Search Results (221)

Hemodynamic management is extremely important in cardiac patients undergoing surgery. Traditionally, the approach towards hemodynamic stabilization included the control of both mean arterial pressure (MAP) and cardiac output (CO) using Sodium Nitroprusside and Dopamine. More efficient and safer drugs have been introduced, such as Norepinephrine. The focus of this manuscript is to provide some preliminary results regarding the closed loop control of MAP using Norepinephrine. However, to design a dedicated control system, a mathematical model describing the effect of Norepinephrine on mean arterial pressure is required. Only a handful of papers describe a pharmacokinetic–pharmacodynamic (PK-PD) model. In this paper, a simplified model suitable for designing a controller is determined based on PK-PD insights and existing clinical data. Existing closed loop controllers are based on the simple proportional integral derivative (PID) controller, with limited robustness to patient variability. In this paper, two advanced control strategies are proposed to replace PID. The closed loop simulation results include reference tracking and disturbance rejection and show the efficiency and robustness of the proposed control algorithms. The preliminary results set the background for further research in this area. Full article

Background: Cefazolin is being increasingly used to treat central nervous system infections caused by methicillin-susceptible Staphylococcus aureus (MSSA) to mitigate the side effects of existing anti-Staphylococcal drugs. This study aims to develop a cerebrospinal pharmacokinetic (PK) model to predict the cefazolin concentration in cerebrospinal fluid (CSF) and to individualize the dosing regimen for MSSA meningitis. Methods: A cerebrospinal PK model was developed based on the existing literature and used to estimate the probability of attaining PK/ pharmacodynamic (PD) targets. These targets were set as 100% time above the minimum inhibitory concentration (T > MIC) in CSF. The cerebrospinal PK/PD breakpoint was defined as the highest MIC at which target attainment probability in CSF was ≥90%. The mean CSF/serum ratio estimated from the literature was 0.0525 after a dose of 1–3 g (sampling time: 1–9 h after dose) in adult patients with suspected meningitis. This ratio was incorporated into this PK model based on a hybrid approach. Results: For patients with creatinine clearance (CL_cr) = 90 mL/min, the cerebrospinal PK/PD breakpoint MICs of continuous infusion regimens (6–12 g/day) reached 0.5 µg/mL, which can inhibit the growth of 90% of the MSSA population (MIC₉₀). Furthermore, for patients with renal dysfunction (CL_cr = 30 mL/min), a dose reduction (4 g/day) may be required to avoid excessive drug exposure. Conclusions: High-dose continuous infusion of cefazolin may be appropriate for MSSA meningitis in patients with normal renal function, while dose adjustments are needed for those with renal impairment. Full article

Anti-PD-1 therapies have transformed cancer treatment by restoring antitumor T cell activity. Despite their broad clinical use, variability in treatment response and immune-related adverse events underscore the need for therapeutic optimization. This article provides an integrative overview of the pharmacokinetics (PKs) of anti-PD-1 antibodies—such as nivolumab, pembrolizumab, and cemiplimab—and examines pharmacokinetic–pharmacodynamic (PK-PD) relationships, highlighting the impact of clearance variability on drug exposure, efficacy, and safety. Baseline clearance and its reduction during therapy, together with interindividual variability, emerge as important dynamic biomarkers with potential applicability across different cancer types for guiding individualized dosing strategies. The review also discusses established biomarkers for anti-PD-1 therapies, including tumor PD-L1 expression and immune cell signatures, and their relevance for patient stratification. The evidence supports a shift from traditional weight-based dosing toward adaptive dosing and therapeutic drug monitoring (TDM), especially in long-term responders and cost-containment contexts. Notably, the inclusion of clearance-based biomarkers—such as baseline clearance and its reduction—into therapeutic models represents a key step toward individualized, dynamic immunotherapy. In conclusion, optimizing anti-PD-1 therapy through PK-PD insights and biomarker integration holds promise for improving outcomes and reducing toxicity. Future research should focus on validating PK-based approaches and developing robust algorithms (machine learning models incorporating clearance, tumor burden, and other validated biomarkers) for tailored cancer treatment. Full article

