Pharmacological Exposure Research Articles

Effects of Valproic Acid Embryonic Exposure on Zebrafish: A Systematic Review and Meta-Analysis.

Exposure to valproic acid (VPA) during embryogenesis has become a valuable tool for modeling neurodevelopmental disorders in animal models such as zebrafish (Danio rerio). This article examines the effects of embryonic exposure to VPA in zebrafish on the basis of 39 articles sourced from PubMed and Google Scholar. We conducted a systematic review and meta-analysis to elucidate the common impacts of VPA exposure and reported that VPA significantly altered development at various levels. Behaviorally, zebrafish exposed to VPA exhibit notable changes in their social interaction patterns. Physiologically, VPA exposure leads to significant alterations, including decreased heart rates, increased mortality rates, and pronounced morphological abnormalities. Pharmacological exposure has been linked to neuroanatomical and neurochemical changes. At the genetic level, VPA exposure is associated with the differential expression of genes involved in neurodevelopment and neuronal function. The synthesized data from these studies underscore the utility of zebrafish as a model organism for investigating the effects of teratogen exposure on neurodevelopment.

A Comprehensive Review on Immunoregulatory Effects of Phytochemicals.

An efficient immune system in the host body plays a crucial role in the preservation of normal biological and immune reactions and processes, as well as the intrinsic environment. This is because the immune system is responsible for fighting off foreign invaders. A healthy immune system strengthens the body's defense against infections, illnesses, and other unwelcome pathogens, thereby reducing the risk of allergic reactions and autoimmune diseases. Innate immune cells and acquired immune system components interact in a corrective fashion to produce optimal immune responses. In recent years, researchers have begun to focus on the immune system as a potential primary target of toxicity from chemical, pharmacological, and environmental exposure. Sex, age, stress, malnutrition, alcohol, genetic variability, lifestyles, environmental pollutants, and chemotherapy are just a few of the many elements that might modify the host's immunological responses. The production, amplification, attenuation, or suppression of immunological responses are all examples of immunomodulation. There are a wide variety of synthetic and traditional treatments available, and many of them cause major side effects and develop pathogenic resistance very quickly. Natural substances called phytochemicals play a crucial role in regulating the body's immune system. Risk factors for immune response changes are discussed, as is the immunomodulatory action of phytochemicals like glycosides, alkaloids, phenolic acids, flavonoids, saponins, tannins, sterols, and steroids.

Exploring the Impact of Pharmacological Target-Mediated Low Plasma Exposure in Lead Compound Selection in Drug Discovery - A Modeling Approach.

Small-molecule drug development faces the challenge of low success rate. In this paper, we propose one potential cause that may occur in the preclinical phase and has rarely been brought up before - the neglected target-mediated low plasma exposure, and the subsequent lead compound mis-selection due to conventional pharmacokinetic criteria requiring sufficient plasma exposure and desired half-life. To evaluate the concept of target-mediate low plasma exposure, we established a minimal physiologically-based pharmacokinetic (mPBPK) model to evaluate the concentration-time profiles of a group of virtual lead series analogs in plasma and in tissues with and without pharmacological target expression. Simulation results demonstrated that the candidate with the highest target binding has the lowest plasma exposure due to target-mediated tissue retention. The traditional PK criteria, such as the requirement of sufficient plasma exposure and desired half-life, may potentially result in lead compound mis-selection by discarding the appropriate and best candidate(s). The mPBPK model was partially validated using 4 tyrosine kinase inhibitors based on our in-house PK and tissue distribution data obtained in animals. The association rate constant (Kass) was estimated to be 49.8h-1, 31.4h-1, 8.58h-1, and 1.91h-1 for afatinib, dasatinib, gefitinib, and sorafenib, respectively. Among these four model drugs, a strong correlation was observed between their Kass values and AUChigh-perfused tissue /AUCplasma ratios, a metric of tissue retention. Our mPBPK modeling and simulation results indicated that the concept of target-mediated low plasma exposure should be kept in mind during the lead compound selection process.

