Suzetrigine was approved by the US American Food and Drug Administration in 2025 as the first oral, non-opioid, selective inhibitor of NaV1.8 sodium channel for the treatment of acute pain. Therefore, it represents a groundbreaking advancement in pain management. This review aims to provide an overview of the milestones in the medicinal-chemical development of NaV1.8 inhibitors, eventually leading to suzetrigine. The multi-step synthesis route of suzetrigine is presented. Taking structural features into account, insights are provided into what plays a role for the inhibition of the NaV1.8 channel. In addition, pharmacodynamic and pharmacokinetic aspects of the new drug, such as bioavailability, metabolism, and interaction with CYP450 enzymes, are discussed. A summary based on a large number of clinical trials demonstrating remarkable efficacy completes this comprehensive drug profile of suzetrigine, while also addressing limitations of the clinical trials and suggesting future perspectives.

Sulcatone is a compound found in citrus fruits and citronella oil, and it exhibits biological effects on the cardiovascular system. This study aimed to investigate the pharmacokinetic and pharmacodynamic aspects of sulcatone through in silico analysis and to evaluate its vasorelaxant, antioxidant, and hemostatic effects in spontaneously hypertensive rats (SHR). To refine the investigation, in silico evaluation was performed using the ADMET-AI, SwissADME, Protox 3.0, and AutoDock v1.5.7 platforms. In non-clinical studies, SHR rats were used (approved by the Institutional Animal Care and Use Committee-CEUA). Aortic rings were isolated for assessment of vasorelaxant response and morphometric analysis. Hemostatic parameters (platelet aggregation and coagulation) were also evaluated. For the antioxidant and coagulation analysis, animals were treated orally (p.o.) with sulcatone or saline for 7days. In silico results demonstrated that sulcatone has high intestinal absorption, does not violate Lipinski's rule, does not inhibit cytochrome P450 isoenzymes, and presents no predicted toxicity risk. Sulcatone interacts with amino acid residues at the active site of the calmodulin (CaM) protein target. Sulcatone induced vasorelaxation both in the presence (EC₅₀ = 3.8 ± 0.3 × 10⁻5M) and absence of vascular endothelium (EC₅₀ = 3.9 ± 0.4 × 10⁻5M), with no statistically significant difference between the values. Morphometric analysis of the aorta revealed reduced wall thickness and increased diameter of aortic rings. Assessment of antithrombotic activity of sulcatone (10⁻⁹ to 10⁻⁷ M) demonstrated an anti-platelet aggregation effect (1.5 ± 0.64%; 1.25 ± 0.47%; 2.5 ± 0.5%, respectively) compared to ADP-induced aggregation (43.75 ± 1.79%), an effect enhanced in the presence of calmodulin inhibitor (calmidazolium). Sulcatone at doses of 50 and 75mg/kg reduced nitrite levels (7.22 ± 0.33 and 6.0 ± 0.61mmol/L, respectively), and at 100mg/kg increased GSH levels (1128 ± 25.37mmol/L). In the coagulation analysis (PT and aPTT), sulcatone-treated SHR rats showed prolonged times (25.44 ± 1.47s and 21.28 ± 0.71s, respectively) compared to Wistar rats (21.91 ± 0.87s and 25.44 ± 1.47s, respectively). However, sulcatone treatment at 50, 75, and 100mg/kg (p.o.) did not present anticoagulant activity. In conclusion, sulcatone demonstrated favorable pharmacokinetic predictions and exerted vasorelaxant and anti-platelet aggregation effects, possibly through a shared mechanism involving interaction with calmodulin active site residues and intracellular calcium modulation. Additionally, sulcatone exhibited antioxidant properties and a low risk of bleeding, as it did not compromise the coagulation pathways.