The proliferation of multidrug-resistant (MDR) ESKAPE pathogens—Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.—constitutes a critical global health crisis, rendering conventional antibiotics increasingly ineffective. This comprehensive review evaluates the re-emerging potential of bacteriophage therapy as a personalized treatment for infections caused by these organisms. Phages, being viruses that specifically infect and lyse bacteria, offer significant advantages, including high specificity that spares host microbiota, self-replication at the infection site, and potent activity against biofilms. This paper synthesizes current preclinical and clinical evidence, including compassionate-use cases, for phage therapy against each of the ESKAPE pathogens. While case reports and small studies demonstrate considerable success, particularly in salvage therapy for otherwise untreatable infections, significant challenges remain. These include the narrow host range of phages, the potential for bacterial resistance, unpredictable pharmacokinetic and pharmacodynamic parameters, and a complex, non-harmonized regulatory landscape. The review highlights that phage–antibiotic synergy and the use of phage cocktails are promising strategies to overcome some of these limitations. Future progress in phage therapy will depend on standardized manufacturing, robust clinical trials to establish dosing and efficacy, and the development of adaptive regulatory pathways. Phage therapy is positioned not as a replacement for antibiotics but as a vital adjunctive tool in the armamentarium against MDR infections, heralding a move towards a more personalized approach to infectious disease management. Full article

Background: Drug–drug interactions (DDIs) involve pharmacokinetic or pharmacodynamic changes that occur when multiple drugs are co-administered, potentially leading to reduced efficacy or adverse effects. As polypharmacy becomes more prevalent, especially among patients with chronic diseases, scalable and accurate DDI prediction has become increasingly important. Although numerous computational approaches have been proposed to predict DDIs using various modalities such as chemical structure and biological networks, the intrinsic heterogeneity of these data complicates unified modeling; Methods: We address this challenge with a multimodal deep learning framework that integrates three complementary, heterogeneous modalities: (i) chemical structure, (ii) BioBERT-derived semantic embeddings (a domain-specific large language model, LLM), and (iii) pharmacological mechanisms through the CTET proteins. To incorporate indirect biological pathways within the PPI network, we apply a random walk with restart (RWR) algorithm. Results: Across features combinations, fusing structural feature with BioBERT embedding achieved the highest classification accuracy (0.9655), highlighting the value of readily available data and the capacity of domain-specific language models to encode pharmacological semantics from unstructured texts. Conclusions: BioBERT embeddings were particularly informative, capturing subtle pharmacological relationships between drugs and improving prediction of potential DDIs. Beyond predictive performance, the framework is readily applicable to real-world clinical workflows, providing rapid DDI references to support the polypharmacy decision-making. Full article

Background: Infections following cardiac surgery are a significant cause of morbidity and mortality, particularly in intensive care units (ICUs). The role of antibiotic prophylaxis (AP) in preventing surgical site infections (SSIs) and other nosocomial infections is crucial; however, the optimal approach to agent selection, dosing, and duration remains controversial. Objective: This narrative review aims to summarise the current evidence and expert recommendations regarding the use of perioperative antibiotic prophylaxis (AP) in adults undergoing cardiac surgery, with a particular focus on intensive care settings, transplant recipients, and adult patients on extracorporeal membrane oxygenation (ECMO). Methods: A comprehensive review of recent literature was conducted, focusing on pharmacokinetic/pharmacodynamic (PK/PD) principles, microbial epidemiology, antimicrobial resistance (AMR), and practical strategies for tailored prophylaxis in high-risk populations. Results: Cefazolin remains the first-line agent for most procedures, with vancomycin or clindamycin reserved for patients who are allergic to β-lactams or who are colonised with MRSA. Redosing is recommended in cases of prolonged surgery or cardiopulmonary bypass. Evidence supports limiting prophylaxis to ≤24 h, with a potential extension to 48 h in select high-risk cases; however, continuation beyond this is discouraged due to the risk of resistance. In heart transplantation, multimodal prophylaxis against bacteria, fungi, and viruses is essential but must be tailored to the individual patient. In the ECMO setting, the current evidence does not support the routine administration of prophylaxis (AP), and therapy should be tailored based on pharmacokinetics (PK)/pharmacodynamics (PD) changes and the clinical context. A multidisciplinary, evidence-based approach to AP in cardiac surgery is essential. Prophylaxis should be patient-specific, microbiologically guided, and limited in duration to reduce the emergence of multidrug-resistant organisms. Integrating antimicrobial stewardship, non-pharmacological measures, and rigorous surveillance is crucial for optimising the prevention of infections in this vulnerable population. Full article

