Drug Selection Research Articles

Improving the efficacy of combinatorial pharmacogenetic testing in schizophrenia therapy in China: a meta-analysis

AimPharmacogenetics/pharmacogenomics (PGx) testing has appeared as a convincing approach to assisting clinicians in adjusting drug selection and dosage according to the patient’s genetic information. The purpose of this meta-analysis was to compare the clinical efficacy of PGx guided treatment (experimental group) and empirical treatment (control group) in schizophrenia patients.MethodsA thorough search and review of the literature referring to PGx testing guided therapy for schizophrenia was conducted in the PubMed, CNKI, VIP, and Wanfang databases. Data were collected from the eligible studies after quality assessment, and RevMan software was used to conduct a meta-analysis comparing the clinical outcomes between the experimental and control groups.ResultsSeven trials were included, encompassing 1557 Chinese patients (767 in the experimental group and 790 in the control group). The pooled results revealed that the experimental group demonstrated more improved symptom remission and functional recovery than the control group; the adverse drug reaction incidence was also lower in the experimental group.ConclusionThe meta-analysis findings confirm the significant beneficial clinical utility of pharmacogenetic testing guided therapy for schizophrenia. The conclusion should be viewed cautiously, considering several limitations in this study.

Mapping Disciplinary Competencies and Learning Outcomes to the Competency-Based Veterinary Education Framework Using Veterinary Pharmacology as an Example.

The competency-based veterinary education (CBVE) framework describes essential domains of competence and related abilities for veterinary graduates. Translating these outcomes into daily teaching is a challenge, particularly regarding the underpinning basic and clinical science knowledge. In this article, we identified a lack of specific reference to the selection and use of drugs within the CBVE framework; this requires pharmacological knowledge and pharmacology-specific competencies. To fill the gap and provide guidance to veterinary pharmacology educators, we first identified competencies within the CBVE framework relevant to the field of veterinary pharmacology. We then mapped the Day One competencies in veterinary pharmacology published by Werners and Fajt in 2021 to the pharmacology-relevant CBVE competencies. This exercise has led to identifying gaps, redundancies, and a lack of reference to clinical practice within the Day One competencies in veterinary pharmacology, as well as gaps and ambiguous wording within the CBVE framework. Further research is necessary to update the Day One competencies in veterinary pharmacology, align basic and clinical pharmacology concepts and skills with the CBVE framework, embed pharmacology-specific competencies into teaching, and identify progression milestones that guide students toward safe prescribing and the appropriate and effective use of drugs.

Inhibitors of malaria parasite cyclic nucleotide phosphodiesterases block asexual blood-stage development and mosquito transmission.

Cyclic nucleotide-dependent phosphodiesterases (PDEs) play essential roles in regulating the malaria parasite life cycle, suggesting that they may be promising antimalarial drug targets. PDE inhibitors are used safely to treat a range of noninfectious human disorders. Here, we report three subseries of fast-acting and potent Plasmodium falciparum PDEβ inhibitors that block asexual blood-stage parasite development and that are also active against human clinical isolates. Two of the inhibitor subseries also have potent transmission-blocking activity by targeting PDEs expressed during sexual parasite development. In vitro drug selection experiments generated parasites with moderately reduced susceptibility to the inhibitors. Whole-genome sequencing of these parasites detected no mutations in PDEβ but rather mutations in downstream effectors: either the catalytic or regulatory subunits of cyclic adenosine monophosphate-dependent protein kinase (PKA) or in the 3-phosphoinositide-dependent protein kinase that is required for PKA activation. Several properties of these P. falciparum PDE inhibitor series make them attractive for further progression through the antimalarial drug discovery pipeline.

Transforming Healthcare in Low-Resource Settings With Artificial Intelligence: Recent Developments and Outcomes.