Oral fentanyl consumption and withdrawal impairs fear extinction learning and enhances basolateral amygdala principal neuron excitatory-inhibitory balance in male and female mice

The number of opioid overdose deaths has increased over the past several years, mainly driven by an increase in the availability of highly potent synthetic opioids, like fentanyl, in the un-regulated drug supply. Over the last few years, changes in the drug supply, and in particular the availability of counterfeit pills containing fentanyl, have made oral use of opioids a more common route of administration. Here, we used a drinking in the dark (DiD) paradigm to model oral fentanyl self-administration using increasing fentanyl concentrations in male and female mice over 5 weeks. Fentanyl consumption peaked in both female and male mice at the 30 μg/mL dose, with female mice consuming significantly more fentanyl than male mice. Mice consumed sufficient fentanyl such that withdrawal was precipitated with naloxone, with males having increased withdrawal symptoms as compared to females, despite lower pharmacological exposure. We also performed behavioral assays to measure avoidance behavior and reward-seeking during fentanyl abstinence. Female mice displayed reduced avoidance behaviors in the open field assay, whereas male mice showed increased avoidance in the light/dark box assay. Female mice also exhibited increased reward-seeking in the sucrose preference test. Fentanyl-consuming mice of both sexes showed impaired cued fear extinction learning following fear conditioning and increased excitatory synaptic drive and increased excitability of BLA principal neurons. Our experiments demonstrate that long-term oral fentanyl consumption results in wide-ranging physiological and behavioral disruptions. This model could be useful to further study fentanyl withdrawal syndrome and behaviors and neuroplasticity associated with protracted fentanyl withdrawal.

Oral Fentanyl Consumption and Withdrawal Impairs Fear Extinction Learning and Enhances Basolateral Amygdala Principal Neuron Excitatory-Inhibitory Balance in Male and Female Mice.

The number of opioid overdose deaths has increased over the past several years, mainly driven by an increase in the availability of highly potent synthetic opioids, like fentanyl, in the un-regulated drug supply. Over the last few years, changes in the drug supply, and in particular the availability of counterfeit pills containing fentanyl, have made oral use of opioids a more common route of administration. Here, we used a drinking in the dark (DiD) paradigm to model oral fentanyl self-administration using increasing fentanyl concentrations in male and female mice over 5 weeks. Fentanyl consumption peaked in both female and male mice at the 30 µg/mL dose, with female mice consuming significantly more fentanyl than male mice. Mice consumed sufficient fentanyl such that withdrawal was precipitated with naloxone, with males having more withdrawal symptoms, despite lower pharmacological exposure. We also performed behavioral assays to measure avoidance behavior and reward-seeking during fentanyl abstinence. Female mice displayed reduced avoidance behaviors in the open field assay, whereas male mice showed increased avoidance in the light/dark box assay. Female mice also exhibited increased reward-seeking in the sucrose preference test. Fentanyl-consuming mice of both sexes showed impaired cued fear extinction learning following fear conditioning and increased excitatory synaptic drive and increased excitability of BLA principal neurons. Our experiments demonstrate that long-term oral fentanyl consumption results in wide-ranging physiological and behavioral disruptions. This model could be useful to further study fentanyl withdrawal syndrome and behaviors and neuroplasticity associated with protracted fentanyl withdrawal.

Novel Psilocin Prodrugs with Altered Pharmacological Properties as Candidate Therapies for Treatment-Resistant Anxiety Disorders.

The psychedelic prodrug psilocybin has shown therapeutic benefits for the treatment of numerous psychiatric conditions. Despite positive clinical end points targeting depression and anxiety, concerns regarding the duration of the psychedelic experience produced by psilocybin, associated with enduring systemic exposure to the active metabolite psilocin, pose a barrier to its therapeutic application. Our objective was to create a novel prodrug of psilocin with similar therapeutic benefits but a reduced duration of psychedelic effects compared with psilocybin. Here, we report the synthesis and functional screening of 28 new chemical entities. Our strategy was to introduce a diversity of cleavable groups at the 4-hydroxy position of the core indole moiety to modulate metabolic processing. We identified several novel prodrugs of psilocin with altered pharmacokinetic profiles and reduced pharmacological exposure compared with psilocybin. These candidate prodrugs have the potential to maintain the long-term benefits of psilocybin therapy while attenuating the duration of psychedelic effects.