Background: Hirudotherapy, the medicinal use of leeches, has evolved from traditional healing practices into a scientifically recognized therapeutic modality. The renewed interest in leech therapy arises from the identification of a wide spectrum of pharmacologically active molecules in leech saliva, many of which exhibit potent anticoagulant, anti-inflammatory, antithrombotic, analgesic, and vasodilatory effects. Objective: This systematic review aims to critically analyze the pharmacologically active compounds present in leech saliva, their mechanisms of action, preclinical and clinical evidence, pharmacokinetic and pharmacodynamic aspects, safety concerns, and future potential in drug discovery. Methods: A systematic literature search was performed across PubMed, Scopus, Google Scholar, Experimental, preclinical, and clinical studies relevant to pharmacology were included. Data extraction focused on bioactive molecules, mechanisms, therapeutic outcomes, and adverse effects. Results: Leech saliva contains over 100 bioactive molecules, including hirudin, calin, destabilase, bdellins, and Eglins. These compounds exert synergistic effects on coagulation pathways, inflammatory mediators, and microcirculatory dynamics. Clinical studies support its use in venous congestion, osteoarthritis, and reconstructive surgery, though standardization remains a challenge. Conclusion: Leech therapy represents a biologically rich source of pharmacologically valuable compounds. Despite promising evidence, further large-scale, standardized clinical trials and molecular studies are essential for its integration into mainstream pharmacotherapy.

Adverse drug reactions (ADRs) represent one of the major health problems worldwide which have high morbidity and mortality rates. The risk of ADR is higher in paediatric patients for various reasons. But knowledge about ADR in children is very poor. Adequate recognition of ADR is challenging in paediatric population. Because of their unique physiological and developmental traits, children—from neonates to adolescents – a particularly difficult demographic for drug treatment. When compared to adults, these alterations can have a substantial impact on pharmacokinetics and pharmacodynamics, resulting in changes in drug absorption, distribution, metabolism, and excretion. Historically, paediatric groups have been overlooked in clinical medication studies, resulting in insufficient data on their safety and efficacy. To address this gap, adult research has been extrapolated to children, with changes in body size and maturation, but without an extensive understanding of developmental pharmacology. Therefore, to maximize therapeutic results and reduce harm, adverse drug reactions (ADRs) in children necessitate careful thought, monitoring, and research. Paediatric pharmacovigilance aims to address knowledge gaps and improve drug safety for patients. Health care providers play a critical role in ADR detection and reporting. ADRs can vary in intensity and variety among paediatric age groups, making it challenging to identify, report, and manage them. This review briefly elaborates the historical background of paediatric pharmacovigilance and also physiological peculiarities of pharmacodynamics and pharmacokinetic aspects of drugs in newborns, infants, toddlers and children and the importance of paediatric pharmacovigilance system. Mugda Med Coll J. 2025; 8(2): 150-156

Different strategies to make biobetters: physicochemical, pharmacodynamics, and pharmacokinetic aspects came into focus.

Impact of cerebral vasospasm therapy on nimodipine exposure in subarachnoid hemorrhage: A population pharmacokinetic study.

Aldosterone is a mineralocorticoid hormone essential for regulating renal function and blood pressure. Despite its clinical relevance, key aspects of aldosterone pharmacokinetics (PK) and physiological dynamics remain incompletely understood. In serial stages, we developed a semi-mechanistic pharmacokinetic-pharmacodynamic (PK-PD) model to characterize aldosterone dynamics under conditions of circadian production and inhibition by lorundrostat, a selective aldosterone synthase inhibitor. Lorundrostat PK from published single- and multiple-dose studies in healthy subjects was modeled using a linear hybrid two-compartment model (2CM) with food-dependent absorption and adrenal distribution. Separate assessment of aldosterone PK yielded 2CM properties that were used in defining both the circadian production and adrenal suppression by lorundrostat. Aldosterone concentrations from 24-hour pre-dose phases were characterized with dual harmonic circadian functions with fasting-induced shifts in the timing and amplitude of hormone production. Lorundrostat suppression of aldosterone production was fitted with an extended indirect response model utilizing both the circadian production and 2CM aldosterone PK. Synthesis inhibition was about 90% while IC50 values were attained at low doses. Such inhibition induced gradual compensatory increases in plasma renin activity, with rebound effects on aldosterone expected after 7 days of dosing and later. Sensitivity analysis supported the determinants of aldosterone dynamics in the model. This model provides a systems-level framework to disentangle physiological and pharmacological drivers of aldosterone regulation, supports trial design for aldosterone synthase inhibitors, and may inform the development of more complex models for RAAS control of renal and cardiovascular function.

