusses the possibility of using hormone levels as indicators of endocrine disruption and presents the literature and authors’ own data on normal levels of relevant hormones in the blood of animals. An analysis of animal blood hormone levels in preclinical programmes will provide an opportunity to evaluate potential iatrogenic risks.

Practical tips for moving your patient panel online.

Patient panels are an inspiring, highly rated educational tool to complement course goals and objectives for students in medical education programs. The COVID-19 pandemic brought challenges on the ability to successfully host in-person patient panels. These challenges resulted in the need to pivot in-person patient panels to online platforms, while still ensuring the quality and intimacy of patient narratives. In this 12 tips article, we share lessons learned in transitioning patient panels in our health systems science curriculum to an online experience for students enrolled in a pre-clinical medical education program.

Pharmaceutical Toxicology is the Most Important Component of Preclinical Studies

The first principle for ensuring patient safety is to do no harm (primum non nocere). It clearly justifies why the legislative requirements for the safety of medicinal products should be strict and meticulous. The aim of preclinical safety evaluation is to protect public health by preventing the clinical use of medicinal products with a potentially unfavourable risk–benefit profile. Traditionally, toxicology is defined as the study of the adverse effects of chemical substances on living organisms. Toxicity studies are integral to preclinical programmes for new medicinal products. The role of toxicology in preclinical studies is explained in this interview by Corresponding Member of the Russian Academy of Sciences, Doctor of Medical Sciences, and Full Professor Andrey D. Durnev. Dr. Durnev is a laureate of the State Prize of the Russian Federation. He holds the positions of Head of the Pharmaceutical Toxicology Department of V.V. Zakusov Institute of Pharmacology, Chairman of the Commission of the Ministry of Health of the Russian Federation for the Certification of Experts for the Right to Perform Regulatory Evaluation of Medicinal Products for Human Use, and Deputy Chairman of the Interdepartmental Council of the Russian Academy of Sciences on the Scientific Substantiation and Maintenance of Drug Policy of the Russian Federation.

Toward Inclusivity in Preclinical Drug Development: A Proposition to Start with Intestinal Organoids.

Representation of humans from diverse backgrounds in the drug development process is key to advancing health equity, and while clinical trial design has recently made strides toward greater inclusivity, preclinical drug development has struggled to make those same gains. One barrier to inclusion is the current lack of robust and established in vitro model systems that simultaneously capture the complexity of human tissues while representing patient diversity. Here, the use of primary human intestinal organoids as a mechanism to advance inclusive preclinical research is proposed. This in vitro model system not only recapitulates tissue functions and disease states, but also retains the genetic identity and epigenetic signatures of the donors from which they are derived. Thus, intestinal organoids are an ideal in vitro prototype for capturing human diversity. In this perspective, the authors call for an industry-wide effort to leverage intestinal organoids as a starting point to actively and intentionally incorporate diversity into preclinical drug programs.

Application of Size Exclusion Chromatography with Multiangle Light Scattering in the Analytical Development of a Preclinical Stage Gene Therapy Program.