An enhanced version of FREM (Fracture Risk Evaluation Model) using national administrative health data: analysis protocol for development and validation of a multivariable prediction model

BackgroundOsteoporosis poses a growing healthcare challenge owing to its rising prevalence and a significant treatment gap, as patients are widely underdiagnosed and consequently undertreated, leaving them at high risk of osteoporotic fracture. Several tools aim to improve case-finding in osteoporosis. One such tool is the Fracture Risk Evaluation Model (FREM), which in contrast to other tools focuses on imminent fracture risk and holds potential for automation as it relies solely on data that is routinely collected via the Danish healthcare registers. The present article is an analysis protocol for a prediction model that is to be used as a modified version of FREM, with the intention of improving the identification of subjects at high imminent risk of fracture by including pharmacological exposures and using more advanced statistical methods compared to the original FREM. Its main purposes are to document and motivate various aspects and choices of data management and statistical analyses.MethodsThe model will be developed by employing logistic regression with grouped LASSO regularization as the primary statistical approach and gradient-boosted classification trees as a secondary statistical modality. Hyperparameter choices as well as computational considerations on these two approaches are investigated by an unsupervised data review (i.e., blinded to the outcome), which also investigates and handles multicollinarity among the included exposures. Further, we present an unsupervised review of the data and testing of analysis code with respect to speed and robustness on a remote analysis environment. The data review and code tests are used to adjust the analysis plans in a blinded manner, so as not to increase the risk of overfitting in the proposed methods.DiscussionThis protocol specifies the planned tool development to ensure transparency in the modeling approach, hence improving the validity of the enhanced tool to be developed. Through an unsupervised data review, it is further documented that the planned statistical approaches are feasible and compatible with the data employed.

High-resolution analyses of associations between medications, microbiome, and mortality in cancer patients

Discerning the effect of pharmacological exposures on intestinal bacterial communities in cancer patients is challenging. Here, we deconvoluted the relationship between drug exposures and changes in microbial composition by developing and applying a new computational method, PARADIGM (parameters associated with dynamics of gut microbiota), to a large set of longitudinal fecal microbiome profiles with detailed medication-administration records from patients undergoing allogeneic hematopoietic cell transplantation. We observed that several non-antibiotic drugs, including laxatives, antiemetics, and opioids, are associated with increased Enterococcus relative abundance and decreased alpha diversity. Shotgun metagenomic sequencing further demonstrated subspecies competition, leading to increased dominant-strain genetic convergence during allo-HCT that is significantly associated with antibiotic exposures. We integrated drug-microbiome associations to predict clinical outcomes in two validation cohorts on the basis of drug exposures alone, suggesting that this approach can generate biologically and clinically relevant insights into how pharmacological exposures can perturb or preserve microbiota composition. The application of a computational method called PARADIGM to a large dataset of cancer patients' longitudinal fecal specimens and detailed daily medication records reveals associations between drug exposures and the intestinal microbiota that recapitulate invitro findings and are also predictive of clinical outcomes.

Does lithium poisoning induce brain injuries?-A histopathological rat study.

Due to a narrow therapeutic index, prolonged lithium treatment and overdose may result in neurotoxicity. Neurotoxicity is deemed reversible with lithium clearance. However, echoing the report of syndrome of irreversible lithium-effectuated neurotoxicity (SILENT) in rare severe poisonings, lithium-induced histopathological brain injuries including extensive neuronal vacuolization, spongiosis and ageing-like neurodegenerative changes were described in the rat following acute toxic and pharmacological exposure. We aimed to investigate the histopathological consequences of lithium exposure in rat models mimicking prolonged treatment and all three patterns of acute, acute-on-chronic and chronic poisonings observed in humans. We performed histopathology and immunostaining-based analyses using optic microscopy of brains obtained from male Sprague-Dawley rats randomly assigned to lithium or saline (controls) and treated according to the therapeutic or to the three poisoning models. No lesion was observed in any brain structure in any of the models. Neuron and astrocyte counts did not differ significantly between lithium-treated rats and controls. Our findings support that lithium-induced neurotoxicity is reversible and brain injury not a common feature of toxicity.