This series focuses on aspects of prescribing for neonates, children and young people, from A–Z. Aspects of pharmacokinetics will be considered, alongside legal considerations, consent and medications in schools

Over the past few decades, discovering new anticancer drugs was considered one of the biggest challenges for researchers. In this study, two series of acylhydrazones Z1-6 and hydrazones K1-6 were synthesized via reacting isoniazid or 2-hydrazinopyridine with some aromatic heterocyclic aldehydes under acidic conditions. The structures of all compounds were proven spectrophotometrically using proton nuclear magnetic resonance (1HNMR) and carbon-13 NMR (13CNMR), in addition to liquid chromatography-mass (LCMS) spectra, infrared (IR) spectra, and elemental analyses. Our compounds were evaluated for their anticancer activity against three types of cancer cells: colon HCT-116, lung A-549, and MCF-7 breast Adenocarcinoma cancer cells by the SRB method. Compounds Z3 and K4 showed the highest inhibition against colon cancer cells with IC50 values of 1.59 and <1 μM, respectively. Moreover, flowcytometric analysis revealed the ability of Z3 to cause cell cycle arrest at sub G1 phase and S phase in HCT-116 colon cancer cell line, in addition to prominent apoptotic effects. Subsequently, molecular docking was conducted to gain insight into the plausible mechanism of action for the most active compounds Z3 and K4 and it suggested Topoisomeras I as a potential biological target of the new counterparts. Absorption, Distribution, Metabolism Excretion, and Toxicity (ADMET) study predicted physicochemical and pharmacokinetic aspects. Furthermore, density functional theory (DFT) was carried out to better understand the structural properties, stability, and chemical reactivity of the most promising derivatives. In summary, this study offers new anticancer candidates with acylhyrazone/hydrazone scaffolds which may need further optimization.

This series focuses on aspects of prescribing for neonates, children and young people, from A–Z. Aspects of pharmacokinetics will be considered, alongside legal considerations, consent and medications in schools

Quercetin-3-O-rutinoside (Q3R) is a bioflavonoid characterized by the attachment of rutinose, an indigestible disaccharide, to quercetin. EubioQuercetin is a standardized Q3R formulation with improved water solubility. This study aimed to clarify the similarities and differences between EubioQuercetin, Q3R, and conventional quercetin by comparing their microbiological and pharmacokinetic properties. Fecal microbiota analyses showed that the addition of EubioQuercetin significantly increased Blautia and [Ruminococcus] gnavus groups (p<0.05) and significantly decreased Faecalibacterium and deoxycholic acid (p< 0.05). Correlation analysis of intestinal bacteria showed a significant positive correlation between the relative abundance of Fusicatenibacter and Christensenellaceae R-7 group before the addition of EubioQuercetin and its fold change before and after the addition of EubioQuercetin. In a randomized, open-label, two-sequence/two-period crossover clinical trial, the eight major blood metabolites and their blood abundance ratios showed almost the same tendency between EubioQuercetin and quercetin, with or without rutinose. The pK profile of EubioQuercetin showed a 5-fold increase in Cmax and a 4-5-fold increase in AUClast compared with those of quercetin; the Tmax was 2-3 times longer; the t1/2 was more than 2-fold longer after 4 weeks of continuous administration. A similar trend to that observed in the in vitro human fecal microbiota assay was seen, with increased fluctuations in intestinal bacterial composition following 4 weeks of EubioQuercetin consumption. Preliminary findings indicate that the increased water solubility of EubioQuercetin promotes catabolic and metabolic reactions in intestinal bacteria, and that the tendency of intestinal bacteria to fluctuate is different from that of conventional quercetin.