Artificial intelligence now encompasses technologies like machine learning, natural language processing, and robotics, allowing machines to undertake complex tasks traditionally done by humans. AI's application in healthcare has led to advancements in diagnostic tools, predictive analytics, and surgical precision. This comprehensive review aims to explore the transformative impact of AI across diverse healthcare domains, highlighting its applications, advancements, challenges, and contributions to enhancing patient care. A comprehensive literature search was conducted across multiple databases, covering publications from 2014 to 2024. Keywords related to AI applications in healthcare were used to gather data, focusing on studies exploring AI's role in medical specialties. AI has demonstrated substantial benefits across various fields of medicine. In cardiology, it aids in automated image interpretation, risk prediction, and the management of cardiovascular diseases. In oncology, AI enhances cancer detection, treatment planning, and personalized drug selection. Radiology benefits from improved image analysis and diagnostic accuracy, while critical care sees advancements in patient triage and resource optimization. AI's integration into pediatrics, surgery, public health, neurology, pathology, and mental health has similarly shown significant improvements in diagnostic precision, personalized treatment, and overall patient care. The implementation of AI in low-resource settings has been particularly impactful, enhancing access to advanced diagnostic tools and treatments. AI is rapidly changing the healthcare industry by greatly increasing the accuracy of diagnoses, streamlining treatment plans, and improving patient outcomes across a variety of medical specializations. This review underscores AI's transformative potential, from early disease detection to personalized treatment plans, and its ability to augment healthcare delivery, particularly in resource-limited settings.

Affinity purification of the outer hair cell motor protein prestin using His-tag

ObjectiveThe high sensitivity and broad frequency selectivity of mammalian hearing are associated with the somatic motility of outer hair cells (OHCs) in the cochlea. This motility is considered to be induced by conformational changes of the motor protein prestin expressing in the lateral plasma membrane of OHCs. Since its identification in 2000, prestin has been actively investigated and its structure and function have gradually been elucidated. These successes are partly due to the development of efficient expression and purification system of the membrane proteins including prestin. To obtain further understandings of prestin, the development of various types of such systems will be essential. However, recent study protocols on membrane proteins have often employed HEK293 cells and have become complexed with expression genes carrying several proteins and peptides for stabilization and purification of the expressed proteins. In the present study, a simple expression and purification system using Chinese hamster ovary (CHO) cells and Hi-tag was developed. MethodsFull length gerbil prestin was transfected into modified mammalian expression vectors with C-terminal 6 × His-tag. After drug selection with G418 for 4 weeks, single colonies were isolated by limiting dilution method. Cell lines highly expressing prestin were selected (named 3D5, 4D7 and 3C8). These cells were gently disrupted using a Dounce tissue grinder. Membrane fractions were extracted by ultracentrifugation and affinity chromatography was performed. The efficiency of the purification process was evaluated by quantitative Western blotting using a standard protein. ResultsAmong the cell lines constructed, Western blotting analysis showed bands at around 100 kDa and the highest intensity was confirmed from the 3C8 cell line, indicating that this cell line has the highest expression of prestin molecules. The membrane fraction was therefore extracted from this cell line and subjected to the following purification procedure. It was found that 78.7 μg of prestin was purified from 2.0 × 109 CHO cells. ConclusionIn the present study, 78.7 μg of prestin was purified from 2.0 × 109 CHO cells, which stably expressing 6 × His-tagged prestin, by extracting cell membrane fractions and standard affinity chromatography for His-tag.

Expression and functional characterization of His-tagged prestin in Chinese hamster ovary cells

The electromotility of outer hair cell is considered to be based on voltage-dependent conformational changes in the motor protein prestin. The structure and function of prestin have been increasingly examined in recent years. To obtain further information on prestin, a method to stably obtain prestin as the material for this research is required. This study attempted to construct a stable expression system for prestin on Chinese hamster ovary (CHO) cells and its function was evaluated. His-tagged prestin expression vectors were transfected into CHO cells and high-expression clones were obtained by drug selection and limiting dilution method. The expression and activity of prestin were examined by Western blotting and immunofluorescent experiments and by patch clamping. Clones with high fluorescent intensity tended to exhibit bell-shaped non-linear capacitance, suggesting the active function of prestin in such clones. The stable expression and activity of prestin in CHO cells were confirmed in 7 clones out of twelve clones developed. Although expression levels were 1/60-1/30 of those in OHCs, cell line maintaining the stable expression of functional prestin with His tag will be advantageous for future analyses of its structure and function.