To provide safe recombinant adeno-associated viruses (rAAV) to patients, scalable manufacturing processes are required. However, these processes may introduce impurities that impact the performance and quality of the final drug product. Empty rAAV capsids are product-related impurities. Regulatory guidance requires that accurate analytical methods be implemented early in product development to measure the level of empty capsids. A process confirmation vector, produced from 200 L production, was used to develop and optimize a size exclusion chromatography with UV and multiangle light scattering (SEC-MALS) method. Vector produced from a 500 L production was used to assess the full-to-empty ratio using the following analytical methods: sedimentation velocity analytical ultracentrifugation (SV-AUC), droplet digital PCR (ddPCR) with capsid enzyme-linked immunosorbent assay (ELISA), bulk absorbance at 260/280 nm, cryogenic electron microscopy, and SEC-MALS. This test article was used for a 30-day, non-Good Laboratory Practices animal study that assessed biodistribution of the product (STRX-330). SEC-MALS outperformed the other methods and correlated well with SV-AUC values of full-to-empty particles. In addition, SEC-MALS agreed with ddPCR and ELISA measurements for vector genomes/mL and capsid particles/mL, respectively. SEC-MALS was linear, accurate, and precise while achieving chromatography quality control (QC) recommendations. Compared to other stability-indicating assays, SEC-MALS performed similarly to ddPCR, capsid ELISA, and infectivity assays in accelerated stress studies. In response to alkaline, but not acidic stress, SEC-MALS indicated distinct changes in the DNA content of the monomer Adeno-associated viruses (AAV) peak for STRX-330, which was supported by ddPCR data. Conversely, acidic treatment resulted in more aggregated vector, but did not impact the DNA content. This work indicates that SEC-MALS is a valuable analytical tool in the analytical development and QC testing of AAV. In addition, this work suggests that SEC-MALS can provide fundamental understanding of AAV in response to environmental stress. This may impact steps of the manufacturing process to minimize conditions that reduce performance.

Preparing allied health students for placement: a contrast of learning modalities for foundational skill development

BackgroundWith increasing pressure on placement capacity for allied health students, a need for novel and creative means through which students can develop foundational skills and prepare for practice-based learning opportunities has arisen. This study aimed to explore the experiences of domestic and international first-year students completing pre-clinical preparation programs, contrasting between in-person simulation and online options to contribute to best practice evidence for program design and delivery.MethodsFirst-year students from physiotherapy, podiatry and occupational therapy self-selected to either a one-weeklong in-person simulation program or an online preparation for placement program. An integrative mixed-methods approach was employed. Qualitative findings from student focus groups were analyzed by reflexive thematic analysis and complemented by quantitative pre-post questionnaires which were examined for patterns of findings.ResultsThere were 53 student participants in the study (simulation n = 29; online n = 24). Self-selecting, international students disproportionately opted for the simulation program while older students disproportionately selected the online program. Students appeared to benefit more from the simulation program than the online program, with alignment of focus group findings to the quantitative questionnaire data. The in-person simulation allowed students to apply their learning and practice patient communication. All simulation students reported asubsequent increase in confidence, although this seemed particularly marked for the international students. By contrast, the online program was most effective at developing students’ clinical reasoning and proficiency with documentation. Both programs faced minor challenges to student perceived relevance and skill development.ConclusionBoth online and in-person simulation preparation programs were perceived to enhance readiness and foundational skills development for novice allied health students, with the practical nature of simulation generating more advantageous findings. This study provides useful information on the benefits and challenges of both types of delivery for foundational skills development and/or clinical preparation of allied health students.

Pfizer invests $25 million in Ribon

Pfizer has invested $25 million in Ribon Therapeutics, a small-molecule drug developer targeting stress support pathways. Ribon intends to put the funds toward the clinical development of two small-molecule inhibitors, one in oncology and one in immunology. A Pfizer exec will also join Ribon’s advisory board as part of the investment. In November 2022, Boehringer Ingelheim agreed to acquire one of Ribon’s preclinical programs for an undisclosed amount.

Editorial introductions.

Editorial introductions.

Innovative Pedagogical Strategies in Health Professions Education: Active Learning in Dental Materials Science.

Dental materials science education is frequently delivered via traditional didactic lectures in preclinical dental programs. This review aimed to appraise the current evidence on innovative pedagogical strategies in teaching dental materials science courses. English-language articles on teaching methods for dental materials science published between January 1990 to October 2022 were searched in nine online databases (Google Scholar, PubMed, Web of Science [WoS], Science Direct, Cochrane Library, EBSCO, LILACS, Open Grey, and EMBASE) according to PRISMA guidelines. The risk of bias (RoB) was assessed using the Cochrane RoB-2 and ROBIN-I tools, whereas the level of evidence was determined based on the OCEBM guidelines. Only 12 primary studies were included. Two randomized studies (RCTs) were deemed as being of "some concern", and one showed a high risk of bias (RoB). Three non-randomized controlled studies (NRS) demonstrated a moderate RoB, whereas the remaining seven were low. Most studies were ranked at Levels 2 and 3 of evidence. Several innovative pedagogical strategies were identified: flipped classrooms, clinical-based learning, computer-assisted learning, group discussion, microteaching with the BOPPPS (bridge-in, learning objective, pre-test, participatory learning, post-test, and summary) model, and game-based learning. The evidence suggested that students generally showed positive perceptions toward these pedagogical strategies. Dental educators should revise their current undergraduate dental materials science curricula and integrate more effective teaching methods.