We aimed to investigate the interaction mechanism of transport protein Human serum albumin (HSA) with a synthesized compound, QP-11, with tested antimalarial properties to monitor the changes in the protein because of QP-11 binding. The interaction between the antimalarial compound QP-11 and HSA was thoroughly investigated through a multidimensional approach, utilizing UV-VIS spectroscopy, fluorescence, time-resolved fluorescence, and CD (Circular dichroism), alongside molecular docking techniques. Our findings unveiled a robust 1:1 binding pattern, signifying a strong affinity between QP-11 and HSA. Employing static quenching, evidenced by time-resolved fluorescence spectroscopy, QP-11 was observed to induce fluorescence quenching of HSA, particularly binding to subdomain IIA. Thermodynamic parameters indicated that van der Waals forces and hydrogen bonding predominantly facilitated the binding, with increased temperature compromising complex stability. The 3D fluorescence and CD results demonstrated QP-11-induced conformational changes in HSA. Both experimental and in silico analyses suggested a spontaneous, exothermic binding reaction. The profound impact of the QP-11–HSA interaction underscores the potential for QP-11 in antimalarial drug development, encouraging further exploration for dose design and enhanced pharmacodynamic and pharmacokinetic properties. Full article

Pharmacotherapy in the geriatric population is one of the greatest challenges in modern medicine. Elderly patients, characterized by multimorbidity and the resulting polypharmacy, are significantly more exposed to adverse drug reactions (ADRs), which often lead to hospitalization and a decline in quality of life. Understanding the reasons for this difference requires an analysis of the physiological changes that occur during the aging process at the molecular level. This article presents a perspective on the molecular aspects of geriatric pharmacotherapy, focusing on the fundamental mechanisms that are modified with age. The analysis covers changes in pharmacokinetics, including the role and regulation of cytochrome P450 (CYP) enzymes, whose activity, especially in phase I reactions, is significantly reduced. The age-dependent dysfunction of drug transporters from the ABC (ATP-binding cassette) and SLC (solute carrier) families in key organs such as the intestines, liver and kidneys is discussed, which affects the absorption, distribution and elimination of xenobiotic compounds, including drugs. The article also provides a comprehensive analysis of the blood–brain barrier (BBB), describing changes in neurovascular integrity, including the dysfunction of tight junctions and a decrease in the activity of P-glycoprotein, sometimes referred to as multidrug resistance protein (MDR). This increases the susceptibility of the central nervous system to the penetration and action of drugs. In the realm of pharmacodynamics, changes in the density and sensitivity of key receptors (serotonergic, dopaminergic, adrenergic) are described based on neuroimaging data, explaining the molecular basis for increased sensitivity to certain drug classes, such as anticholinergics. The paper also explores new research perspectives, such as the role of the gut microbiome in modulating pharmacokinetics by influencing gene expression and the importance of pharmacoepigenetics, which dynamically regulates drug response throughout life via changes in DNA methylation and histone modifications. The clinical implications of these molecular changes are also discussed, emphasizing the potential of personalized medicine, including pharmacogenomics, in optimizing therapy and minimizing the risk of adverse reactions. Such an integrated approach, incorporating data from multiple fields (genomics, epigenomics, microbiomics) combined with a comprehensive geriatric assessment, appears to be the future of safe and effective pharmacotherapy in the aging population. Full article