Biased agonism at free-fatty acid receptor-4 (FFA4/GPR120).

Free-fatty acid receptor-4 (FFA4), previously known as GPR120, is a G protein-coupled receptor (GPCR) activated by medium-to-long chain free fatty acids (FFAs), including saturated, monounsaturated, and polyunsaturated fats, many of which (e.g., omega-3 fatty acids) are critical contributors to human health and disease. FFA4 is widely expressed across human tissues, and its activation supports a range of physiological functions, including the release of gastrointestinal incretin hormones like glucagon-like peptide-1 (GLP-1), regulation of pancreatic hormone secretion, peripheral glucose uptake, adipose regulation, and anti-inflammatory responses in macrophages. Due to its pivotal role in energy metabolism and inflammation, FFA4 has emerged as a major target in drug discovery. Historically, FFA4 signaling was linked to the Gαq/11 family of intracellular heterotrimeric G proteins, which mediate its GLP-1 releasing effects. However, emerging evidence indicates that FFA4 can signal through other Gα proteins in various cellular contexts. Notably, its anti-inflammatory effects are also dependent on interactions with β-arrestin proteins, further broadening the receptor's signaling versatility. This review explores the concept of biased agonism at FFA4, emphasizing how this receptor selectively signals through distinct transduction pathways, including Gα proteins and β-arrestins. We also examine the key structural elements of FFA4 that govern its interactions with different signaling partners, the elucidation of which has laid the groundwork for the development of biased agonists aimed at selectively modulating these FFA4-mediated pathways for therapeutic application.

Serotonin 5-HT1A receptor biased agonists: The challenge of translating an innovative neuropharmacological concept into therapeutics.

Serotonin 5-HT1A receptor agonists are prime candidates for CNS drug discovery due to their involvement physiological and pathological processes relevant to neurology and psychiatry. However, the lack of target specificity of many previously characterized agonists has long been a barrier to pharmacological and therapeutic progress. Some of the obstacles may be overcome through the recent concept of biased agonism, which has attracted considerable attention to the development of novel chemical entities at 5-HT, and particularly 5-HT1A receptors, by specifically targeting intracellular signalling pathways that may themselves be linked to specific brain regions and therapeutic indications. There is now abundant translational data demonstrating distinct molecular and functional pharmacological signatures between different 5-HT1A receptor agonists, opening new opportunities for research in neurology and psychiatry. Nevertheless, important limitations need to be overcome, including understanding the precise molecular basis for biased agonism, the need for improved translatable models, and the currently limited clinical data on biased agonists. Here, we review the current limits of our knowledge of 5-HT1A receptor biased agonists and the limitations of available pharmacological tools, counterbalanced by the translational possibilities and therapeutic perspectives opened by novel, highly selective 5-HT1A receptor drug-candidates.

Ultrasonication outperforms electroporation for extracellular vesicle cargo depletion

Extracellular vesicles (EVs), submicron-sized membranous structures released by cells, serve as vehicles of tissue-specific proteins and nucleic acids, facilitating intercellular communication and playing roles in pathophysiological processes. Leveraging their unique characteristics, EVs have emerged as promising drug delivery nanocarriers. Electroporation (EP) and ultrasonication (US) are among the prevalent techniques used for loading exogenous drugs into EVs owing to their simplicity and efficiency. However, the effectiveness of the two methods in depleting initial EV cargo has been overlooked. But this information is indispensable, as the bioactive residuals of EVs, notably derived from tumor or stem donor cells, may impact downstream therapeutic effects. Bridging this knowledge gap, therefore, can guide the selection of optimal drugs and loading methods tailored to therapeutic objectives. Here, we used high-throughput sequencing to investigate the protein and small RNA cargo of EVs treated with EP and US, respectively. We found that US exhibits higher efficacy in depleting EV cargo compared to EP, while US may also deplete essential endogenous molecules for combination therapy. Neither method demonstrated significant selectivity in cargo depletion, but they might preferentially retain few specific molecules. Additionally, membrane proteins are more prone to loss during US and EP treatments than cytoplasmic proteins.