S-19-4: ANGIOTENSINOGEN SIRNA FOR HYPERTENSIVE PATIENTS

Multiple types of renin-angiotensin system (RAS) blockers exist, allowing interference with the system at the level of renin, angiotensin-converting enzyme or the angiotensin II receptor. Yet, in particular for the treatment of hypertension, the number of patients with uncontrolled hypertension continues to rise, either due to patient non-compliance, or because of the significant renin rises that may, at least partially, overcome the effect of RAS blockade (RAS escape). New approaches to target the RAS are either direct antisense oligonucleotides (ASO) that inhibit angiotensinogen RNA translation, or small interfering ribonucleic acids (siRNA) that function via the RNA interference pathway. Since all angiotensins stem from angiotensinogen, lowering angiotensinogen has the potential to circumvent the RAS escape phenomenon. Moreover, ASO and siRNA require injections only every few weeks to months, which might reduce non-compliance. Of course, angiotensinogen suppression also poses a threat in situations where the RAS is acutely needed, for instance in women becoming pregnant during treatment, or in cases of emergency, when severe hypotension occurs. This presentation discusses all preclinical data on angiotensinogen suppression, as well as the limited clinical data that are currently available. It concludes that it is an exciting new tool to target the RAS with high specificity and a low side effect profile. Its long-term action might revolutionize pharmacotherapy, as it could overcome compliance problems. Preclinical and clinical programs are now carefully investigating its efficacy and safety profile, allowing an optimal introduction as a novel drug to treat cardiovascular and renal diseases in due time.

A method for detection of anti-drug antibodies to a biotherapeutic (CSL112) with endogenous counterpart (apolipoprotein A-I) using a novel sample pre-treatment electrochemiluminescence assay

BackgroundThere are numerous challenges encountered during clinical testing for an immunogenic response to a plasma-derived therapeutic. Distinguishing between antibodies that recognize endogenous versus therapeutic protein can be particularly difficult. This study focused on CSL112 (human plasma-derived apolipoprotein A-I; apoA-I), which is in clinical development for reducing the risk of recurrent major adverse cardiovascular events following acute myocardial infarction. AimTo develop and validate a high-throughput, highly sensitive and specific assay to detect antibodies to CSL112 that can be used for immunogenicity assessment in large clinical studies. ResultsWe developed a clinical anti-drug antibody (ADA) assay utilizing an immunoglobulin purification step that improved specificity and drug tolerance, demonstrating that measurement of pre-existing or treatment emergent ADAs was highly dependent on assay format. The Sample Pre-treatment Electrochemiluminescence (ECL; SPECL) assay incorporates a protein A extraction of serum samples before a bridging assay is performed on an ECL platform. The assay is qualitative, sensitive (lower limit of quantification <39 ng/mL) and has a drug tolerance of 0.5 mg/mL in line with U.S. Food and Drug Administration requirements for clinical immunogenicity assays for therapeutic proteins. Importantly, the SPECL assay demonstrated the absence of antibodies to both apoA-I and CSL112 both prior to drug exposure and after repeated dosing across multiple trials (n = 970 subjects). ConclusionThe SPECL method has been validated and applied to support the CSL112 preclinical and clinical development program and has broader application to similar protein therapeutics. Attributes of the methodology include high drug tolerance, high sensitivity, selectivity, and precision. This format is amenable to automation providing the high throughput and reduced variability required to support large scale clinical studies that span extended time periods.