Background/Objectives: Adapalene is a synthetic retinoid used as a treatment for acne vulgaris. In this study, we attempted to evaluate the dermal pharmacokinetics of adapalene utilizing experimental and in silico tools. Methods: We utilized three over the counter (OTC) adapalene gels to evaluate local dermal pharmacokinetics. A data-driven, robust, mechanistic dermal physiologically based pharmacokinetic (PBPK) model was developed by integrating the physicochemical properties of adapalene, the formulation attributes of the gels, and the biophysical aspects of dermal absorption. The dermal PBPK model was validated against experimental data using in vitro release studies and in vitro permeation studies with human cadaver skin. A clinical study was performed to evaluate the effects of adapalene from the three gel formulations. The impact of adapalene delivery from three gels on the stratum corneum (SC) thickness, pilosebaceous unit area, keratinocyte number, and epidermal thickness was captured using a non-invasive technique, line-field confocal optical coherence tomography (LC–OCT). These responses were evaluated using an Emax model. Results: The dermal PBPK model has successfully predicted adapalene penetration profiles across different gel formulations. The model accuracy, in predicting drug release and permeation characteristics, was confirmed using the experimental data. Clinical evaluation revealed formulation-dependent differences in adapalene’s effects on measured skin parameters, with distinct pharmacodynamic profiles observed for each gel formulation. Conclusions: The overall study gave us a detailed insight into potential effects of formulation on the dermal pharmacokinetics and pharmacodynamics of adapalene using three marketed gels. Full article

Tuberculosis remains a serious infectious disease that causes over 1.3 million deaths annually. Following the COVID-19 pandemic, the global incidence of tuberculosis has increased to 10.8 million cases. Pregnant women represent a particularly vulnerable population requiring tailored approaches to the prevention, diagnosis, and treatment of tuberculosis. SARS-CoV-2 infection may have impacted existing clinical protocols. Implementing updated methods of tuberculosis prevention, diagnosis, and treatment in pregnant women could help reduce adverse maternal and fetal outcomes. The aim of this review was to explore potential modifications in tuberculosis management among pregnant women in the post-COVID-19 era, including co-infection with SARS-CoV-2. Methods: A review was conducted, incorporating a systematic literature search across major international databases, including Medline, PubMed, Web of Science, Scopus, and Google Scholar. The search covered publications released between December 2019 and September 2024 and used targeted keywords such as “COVID-19” OR “SARS-CoV-2”, “tuberculosis” OR “TB” OR “latent tuberculosis infection” OR “pulmonary tuberculosis”, and “pregnancy” OR “pregnant women”. Results: Pregnant women living with HIV are at increased risk of developing tuberculosis, which can negatively affect both maternal and perinatal outcomes. Screening for tuberculosis is recommended for all HIV-positive pregnant women, even in the absence of clinical symptoms. Notably, immunological testing before and during pregnancy facilitates the timely and safe detection of tuberculosis infection, enabling preventive and therapeutic interventions during any stage of gestation and the early postpartum period, for the benefit of both mother and child. Drug–drug interactions play a significant role in tuberculosis management, both among anti-tuberculosis agents and with medications for comorbid conditions. Current knowledge of the pharmacokinetics and pharmacodynamics of antituberculosis agents, coupled with therapeutic drug monitoring, supports the development of individualized and effective treatment regimens, which are particularly critical for pregnant patients. Recommendations for managing tuberculosis in pregnant women after COVID-19 infection include measuring D-dimer levels, performing echocardiography, and consulting cardiologists to prevent treatment-related complications. Conclusions: Pregnant women represent a distinct subgroup of tuberculosis patients requiring individualized management. Changes observed in tuberculosis progression and treatment responses in pregnant women before and after SARS-CoV-2 infection should inform therapeutic choices, especially in cases of drug-resistant tuberculosis treated with bedaquiline. COVID-19 has been associated with increased cardiovascular risk, which may heighten the likelihood of adverse drug reactions in this population, especially given the limited therapeutic options. Further research is required to assess the long-term outcomes of latent tuberculosis infection in pregnant women and to evaluate the safety and efficacy of novel regimens for drug-resistant TB during pregnancy. Full article