Selection of Antiplatelet Drugs for Preventing Recurrent Stroke in Non-cardiogenic Ischemic Stroke with Recurrent Gastrointestinal Bleeding: A Case Report

<p>腦中風的發生率在臺灣每十萬人約300至500人，其中缺血性腦中風約佔74%。預防再次缺血性腦中風以抗血小板藥物為主，常見的藥物包括aspirin及clopidogrel，但有些病人使用後會增加出血的風險甚至出現危及生命的嚴重出血副作用，因此要如何達到最大的淨效益(net benefit)是一個重要的課題。此篇病例報告呈現一位需使用抗血小板藥物預防再次缺血性腦中風但併有反覆腸胃道出血的個案，在無法忍受使用aspirin或clopidogrel的情況下，以實證醫學為基礎選擇cilostazol當作預防再次缺血性腦中風之抗血小板藥物，後續追蹤至今約一年，個案無再次發生腸胃道出血及再中風之情形。</p> <p> </p><p>In Taiwan, the incidence rate of stroke is approximately 300 to 500 per 100,000 people, with ischemic stroke accounting for approximately 74% of the cases. Antiplatelet medications, especially aspirin and clopidogrel, are commonly used to prevent recurrent ischemic stroke but may increase the risk of bleeding, even potentially life-threatening severe bleeding, in some patients. Therefore, achieving the maximum net benefit is an important issue. This case report presents a patient who required antiplatelet medication for preventing recurrent ischemic stroke but experienced repeated gastrointestinal bleeding. Unable to tolerate aspirin or clopidogrel, the patient was prescribed cilostazol for the prevention of recurrent ischemic stroke. Follow-up for approximately one year found no recurrence of gastrointestinal bleeding or stroke in this case.</p> <p> </p>

Genetic structure of the population of Przewalski’s horse (Equus przewalskii) according to cytogenetic and ISSR markers

Background. Przewalski’s horse is included in the Red List of the International Union for Conservation of Nature and the Red Data Book of Ukraine as an endangered species. To confirm the uniqueness and consolidation of rare animal species, cytogenetic and molecular genetic monitoring is necessary. Obtaining biological material (blood) for genetic research is preceded by immobilization of wild ungulates. The successful selection of drugs for the purpose of sedation and analgesia helps to preserve the life and health of the animal. Materials and Methods. Przewalski’s wild horse population (10 heads) of the F. E. Falz-Fein “Askania-Nova” biosphere reserve, immobilization of animals with the Madison drug and the Reverson antidote, cytogenetic and molecular genetic (ISSR-fingerprinting) analysis. Results. The effectiveness indicators of doses of Madison and Reverson were: in horses m = 200 kg – a dose of Madison 20 mL/head, immobilization after 22 min, in horses m = 300 kg, a dose of Madison – 25 mL/head, immobilization in 20–22 min. The Reverson antidote was applied in the following doses: animal m = 200 kg – a dose of Reverson 5–15 mL/goal, cessation of the sedative effect – 12 min; animal m = 300 kg – a dose of Reverson 5–15 mL/goal, cessation of the sedative effect – 18 min. Observation of the effect of the drugs did not reveal any negative side effects. Cytogenetic analysis determined the karyotype norm of somatic cells with 2n = 66 chromosomes. Genomic disorders, aneuploidy, accounted for 6.7%, polyploidy – 1.3 %. Structural violations (chromosomal and chromatid breaks) were not detected. The results of the micronucleus test: the share of lymphocytes with a micronucleus – 3.0 ‰, binuclear lymphocytes – 2.3 ‰, mitotic index – 7.7 ‰. Genetic indicators of the population of Przewalski’s horses according to ISSR markers: when using (GA)9C as a primer, microsatellite repeats of polymorphic loci were not found, and according to primer (GAG)6C – 50 % of polymorphic loci. The main indicators of genetic diversity, with the help of ISSR markers: the share of polymorphic loci was 25 %, the average gene diversity per locus – 0.39, the Shannon–Wiener information index – 2.5. Conclusions. No negative side effects occur when Madison and Reverson drugs are used to immobilize Przewalski’s horses. According to the results of cytogenetic analy­sis, the stability of the karyotype of the studied animals was established. The study of genetic polymorphism of the horse population by ISSR markers (AG)9C and (GAG)6C indicates a high degree of genetic consolidation. All tested animals are relatively safe according to the revealed intra-population genetic diversity.