Comorbidities in the Spondyloarthritis GISEA Cohort: an average treatment effect analysis on patients treated with bDMARDs.

We aimed to investigate the effectiveness of tumour necrosis factor inhibitors (TNFi), anti-interleukin-17 or interleukin-12/23 monoclonal antibodies (anti-IL) on comorbidities in a cohort of patients with spondyloarthritis (SpA), using an average treatment effect (ATE) analysis. SpA patients from the multicentre Italian GISEA Registry were divided into groups according to pharmacological exposure: no treatment (G0), TNFi (G1) and non-responders to TNFi switched to anti-IL (G2). In each group, we recorded the prevalence and incidence of infectious, cardiopulmonary, endocrinological, gastrointestinal, oncologic, renal and neurologic comorbidities. Each comorbidity was then fitted for ATE and baseline features were evaluated for importance. The main findings of this study comprising 4458 SpA patients relate to cancer, other gastrointestinal diseases (OGID) and fibromyalgia. ATE showed no increased risk of solid cancer in G1 (0.42 95% CI 0.20-0.85) and G2 (0.26 95% CI 0.08-0.71) vs. G0, with significantly higher incidence in G0 (14.07/1000 patient-years, p=0.0001). Conversely, a significantly higher risk of OGID and fibromyalgia was found in G1 (1.56 95% CI 1.06-2.33; 1.69 95% CI 1.05-2.68, respectively) and G2 (1.91 95% CI 1.05-3.24; 2.13 95% CI 1.14-3.41, respectively) vs. G0. No treatment risk reduction was observed in haematological malignancies, cardiovascular events and endocrinological comorbidities. Overall, our study confirms the safety of TNFi and anti-IL in SpA patients, albeit with some caveats pertaining to solid cancers, OGID and fibromyalgia. Furthermore, taking into consideration causality with observational data may yield more reliable and relevant clinical information.

A regression analysis using simple descriptors for multiple dermal datasets: Going from individual membranes to the full skin.

In silico methods to estimate and/or quantify skin absorption of chemicals as a function of chemistry are needed to realistically predict pharmacological, occupational, and environmental exposures. The Potts-Guy equation is a well-established approach, using multi-linear regression analysis describing skin permeability (Kp) in terms of the octanol/water partition coefficient (logP) and molecular weight (MW). In this work, we obtained regression equations for different human datasets relevant to environmental and cosmetic chemicals. Since the Potts-Guy equation was published in 1992, we explored recent datasets that include different skin layers, such as dermatomed (including dermis to a defined thickness) and full skin. Our work was consistent with others who have observed that fits to the Potts-Guy equation are stronger for experiments focused on the epidermis. Permeability estimates for dermatomed skin and full skin resulted in low regression coefficients when compared to epidermis datasets. An updated regression equation uses a combination of fitted permeability values obtained with a published 2D compartmental model previously evaluated. The resulting regression equation was: logKp = -2.55 + 0.65logP - 0.0085MW, R2 = 0.91 (applicability domain for all datasets: MW ranges from 18 to >584 g/mol and -4 to >5 for logP). This approach demonstrates the advantage of combining mechanistic with structural activity relationships in a single modeling approach. This combination approach results in an improved regression fit when compared to permeability estimates obtained using the Potts-Guy approach alone. The analysis presented in this work assumes a one-compartment skin absorption route; future modeling work will consider adding multiple compartments.