The herbal drug industry faces a significant challenge due to the scarcity of classical drugs with proven efficacy and established clinical utility. This necessitates the exploration of alternative drugs, particularly Extrapharmacopeial drugs, which hold immense potential. Ayurvedic pharmacology's fundamental principle, "nothing on earth is non-medicinal," underscores the importance of investigating these drugs. This study focuses on Cocos nucifera Linn. (Coconut shell), a folklore drug with diverse utility but limited scientific documentation. We employed analytical and experimental in-vivo models to elucidate the pharmacodynamic and pharmacokinetic aspects of this Extrapharmacopeial drug. Our research included organoleptic evaluation, Rasa (taste) analysis, Veerya (potency) analysis, and Vipaka (pharmacokinetic) studies. This comprehensive approach can be applied to unlock the therapeutic potential of numerous undocumented natural plant resources, ultimately contributing to new drug development.

Edema is a typical pathological process that complicates a wide spectrum of disorders and conditions. Edema management is necessary to restore normal tissue perfusion and nutrient supply, prevent secondary injury and complications, relieve pain, and improve patient overall well-being. This article reviews the mechanisms of anti-edematous activity of escin, a triterpene saponin, in edema of different origins and locations. Escin inhibits hydrolytics enzymes, prevents the induction of cell adhesion molecules, downregulates pro-inflammatory signaling pathways, supports intercellular junction integrity, ameliorates endothelial cell damage and dysfunction. Experimental and clinical studies have found escin to possess additional anti-inflammatory, analgesic, and antioxidant effects.

This series focuses on aspects of prescribing for neonates, children and young people, from A–Z. Aspects of pharmacokinetics will be considered, alongside legal considerations, consent and medications in schools

L-3-[18F]-fluoro-α-methyl tyrosine ([18F]FAMT) is an amino acid positron emission tomography (PET) tracer with high specificity for malignant tumors through its selective transport via L-type amino acid transporter (LAT) 1. Although extensively studied for its diagnostic performance, a comprehensive review of its molecular and clinical characteristics remains lacking. A systematic literature review (1997-2025) was conducted using PubMed and Web of Science, with keywords including "L-3-[18F]-fluoro-α-methyl tyrosine", "[18F]FAMT", "amino acid PET", and "tumor imaging". The review covered aspects of synthesis, structural properties, pharmacokinetics, and clinical applications. Notably, while research on [18F]FAMT has declined significantly in recent years, [18F]FAMT PET demonstrates superior specificity to [18F]FDG PET in distinguishing malignancies from inflammatory lesions and offers distinct advantages in lung, esophageal, and oral cancers, though with slightly lower sensitivity. Its key features include tumor-specific uptake patterns, rapid blood clearance, and a significant correlation between its uptake levels and both LAT1 expression and tumor proliferation. In conclusion, [18F]FAMT is a promising PET tracer with notable advantages in tumor imaging, particularly due to its LAT1 selectivity and favorable pharmacokinetics. Despite challenges in production, these characteristics underscore its clinical value in cancers requiring precise imaging. Future research should focus on optimizing synthesis, expanding clinical validation, and exploring theranostic applications.

Bacterial meningitis remains a life-threatening central nervous system (CNS) infection with high morbidity and mortality rates, demanding rapid and effective therapeutic intervention. Traditional systemic antibiotic therapies often face challenges such as the blood-brain barrier (BBB) limiting drug penetration, systemic toxicity, and poor patient compliance. Nasal drug delivery emerges as a promising non-invasive alternative route to bypass the BBB and deliver therapeutic agents directly to the brain. Microemulsions, with their nanoscale droplet size, high solubilization capacity, and enhanced permeation properties, offer significant potential for intranasal delivery of antibiotics targeting CNS infections. This review focuses on the formulation strategies, key excipients, and evaluation parameters critical for developing effective microemulsion systems for nasal administration. It also discusses recent advances, in vitro and in vivo studies, pharmacokinetic aspects, and the challenges associated with the clinical translation of such systems. The integration of microemulsion technology with nasal drug delivery holds great promise for improving therapeutic outcomes in bacterial meningitis.