PP31 Logical Model Articulating Pharmacy Commissions And Hospital-Based Health Technology Assessment Nuclei: Collaborative Strategies For The Drug Selection

IntroductionCollaborative strategies between the Pharmacy and Therapeutics Committee (Group 1) and hospital-based health technology assessment (HTA) nuclei (Group 2) using HTA tools can promote rational use and medicines access. The aim was to develop a logical model for the drug selection process in Brazilian university hospitals, considering the articulation between the Pharmacy and Therapeutics Committee and hospital-based HTA nuclei (NATS).MethodsA qualitative study created and validated a logical model. The data collection considered documental analysis and semistructured interviews with key informants from both groups about the processes adopted by eight federal university hospitals. The European Project on Hospital-Based Health Technology Assessment (AdHopHTA) was selected as a theoretical reference. The model was discussed in a focal group with the participation of five experts in medicine selection tasks and HTA. The final version of the model was submitted for consistency and vulnerability analysis by the authors. The ethical approval number is 4.784.861.ResultsThe logical model was conceived with dimensions of resources, actions, products, results, and impacts. It has allowed a structured and organized view of the 15 actions in the medicine selection. From these 15 actions, seven can be articulated between both groups. The high management support, training, and dissemination of the procedures and flows that organize HTA processes were solutions to minimizing collaborative barriers. The selection of medicines was considered a dynamic process. Some actions, such as the use of pharmacovigilance data, post-selection monitoring, and horizon technology scanning can bring results in terms of treatment innovations and compliance with clinical guidelines.ConclusionsCollaborative strategies were presented in a logical model with seven joint actions to guide the medicine selection process in hospitals involving tools, flow audits, governance, and human resources. The consistency and vulnerability model analysis defined indicators for HTA collaborative actions.

MSR206 A Rough Multi-Criteria Decision-Making Framework With Complex Linguistic Information for the Drug Selection Process in Medical Institutions

MSR206 A Rough Multi-Criteria Decision-Making Framework With Complex Linguistic Information for the Drug Selection Process in Medical Institutions

Exploring Bias in GPCR Signaling and its Implication in Drug Development: A One-Sided Affair.

G protein-coupled receptors (GPCRs) play a pivotal role in regulating numerous physiological processes through their interactions with two key effectors: G proteins and β-arrestins (βarrs). This makes them crucial targets for therapeutic drug development. Interestingly, the evolving concept of biased signaling where ligands selectively activate either the G proteins or the βarrs has not only refined our understanding of segregation of physiological responses downstream of GPCRs but has also revolutionized drug discovery, offering the potential for treatments with enhanced efficacy and minimal side effects. This Review explores the mechanisms behind biased agonism, exploring it through various lenses, including ligand, receptor, cellular systems, location, and tissue-specific biases. It also offers structural insights into both orthosteric and allosteric ligand-binding pockets, structural rearrangements associated with the loops, and how ligand-engineering can contribute to biased signaling. Moreover, we also discuss the unique conformational signature in an intrinsically biased GPCR, which currently remains relatively less explored and adds a new dimension in biased signaling. Lastly, we address the translational challenges and practical considerations in characterizing bias, emphasizing its therapeutic potential and the latest advancements in drug development. By designing ligands that target specific signaling pathways, biased signaling presents a transformative approach to creating safer and more effective therapies. This Review focuses on our current understanding of GPCR-biased signaling, discussing potential mechanisms that lead to bias, the effect of bias on GPCR structures at a molecular level, recent advancements, and its profound potential to drive innovation in drug discovery.