Background/Objectives: Pain—whether acute, chronic, or neuropathic—remains a leading cause of disability and reduced quality of life worldwide. Despite advances in pharmacologic options, interindividual variability in response and susceptibility to adverse effects continues to challenge clinicians. In recent years, pharmacogenetics has emerged as a promising approach to optimize analgesic selection and dosing based on patient-specific genetic profiles. This perspective examines current pharmacogenetic evidence in pain management, focusing on validated biomarkers and their clinical implications. Methods: A narrative review was conducted of recent literature addressing the impact of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of analgesic agents. Particular focus was given to genes involved in drug metabolism and transport as well as receptor signaling, along with the clinical applications of genotype-informed prescribing. Results: Substantial evidence indicates that genetic variants significantly influence patient responses to analgesics, contributing to both inadequate pain relief and heightened sensitivity to adverse effects. The main pharmacogenetic biomarkers appear to be CYP2C9 (for NSAIDs), CYP2D6 (for opioids and tricyclic antidepressants), CYP2C19 (for tricyclic antidepressants) and HLA-B*15:02 and HLA-A*31:01 for carbamazepine. PGx-informed strategies have shown promise in improving analgesic effectiveness, reducing opioid-related complications, and supporting opioid-sparing protocols. Conclusions: Pharmacogenetic screening represents a valuable tool for personalizing pain management. Incorporating validated pharmacogenetic biomarkers into clinical practice could improve treatment outcomes and patient safety. Further research, infrastructure development, and clinician education are essential for scaling PGx implementation in pain care. Full article

High-mobility group box 1 (HMGB1) is a nuclear protein that can interact with a transmembrane cell surface receptor for advanced glycation end products (RAGEs) and mediates the inflammatory pathways that lead to various pathological conditions like cancer, diabetes, cardiovascular diseases, and neurodegenerative disorders. Blocking the HMGB1/RAGE axis using various small synthetic or natural molecules has been proven to be an effective therapeutic approach to treating these inflammatory conditions. However, the low water solubility of these pharmacoactive molecules limits their clinical use. Pharmaceutically active molecules with low solubility and bioavailability in vivo convey a higher risk of failure for drug development and drug innovation. The pharmacokinetic and pharmacodynamics parameters of these compounds are majorly affected by their solubility. Enhancement of the bioavailability and solubility of drugs is a significant challenge in the area of pharmaceutical formulations. This review mainly describes various technologies utilized to improve the bioavailability of synthetic or natural molecules which have been particularly used in various inflammatory conditions acting specifically through the HMGB1/RAGE pathway. Full article

Background: Sodium–glucose cotransporter 2 (SGLT2) inhibitors have transformed type 2 diabetes mellitus (T2DM) management by promoting glucosuria, lowering glycated hemoglobin (HbA1c), blood pressure, and weight; however, their use is limited by genitourinary infections and ketoacidosis. Phytocannabinoids—bioactive compounds from Cannabis sativa—exhibit multi-target pharmacology, including interactions with cannabinoid receptors, Peroxisome Proliferator-Activated Receptors (PPARs), Transient Receptor Potential (TRP) channels, and potentially SGLT2. Objective: To evaluate the potential of phytocannabinoids as novel modulators of renal glucose reabsorption via SGLT2 and to compare their efficacy, safety, and pharmacological profiles with synthetic SGLT2 inhibitors. Methods: We performed a narrative review encompassing the following: (1) the molecular and physiological roles of SGLT2; (2) chemical classification, natural sources, and pharmacokinetics/pharmacodynamics of major phytocannabinoids (Δ⁹-Tetrahydrocannabinol or Δ⁹-THC, Cannabidiol or CBD, Cannabigerol or CBG, Cannabichromene or CBC, Tetrahydrocannabivarin or THCV, and β-caryophyllene); (3) in silico docking and drug-likeness assessments; (4) in vitro assays of receptor binding, TRP channel modulation, and glucose transport; (5) in vivo rodent models evaluating glycemic control, weight change, and organ protection; (6) pilot clinical studies of THCV and case reports of CBD/BCP; (7) comparative analysis with established synthetic inhibitors. Results: In silico studies identify high-affinity binding of several phytocannabinoids within the SGLT2 substrate pocket. In vitro, CBG and THCV modulate SGLT2-related pathways indirectly via TRP channels and CB receptors; direct IC₅₀ values for SGLT2 remain to be determined. In vivo, THCV and CBD demonstrate glucose-lowering, insulin-sensitizing, weight-reducing, anti-inflammatory, and organ-protective effects. Pilot clinical data (n = 62) show that THCV decreases fasting glucose, enhances β-cell function, and lacks psychoactive side effects. Compared to synthetic inhibitors, phytocannabinoids offer pleiotropic benefits but face challenges of low oral bioavailability, polypharmacology, inter-individual variability, and limited large-scale trials. Discussion: While preclinical and early clinical data highlight phytocannabinoids’ potential in SGLT2 modulation and broader metabolic improvement, their translation is impeded by significant challenges. These include low oral bioavailability, inconsistent pharmacokinetic profiles, and the absence of standardized formulations, necessitating advanced delivery system development. Furthermore, the inherent polypharmacology of these compounds, while beneficial, demands comprehensive safety assessments for potential off-target effects and drug interactions. The scarcity of large-scale, well-controlled clinical trials and the need for clear regulatory frameworks remain critical hurdles. Addressing these aspects is paramount to fully realize the therapeutic utility of phytocannabinoids as a comprehensive approach to T2DM management. Conclusion: Phytocannabinoids represent promising multi-target agents for T2DM through potential SGLT2 modulation and complementary metabolic effects. Future work should focus on pharmacokinetic optimization, precise quantification of SGLT2 inhibition, and robust clinical trials to establish efficacy and safety profiles relative to synthetic inhibitors. Full article