Recording of cellular physiological histories along optically readable self-assembling protein chains

Observing cellular physiological histories is key to understanding normal and disease-related processes. Here we describe expression recording islands—a fully genetically encoded approach that enables both continual digital recording of biological information within cells and subsequent high-throughput readout in fixed cells. The information is stored in growing intracellular protein chains made of self-assembling subunits, human-designed filament-forming proteins bearing different epitope tags that each correspond to a different cellular state or function (for example, gene expression downstream of neural activity or pharmacological exposure), allowing the physiological history to be read out along the ordered subunits of protein chains with conventional optical microscopy. We use expression recording islands to record gene expression timecourse downstream of specific pharmacological and physiological stimuli in cultured neurons and in living mouse brain, with a time resolution of a fraction of a day, over periods of days to weeks.

Identification of the Role of TGR5 in the Regulation of Leydig Cell Homeostasis

Understanding the regulation of the testicular endocrine function leading to testosterone production is a major objective as the alteration of endocrine function is associated with the development of many diseases such as infertility. In the last decades, it has been demonstrated that several endogenous molecules regulate the steroidogenic pathway. Among them, bile acids have recently emerged as local regulators of testicular physiology and particularly endocrine function. Bile acids act through the nuclear receptor FXRα (Farnesoid-X-receptor alpha; NR1H4) and the G-protein-coupled bile acid receptor (GPBAR-1; TGR5). While FXRα has been demonstrated to regulate testosterone synthesis within Leydig cells, no data are available regarding TGR5. Here, we investigated the potential role of TGR5 within Leydig cells using cell culture approaches combined with pharmacological exposure to the TGR5 agonist INT-777. The data show that activation of TGR5 results in a decrease in testosterone levels. TGR5 acts through the PKA pathway to regulate steroidogenesis. In addition, our data show that TGR5 activation leads to an increase in cholesterol ester levels. This suggests that altered lipid homeostasis may be a mechanism explaining the TGR5-induced decrease in testosterone levels. In conclusion, the present work highlights the impact of the TGR5 signaling pathway on testosterone production and reinforces the links between bile acid signaling pathways and the testicular endocrine function. The testicular bile acid pathways need to be further explored to increase our knowledge of pathologies associated with impaired testicular endocrine function, such as fertility disorders.

The use of ace inhibitors influences the risk of progression of BD-IPMNs under follow-up

Chemoprevention's ability to slow down or prevent the progression of BD-IPMNs is extremely appealing. Aspirin (ASA), Ace Inhibitors/Angiotensin Receptor Blockers (ACEIs/ARBs) and Statins (STATs) are frequently prescribed drugs with a possible beneficial effect on different cancer types. Their effect on IPMNs is largely unknown. To evaluate the association between the use of ASA, ACEIs/ARBs and STATs and the risk of progression of BD-IPMNs in follow-up. multicenter, retrospective cohort study on patients with presumed BD-IPMNs without relative or absolute indication for surgery. Pharmacological exposures and risk factors were collected. We identified clinically relevant progression (occurrence of radiological absolute or relative indication for surgery) and any progression (occurrence of clinically relevant progression OR any dimension increase OR the occurrence of new cysts). Overall 594 patients were included. ACEIs were associated with a lower occurrence of any progression (HR=0.70; 95% CI 0.49-0.98, p=0.04) and clinically relevant progression, HR=0.42 (95% CI 0.20-0.88; p=0.02). No significant effect was shown for factors associated with the occurrence of pancreas cancer such as smoking, alcohol consumption and 1st degree family history of pancreas cancer. Among pharmacological exposures, no convincing effect was shown for the chronic use of ASA, ARB and STAT. ACEIs might have an effect in slowing the progression of BD-IPMNs. ASA, STAT and ARBs show no convincing effect on the progression of BD-IPMNs. Further, prospective, and long-term multicenter studies are needed to verify such association and to define the potential underlying mechanisms.

Clomiphene Citrate and Enclomiphene Hydrochloride Exposure Is Associated With Interfrontal Suture Fusion in Zebrafish.