Impact of pharmacist-led aminoglycoside stewardship: a 10-year observational study

BackgroundAminoglycosides are crucial for treating multidrug-resistant gram-negative infections and endocarditis. However, aminoglycosides are associated with significant risks of nephrotoxicity, necessitating careful dose selection and therapeutic drug monitoring. Therapeutic drug monitoring is essential for minimizing risk; however, few institutions routinely perform it. This study aimed to assess the impact of a pharmacist-driven therapeutic drug monitoring intervention on aminoglycoside usage trends and clinical outcomes.MethodsThis retrospective cohort study included 263 patients treated with aminoglycosides between 2014 and 2023. A pharmacist-led therapeutic drug monitoring intervention began in 2017, focusing on monitoring renal function, documenting patient weight, and closely managing aminoglycoside concentrations. Trends in aminoglycoside use and renal outcomes were analyzed.ResultsOver the study period, appropriate use of aminoglycosides at the time of initial prescription increased from 49 to 82% (P < 0.01). Pharmacist dosing design at initial prescription increased significantly from 21% pre-intervention to 60% post-intervention (P < 0.01). The proportion of pharmacist intervention in initial dosing design increased over time. The proportion of patients with measured aminoglycoside blood concentrations significantly increased from 53% pre-intervention to 72% post-intervention (P < 0.01). The proportion of patients who were able to manage target blood concentrations from the initial aminoglycoside dose without dose adjustments increased from 31% pre-intervention to 42% post-intervention, although the results were not significantly different (P = 0.07). The incidence rate of renal impairment remained similar (11% vs. 12%; P = 0.85), although the annual average number of cases decreased from 4.3 before the intervention to 2.5 after. Similarly, there were no significant differences in clinical efficacy before and after the intervention (65% vs. 71%; P = 0.35). Furthermore, aminoglycoside stewardship led to a 56% cost saving.ConclusionsPharmacist-led aminoglycoside stewardship significantly improved the appropriate use of aminoglycosides and decreased the associated costs. Thus, pharmacist involvement is essential for the proper use of aminoglycosides. However, many patients required aminoglycoside dose reductions despite the pharmacist’s guideline-based dosing design. Therefore, further accumulation of information on the management of aminoglycoside blood concentration may be necessary for the revision of these guidelines.

Development and Characterization of a Lysosome-Targeting SLC3A2/PD-L1 Bispecific Antibody-Drug Conjugate for Enhanced Anti-Tumor Efficacy in Solid Tumors.

Bispecific antibodies (BsAbs) and antibody-drug conjugates (ADCs) have shown significant promise in cancer treatment, enhancing drug selectivity and therapeutic efficacy as demonstrated in multiple clinical studies. Bispecific antibody-drug conjugates (BsADCs), which combine the targeting capabilities of BsAbs with the cytotoxic potential of ADCs, offer a novel approach to overcoming several challenges associated with ADCs, including limited internalization, off-target toxicity, and drug resistance. In this study, we identified solute carrier family 3 member 2 (SLC3A2) as a highly expressed protein in a variety of solid tumors, making it a promising therapeutic target. We developed a bispecific antibody targeting SLC3A2 and PD-L1, and conjugated it to monomethyl auristatin E (MMAE) to create the SLC3A2/PD-L1 BsADC. The SLC3A2/PD-L1 BsAb effectively blocked PD-1 binding to PD-L1 and activated T cells, while also facilitating lysosomal targeting and degradation of poorly internalized PD-L1 antibodies. The SLC3A2/PD-L1 BsADC demonstrated superior anti-tumor efficacy in PD-L1 low-expressing tumor cells compared to single-target ADCs in both in vitro studies and in multiple xenograft and immunocompetent mouse models. Overall, our engineered SLC3A2/PD-L1 BsADC exhibited enhanced internalization and improved tumor cell targeting, highlighting the potential of lysosome-targeting BsAbs in advancing ADC therapeutic strategies for solid tumors.

