Pharmacodynamic Aspects Research Articles

Erratum: Feasibility exploration of GSH in the treatment of acute hepatic encephalopathy from the aspects of pharmacokinetics, pharmacodynamics, and mechanism

Erratum: Feasibility exploration of GSH in the treatment of acute hepatic encephalopathy from the aspects of pharmacokinetics, pharmacodynamics, and mechanism

Podophyllotoxin and Aryltetralin Lignans: Methods for the Synthesis of Rings A, B, C, D

Podophyllotoxin, its derivatives and structural analogues are an extensive group of aryl-tetralin-lignans of interest in pharmacology due to their promising anticancer and antitumor activity. The synthesis methods that have been proposed to date seek to resolve synthetic, stereochemical, pharmacodynamic and environmental aspects. In this review we have updated and brought together different classifications of lignan and podophyllotoxin synthesis. Transformation methods focus on the strategies used to form or functionalize rings A, B, C and D, as well as the configuration of the system of four stereogenic centers that fuse rings C and D.

Exploring Nanoparticles: Types, Advantages, Challenges, and Applications in Drug Delivery and Technology

ABSTRACT: Recently the use of particulate systems, such as nanoparticles, has physically altered and improved the pharmacokinetic and pharmacodynamic aspects of many different types of pharmaceutical compounds. They have been used in vivo to protect the drug entity in systemic circulation, restrict drug access to the desired locations, and deliver the drug at a steady and controlled rate to the site of action. Without a doubt, the size of medication delivery research is getting smaller and smaller. Nanotechnologies are therefore emerging as a field in medicine that promises to produce significant therapeutic benefits. One of the most challenging issues facing the pharmaceutical business is the development of effective, small delivery devices that can safely and accurately deliver a medication to a designated site of action. They are working to reformulate the blockbuster drugs that are presently on the market and add new indications in order to maintain valuable scientific findings and therapeutic advancements. Nano emulsions, liposomes, and lipid or polymeric nanoparticles are the fundamental elements of nano delivery systems.

Remdesivir: A Review of Analytical Methods for the Drug Substance, Pharmaceutical Formulations and Biological Matrices

Remdesivir (RDV) is a nucleoside analogue prodrug that acts as a viral RNA polymerase inhibitor, triggering chain termination following its incorporation. Approved for the treatment of COVID-19 in 2020, RDV is administered intravenously. This article presents the main physicochemical characteristics of the compound and outlines the most relevant pharmacokinetic and pharmacodynamic aspects. The main analytical methods described in the literature for the detection and quantification of RDV in biological matrices, raw materials, and formulations are presented herein, as well as those for the analysis of degradation products and synthesis impurities. Discussion includes the advantages and disadvantages of these methods, alongside their limits of detection and quantification. Chromatographic methods using a C18 stationary phase, gradient elution with a mobile phase containing up to 100% acetonitrile, and mass spectrometry detection with electron spray ionization in positive mode represent the main choice for RDV determination in biological matrices. While for raw material and formulation analysis, detection is conducted mainly by employing UV in the 237–254 nm range. Impurity detection primarily utilizes C18 columns, isocratic elution with a mobile phase containing up to 70% acetonitrile, and UV detection (237–247 nm). The literature reports fifteen impurities, requiring further RDV stability studies for identifying and quantifying impurities, as well as the development of chiral methods and pharmacopeia standardization.

Co-Administration of Amiodarone Increases Bleeding by Affecting Rivaroxaban Pharmacokinetics in Patients with Atrial Fibrillation.

This study aimed to investigate the impact of the drug-drug interaction between rivaroxaban and amiodarone on the clinical outcomes in patients with non-valvular atrial fibrillation (NVAF), focusing on pharmacokinetic and pharmacodynamic (PK/PD) aspects. A prospective study enrolling 174 patients with NVAF who were treated with rivaroxaban was conducted. The patients were divided into two groups based on postoperative antiarrhythmic and anticoagulation strategies: the rivaroxaban group (Control group) and the rivaroxaban plus amiodarone group (Riv/Amio group). The trough plasma concentrations (Ctrough) of rivaroxaban, activated partial thromboplastin time (APTT), prothrombin time (PT), and the clinical outcomes between the two groups were compared. Patients receiving 20 mg of rivaroxaban in the Riv/Amio group had a higher concentration of rivaroxaban Ctrough than those in the Control group (p = 0.009). Furthermore, in patients with moderate to severe renal impairment, rivaroxaban Ctrough was significantly increased in the Riv/Amio group. There was no significant difference in PT and APTT between the two groups. Regarding the clinical outcomes, the combination of rivaroxaban and amiodarone medication was associated with a higher incidence of bleeding events (p = 0.041; HR = 2.83, 95% CI 1.05-7.66) and clinically relevant non-major bleeding (p = 0.021; HR = 3.65, 95% CI 1.21-10.94). Finally, independent risk factors for bleeding in NAVF patients treated with rivaroxaban were identified as its combination with amiodarone (p = 0.044; OR = 2.871, 95% CI 1.028-8.023). The combination of rivaroxaban and amiodarone led to changes in rivaroxaban pharmacokinetics and an elevated risk of bleeding events. Therefore, physicians prescribing rivaroxaban medications should assess the potential bleeding risk associated with the concurrent use of amiodarone, particularly in patients with renal impairment.