Background: The last several decades have witnessed an increase in metopic craniosynostosis incidence. Population-based studies suggest that pharmacological exposure in utero may be responsible. This study examined effects of the fertility drug clomiphene citrate (CC) on calvarial development in an established model for craniofacial development, the zebrafish Danio rerio. Results: Zebrafish larvae were exposed to clomiphene citrate or its isomer enclomiphene for five days at key points during calvarial development. Larvae were then raised to adulthood in normal rearing water. Zebrafish were analyzed using whole-mount skeletal staining. We observed differential effects on survivability, growth and suture formation depending on the treatment. Treatments with CC or enclomiphene at 5.5 mm SL led to increased fusion of the interfrontal suture (p < .01) compared to controls. Conclusions: Exposure to fertility drugs appears to affect development of the cranial vault, specifically the interfrontal suture, in zebrafish. Further research is required to identify the signaling mechanisms at play. This work suggests that fertility drug treatment may contribute to the increased incidence of metopic craniosynostosis observed globally.

445. COVID-19 Pharmacotherapy Was Not Associated with Mortality in a Community Teaching System

BackgroundDuring the COVID-19 pandemic, a task force was assembled to collect data on patient characteristics and treatment exposures to assess what factors may contribute to patient outcomes, and to help develop institutional treatment guidelines. MethodsA retrospective study was performed on COVID-19 inpatient admissions within a four-hospital community health system over a six-month period from April-October 2020. Positive COVID-19 immunology results and/in conjunction with an inpatient admission was criteria for inclusion. Covariates for age, gender, race were added apriori. Covariates of interest included baseline comorbidities, admission level-of-care, vital signs, mortality outcomes, need for intubation, and specific pharmacological treatment exposures. Logistic regression was performed on our final model and reported as OR +/- 95% CI. ResultsA total of 349 patients met inclusion criteria. Pharmacotherapies were not associated with a difference in mortality in a four-hospital system. Corticosteroids (p = 0.99); Remdesivir (p = 0.79); hyrdroxychloroquine (p = 0.32); tocilizumab (p = 0.91); were not associated with mortality. ACE-inhibitor or angiotensin II receptor blockers OR 0.29 (0.09-0.93) (p = 0.03); convalescent plasma OR 7.85 (1.47-42.1) (p = 0.02); neuromuscular blocking agents (NMBA) OR 5.51 (1.28-23.8) (p = 0.02); vasopressors OR 17.6 (5.62-54.9) (p = 0.00) were associated with in-hospital mortality. Covariates that were associated with a difference in mortality were: age > 60 years OR 2.73 (1.04-7.14) (p = 0.04); structural lung disease OR 3.02 (1.28-7.10) (p = 0.01). Covariates not associated with mortality included African American race (p = 0.30); critical care admission (p = 0.19); obesity (p = 0.06); cardiovascular disease (p = 0.89); diabetes (p = 0.28).ConclusionThe use of corticosteroids, remdesivir, tocilizumab, and hydroxychloroquine, and admission to a critical care bed was not associated with a difference of in-hospital mortality. Patients who required vasopressors or NMBA were associated with in-hospital mortality. Despite national trends reporting increased mortality in patients with obesity, diabetes, cardiovascular disease, and of African American race, this was not observed in our health system safety net hospitals. Disclosures All Authors: No reported disclosures

A self-exciting point process to study multicellular spatial signaling patterns

Multicellular organisms rely on spatial signaling among cells to drive their organization, development, and response to stimuli. Several models have been proposed to capture the behavior of spatial signaling in multicellular systems, but existing approaches fail to capture both the autonomous behavior of single cells and the interactions of a cell with its neighbors simultaneously. We propose a spatiotemporal model of dynamic cell signaling based on Hawkes processes-self-exciting point processes-that model the signaling processes within a cell and spatial couplings between cells. With this cellular point process (CPP), we capture both the single-cell pathway activation rate and the magnitude and duration of signaling between cells relative to their spatial location. Furthermore, our model captures tissues composed of heterogeneous cell types with different bursting rates and signaling behaviors across multiple signaling proteins. We apply our model to epithelial cell systems that exhibit a range of autonomous and spatial signaling behaviors basally and under pharmacological exposure. Our model identifies known drug-induced signaling deficits, characterizes signaling changes across a wound front, and generalizes to multichannel observations.