Real-world study of adverse events associated with triptan use in migraine treatment based on the U.S. Food and Drug Administration (FDA) adverse event reporting system (FAERS) database

BackgroundTriptans selectively agoniste 5-Hydroxytryptamine(5-HT) receptors and are widely used in the treatment of migraine. Nevertheless, there is a dearth of comprehensive real-world clinical research on the safety of triptans. In light of the growing prevalence of migraine, it is imperative to gain a deeper understanding of the true extent of adverse events (AEs) associated with triptans in the clinical management of migraine.MethodsA database query of AEs reported to the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database for triptans was performed using the online platform Open Vigil 2.1. The query spanned the period from 1 January 2018 to 31 December 2023 and extracted all AEs for ‘sumatriptan’, ‘zolmitriptan’, ‘rizatriptan’, and ‘naratriptan’ from the 15–49 years old population and retrospective quantitative analyses. A proportional reporting ratio (PRR), reporting odds ratio (ROR), and Bayesian Confidence Propagation Neural Network (BCPNN) methodology were utilized to contrast AEs across the four triptans.ResultsA total of 1.272 AEs reports for sumatriptan, 114 for zolmitriptan, 162 for rizatriptan, and 15 for naratriptan were identified. The ratio of females to males was approximately three times higher in all cases, with the highest number of reports originating from the Americas. A review of the FAERS database revealed that nervous system disorders were the primary SOC category for four drugs, with all four drugs exhibiting the AE indicative of reversible cerebral vasoconstriction syndrome, also classified as Nervous system disorders. The most frequently reported AE signal for sumatriptan was dyspnea, which is classified as respiratory, thoracic and mediastinal disorders. The most frequently reported AEs signals for the remaining three drugs were nausea, vomiting and terminal ileitis, all of which are classified as gastrointestinal disorders.ConclusionAnalyses have demonstrated that AEs are present in a range of systems, including cardiac, nervous, gastrointestinal, and musculoskeletal disorders. It should be noted, however, that the incidence and signal intensity of these AEs vary depending on the specific drug in question. In clinical practice, the selection of an appropriate drug and the monitoring of AEs should be tailored to the individual patient’s and specific characteristics.

Antihypertensive Drug Recommendations for Reducing Arterial Stiffness in Patients With Hypertension: Machine Learning-Based Multicohort (RIGIPREV) Study.

High systolic blood pressure is one of the leading global risk factors for mortality, contributing significantly to cardiovascular diseases. Despite advances in treatment, a large proportion of patients with hypertension do not achieve optimal blood pressure control. Arterial stiffness (AS), measured by pulse wave velocity (PWV), is an independent predictor of cardiovascular events and overall mortality. Various antihypertensive drugs exhibit differential effects on PWV, but the extent to which these effects vary depending on individual patient characteristics is not well understood. Given the complexity of selecting the most appropriate antihypertensive medication for reducing PWV, machine learning (ML) techniques offer an opportunity to improve personalized treatment recommendations. This study aims to develop an ML model that provides personalized recommendations for antihypertensive medications aimed at reducing PWV. The model considers individual patient characteristics, such as demographic factors, clinical data, and cardiovascular measurements, to identify the most suitable antihypertensive agent for improving AS. This study, known as the RIGIPREV study, used data from the EVA, LOD-DIABETES, and EVIDENT studies involving individuals with hypertension with baseline and follow-up measurements. Antihypertensive drugs were grouped into classes such as angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), β-blockers, diuretics, and combinations of diuretics with ACEIs or ARBs. The primary outcomes were carotid-femoral and brachial-ankle PWV, while the secondary outcomes included various cardiovascular, anthropometric, and biochemical parameters. A multioutput regressor using 6 random forest models was used to predict the impact of each antihypertensive class on PWV reduction. Model performance was evaluated using the coefficient of determination (R2) and mean squared error. The random forest models exhibited strong predictive capabilities, with internal validation yielding R2 values between 0.61 and 0.74, while external validation showed a range of 0.26 to 0.46. The mean squared values ranged from 0.08 to 0.22 for internal validation and from 0.29 to 0.45 for external validation. Variable importance analysis revealed that glycated hemoglobin and weight were the most critical predictors for ACEIs, while carotid-femoral PWV and total cholesterol were key variables for ARBs. The decision tree model achieved an accuracy of 84.02% in identifying the most suitable antihypertensive drug based on individual patient characteristics. Furthermore, the system's recommendations for ARBs matched 55.3% of patients' original prescriptions. This study demonstrates the utility of ML techniques in providing personalized treatment recommendations for antihypertensive therapy. By accounting for individual patient characteristics, the model improves the selection of drugs that control blood pressure and reduce AS. These findings could significantly aid clinicians in optimizing hypertension management and reducing cardiovascular risk. However, further studies with larger and more diverse populations are necessary to validate these results and extend the model's applicability.