Background: Sirolimus (SRL, rapamycin) is a clinically important mTOR inhibitor used in immunosuppression, oncology, and cardiovascular drug-eluting devices. Despite its long-standing FDA approval, the human metabolic profile of SRL remains incompletely characterized. SRL is primarily metabolized by CYP3A enzymes in the liver and intestine, but the diversity, pharmacokinetics, and biological activity of its metabolites have been poorly explored due to the lack of structurally identified standards. Methods: To investigate SRL metabolism, we incubated SRL with pooled human liver microsomes (HLM) and isolated the resulting metabolites. Structural characterization was performed using high-resolution mass spectrometry (HRMS) and ion trap MSⁿ. We also applied Density Functional Theory (DFT) calculations to assess the energetic favorability of metabolic transformations and conducted molecular dynamics (MD) simulations to model metabolite interactions within the CYP3A4 active site. Results: We identified 21 unique SRL metabolites, classified into five major structural groups: O-demethylated, hydroxylated, didemethylated, di-hydroxylated, and mixed hydroxylated/demethylated derivatives. DFT analyses indicated that certain demethylation and hydroxylation reactions were energetically preferred, correlating with metabolite abundance. MD simulations further validated these findings by demonstrating the favorable orientation and accessibility of key sites within the CYP3A4 binding pocket. Conclusions: This study provides a comprehensive structural map of SRL metabolism, offering mechanistic insights into the formation of its metabolites. Our integrated approach of experimental and computational analyses lays the groundwork for future investigations into the pharmacodynamic and toxicodynamic effects of SRL metabolites on the mTOR pathway. Full article

Background: The landscape of antimicrobial therapy is undergoing a profound transformation; the contemporary arsenal of antimicrobials, particularly those with extended half-lives and enhanced tissue penetration, necessitates critically reassessing these traditional paradigms. The growing emphasis on antimicrobial stewardship programs has underscored the importance of optimizing antimicrobial agents to minimize the development and spread of resistance. Shorter treatment durations, when clinically appropriate, represent a key strategy in this endeavor. Methods: This narrative review provides a comprehensive synthesis of current evidence on the duration of antimicrobial therapy, with a particular focus on the clinical and pharmacological implications of novel agents, including long-acting formulations. Results: We critically examine the pharmacokinetic and pharmacodynamic properties of these agents, evaluate the opportunities and limitations associated with treatment shortening strategies, and underscore the pivotal role of antimicrobial stewardship in optimizing therapeutic outcomes within an increasingly complex and evolving landscape. Conclusions: The future of antimicrobial therapy lies in a personalized approach, where treatment decisions are tailored to the individual patient, but detailed clinical trials are necessary to evaluate these approaches. Full article