Background: Our understanding of opioid pharmacology has expanded significantly in recent years. Both naturally occurring and synthetic opioids bind to specific receptor types, which play a key role in their effects and mechanisms of action. Objective: To provide an overview of the opioid receptor types, their classifications, associated pharmacological effects, mechanisms of dependence, and key aspects of opioid pharmacokinetics, interactions, and therapeutic uses. Methods: A comprehensive analysis of opioid receptor families, including nociceptin, mu, kappa, and delta, and their pharmacological interactions. Opioids are categorized as agonists, antagonists, partial agonists, or agonist-antagonists based on their affinity and efficacy. Results: Opioid administration commonly leads to side effects such as sedation, euphoria, analgesia, nausea, vomiting, miosis, respiratory depression, cough suppression, stiffness, constipation, facial redness and itching, urinary retention, and the potential for dependence (tolerance and abstinence). The development of tolerance and physical dependency is linked to elevated cAMP and adenyl cyclase levels. Long-term use can result in increased transcription factors, such as CREB and ΔFosB, which are associated with relapses and sustained effects. Conclusion: This study outlines the pharmacokinetics, drug interactions, and therapeutic applications of commonly used opioids, providing a comprehensive understanding of their clinical and pharmacological profiles

This series focuses on aspects of prescribing for neonates, children and young people, from A–Z. Aspects of pharmacokinetics will be considered, alongside legal considerations, consent and medications in schools

Berberis aristata DC. (Indian barberry): Current insight into botanical, phytochemical, and pharmacological aspects, pharmacokinetics, safety of use and modern therapeutic applications.

Abstract Heterocyclic scaffolds, especially oxazines, constitute a significant component of clinically pertinent pharmaceuticals. Morpholine enhances the solubility, bioavailability, and metabolic stability of drug molecules because of its structural feature that gives optimum basicity (pK a = ca. 8.7), hydrogen bonding, and an electron-deficient ring system. Apart from structural features, incorporating morpholine ring systems in drug molecules improved their pharmacokinetic profiles also. It provides optimum lipid solubility as well as aqueous solubility. As a bioisosteric replacement unit for piperazine, piperidine, etc., the morpholine ring provides optimum basicity and lipophilicity. We have examined U.S. FDA approved small-molecule drugs (2012–2023) incorporating morpholine as core ring structures. The analysis identified 14 drugs approved in the past decade that contain morpholine ring systems, with 50% classified as anticancer agents. The CYP3A4 enzyme was identified as the main driver for the metabolism of these drugs, with the majority being excreted via feces. Three morpholine-containing drugs were identified as possessing chiral centers, taking into account stereochemical aspects. In addition to covering drugs with morpholine rings, the perspective offers a comprehensive analysis utilizing molecular descriptors, chemical space parameters, and commentary on these medications’ pharmacokinetic and pharmacodynamic aspects. This enhances the article’s medicinal chemistry dimension and renders it a valuable resource for the medicinal and allied science community.1 Introduction2 Insights towards the Chemistry of Morpholine3 Synthetic Strategies to Develop Morpholine Derivatives4 Implication of Morpholine in Improvising the Pharmacokinetics and Efficacy of Pharmaceutical Drugs: Case Studies5 Comparative Analysis of the Pharmacological Class of the Approved Drugs Possessing Morpholine System6 Delving Deeper into the Approved Drugs Bearing the Morpholine-Based Core Systems7 Analysis and Conclusion8 Summary