Comparative Economic and Clinical Utility of Adding Candesartan for Hypertension Management

Introduction: Antihypertensive drugs require high costs because they are used over a long period. Therefore, consideration is needed in drug selection requirements, effectiveness, and price. This study aimed to see the beneficial results of hypertension therapy and the non-medical costs incurred by patients using cost-utility analysis (CUA). Method: This research was a prospective study. The incremental Cost-Utility Ratio (ICUR) of antihypertensive treatment was calculated using cost-utility data obtained through EQ-5D-5L questionnaires from outpatients at Universitas Andalas Hospital in January- March 2023 who met the inclusion and exclusion criteria. The costs used were from a patient perspective, consisting of direct medical and non-medical costs. This study compared standard treatment (amlodipine) with the addition of candesartan. Results: The number of respondents in this study was 67, consisting of 23 respondents (34.33%) using amlodipine alone and 44 respondents (65.67%) using the amlodipine-candesartan combination. The ICUR value obtained was IDR7,318,674/QALY. The difference in the average utility value of the amlodipine-candesartan combination with amlodipine alone is -0.02, and the difference in cost is -IDR12,224. Based on the cost-utility diagram, the amlodipine-candesartan combination group is included in the southwest quadrant (quadrant III), which illustrates that the cost required for the amlodipine-candesartan combination group is lower than the cost of the amlodipine single treatment group and the outcome is also not better (slightly lower or the same). Conclusion: It was recommended to prioritize using amlodipine alone for hypertension management, as it provides similar outcomes to the amlodipine-candesartan combination while incurring lower costs.

Induction Agents for Tracheal Intubation in Critically Ill Patients.

Concise definitive review of the use of induction agents in critically ill patients undergoing tracheal intubation and their association with outcomes. Original publications were retrieved through a PubMed search with search terms related to induction agents for tracheal intubation in critically ill patients. We included randomized controlled trials and observational studies that reported patient outcomes. Data from included studies, including choice of induction agents and clinically relevant outcomes, were extracted. Etomidate and ketamine have been the most studied induction agents in critical care during last years. Recent studies on etomidate investigated the clinical impact of its recognized adrenal suppression in terms of morbidity and mortality. Etomidate may carry a non-negligible mortality risk without definitive hemodynamic benefits compared with ketamine. Available data then support the use of ketamine over etomidate, since the difference in the hemodynamic profile seems to be of minor clinical relevance. No multicenter randomized studies are available comparing propofol to other induction agents but evidence from a large observational study identified an association of propofol with post-intubation cardiovascular instability in critically ill patients. Despite the observational nature of these findings cannot exclude the role of confounders, the association of propofol with post-induction cardiovascular instability is pharmacologically plausible, justifying its avoidance in favor of drugs with a better safety profile in critical care such as ketamine. Although no definitive conclusions can be drawn based on the available evidence, recent evidence pointed out the potential negative effect of etomidate on survival and the association of propofol with cardiovascular instability. Ketamine may be considered the drug with a safer profile, widespread availability and low cost but future research should provide definitive data on optimal drug selection, its dosage in the context of critical illness and concomitant interventions to minimize the risk of peri-intubation complications.