Acute toxic exposures in children: analysis of a three year registry managed by a Pediatric poison control Center in Italy

IntroductionAcute pediatric poisoning is an emerging health and social problem. The aim of this study is to describe the characteristics of a large pediatric cohort exposed to xenobiotics, through the analysis of a Pediatric Poison Control Center (PPCc) registry.MethodsThis study, conducted in the Pediatric Hospital Bambino Gesù of Rome, a reference National Pediatric Hospital, collected data of children whose parents or caregivers contacted the PPCc by phone (group “P”), or who presented to the Emergency Department (group “ED”), during the three-year period 2014–2016. Data were prospectively and systematically collected in a pre-set electronic registry. Comparisons among age groups were performed and multivariable logistic regression models used to investigate associations with outcomes (hospital referral for “P”, and hospital admission for “ED”group).ResultsWe collected data of 1611 children on group P and 1075 on group ED. Both groups were exposed to both pharmaceutical and non-pharmaceutical agents. Pharmaceutical agent exposure increased with age and the most common route of exposure was oral. Only 10% among P group were symptomatic children, with gastrointestinal symptoms. Among the ED patients, 30% were symptomatic children mostly with gastrointestinal (55.4%) and neurologic symptoms (23.8%). Intentional exposure (abuse substance and suicide attempt), which involved 7.7% of patients, was associated with older age and Hospital admission.ConclusionsOur study describes the characteristics of xenobiotics exposures in different paediatric age groups, highlighting the impact of both pharmacological and intentional exposure. Furthermore, our study shows the utility of a specific PPCc, either through Phone support or by direct access to ED. PPCc phone counselling could avoid unnecessary access to the ED, a relevant achievement, particularly in the time of a pandemic.

AN ANIMATED MODELS DEVELOPMENT OF CARDIOVASCULAR SYSTEM IN PHARMACOLOGY LEARNING MODULE FOR MEDICAL STUDENTS

Hypertension is the most known common cardiovascular disease. Based on the Indonesian Competency Standard of Medical Doctors (StandarKompetensiDokter Indonesia or SKDI), the management of essential hypertension is at 4A or the highest level. Therefore, doctors should be able to establish a complete and independent diagnosis and management. The student passing rate in the cardiovascular system at the undergraduate level of medical education of Faculty of Medicine Widya Mandala Catholic University (FK UKWMS) was around 60-70%. This study is an evaluation to develop learning methods that would improve student learning outcomes. The development of this animation model is aimed to increase the engagement process in Pharmacology learning, especially in the cardiovascular system. 98 active students participated in this study, divided into 74 undergraduate students and 24 clinical internship students. The evaluation was carried out using a pre-test and a post-test related to pharmacological animation video exposure. Using the Wilcoxon different test, there was a significant difference between the pre-test and post-test results, especially in the clinical internship program’s students. This animated model was expected to help students to determine the rational determination of hypertension therapy.

Activation of Serotonin System in the Medial Prefrontal Cortex by Sound Signals of Danger

Abstract—Intracerebral microdialysis in Sprague-Dawley rats showed that a conditioned sound signal (CS+) previously reinforced by unavoidable electrocutaneous stimulation (fear conditioning test) is accompanied by an increased level of extracellular serotonin in the medial prefrontal cortex and provokes freezing behavior (fear index). A differential sound signal (CS–) not associated with pain stimulation (fear generalization test) also led to an increase in the level of extracellular serotonin in the medial prefrontal cortex but with decreased freezing behavior. These changes were absent in control group animals (same procedures, no electrocutaneus stimulation). Administration of the selective serotonin reuptake inhibitor fluoxetine (1 µmol) in the medial prefrontal cortex increased the elevation of extracellular serotonin levels caused by CS+ and CS–. This pharmacological exposure did not affect the freezing response to CS+ or CS– during the tests, however, it did cause longer periods of immobility between CS+ signals but not CS–. The data show that activation of the serotonin system of the medial prefrontal cortex by potentially threatening conditioned signals, but not neutral differential signals, takes part in the regulation of defensive behavior in the intervals between signals.