Feasibility exploration of GSH in the treatment of acute hepatic encephalopathy from the aspects of pharmacokinetics, pharmacodynamics, and mechanism.

Our previous study highlighted the therapeutic potential of glutathione (GSH), an intracellular thiol tripeptide ubiquitous in mammalian tissues, in mitigating hepatic and cerebral damage. Building on this premise, we posited the hypothesis that GSH could be a promising candidate for treating acute hepatic encephalopathy (AHE). To verify this conjecture, we systematically investigated the feasibility of GSH as a therapeutic agent for AHE through comprehensive pharmacokinetic, pharmacodynamic, and mechanistic studies using a thioacetamide-induced AHE rat model. Our pharmacodynamic data demonstrated that oral GSH could significantly improve behavioral scores and reduce hepatic damage of AHE rats by regulating intrahepatic ALT, AST, inflammatory factors, and homeostasis of amino acids. Additionally, oral GSH demonstrated neuroprotective effects by alleviating the accumulation of intracerebral glutamine, down-regulating glutamine synthetase, and reducing taurine exposure. Pharmacokinetic studies suggested that AHE modeling led to significant decrease in hepatic and cerebral exposure of GSH and cysteine. However, oral GSH greatly enhanced the intrahepatic and intracortical GSH and CYS in AHE rats. Given the pivotal roles of CYS and GSH in maintaining redox homeostasis, we investigated the interplay between oxidative stress and pathogenesis/treatment of AHE. Our data revealed that GSH administration significantly relieved oxidative stress levels caused by AHE modeling via down-regulating the expression of NADPH oxidase 4 (NOX4) and NF-κB P65. Importantly, our findings further suggested that GSH administration significantly regulated the excessive endoplasmic reticulum (ER) stress caused by AHE modeling through the iNOS/ATF4/Ddit3 pathway. In summary, our study uncovered that exogenous GSH could stabilize intracerebral GSH and CYS levels to act on brain oxidative and ER stress, which have great significance for revealing the therapeutic effect of GSH on AHE and promoting its further development and clinical application.

Dietary Influence on Drug Efficacy: A Comprehensive Review of Ketogenic Diet-Pharmacotherapy Interactions.

It is widely acknowledged that the ketogenic diet (KD) has positive physiological effects as well as therapeutic benefits, particularly in the treatment of chronic diseases. Maintaining nutritional ketosis is of utmost importance in the KD, as it provides numerous health advantages such as an enhanced lipid profile, heightened insulin sensitivity, decreased blood glucose levels, and the modulation of diverse neurotransmitters. Nevertheless, the integration of the KD with pharmacotherapeutic regimens necessitates careful consideration. Due to changes in their absorption, distribution, metabolism, or elimination, the KD can impact the pharmacokinetics of various medications, including anti-diabetic, anti-epileptic, and cardiovascular drugs. Furthermore, the KD, which is characterised by the intake of meals rich in fats, has the potential to impact the pharmacokinetics of specific medications with high lipophilicity, hence enhancing their absorption and bioavailability. However, the pharmacodynamic aspects of the KD, in conjunction with various pharmaceutical interventions, can provide either advantageous or detrimental synergistic outcomes. Therefore, it is important to consider the pharmacokinetic and pharmacodynamic interactions that may arise between the KD and various drugs. This assessment is essential not only for ensuring patients' compliance with treatment but also for optimising the overall therapeutic outcome, particularly by mitigating adverse reactions. This highlights the significance and necessity of tailoring pharmacological and dietetic therapies in order to enhance the effectiveness and safety of this comprehensive approach to managing chronic diseases.

Effects of sodium ferulate for injection on anticoagulation of warfarin in rats in vivo

BackgroundHerb-drug interactions may result in increased adverse drug reactions or diminished drug efficacy, especially for drugs with a narrow therapeutic index such as warfarin. The current study investigates the effects of sodium ferulate for injection (SFI) on anticoagulation of warfarin from aspects of pharmacodynamics and pharmacokinetics in rats and predicts the risk of the combination use.MethodsRats were randomly divided into different groups and administered single- or multiple-dose of warfarin (0.2 mg/kg) with or without SFI of low dose (8.93 mg/kg) or high dose (26.79 mg/kg). Prothrombin time (PT) and activated partial thromboplastin time (APTT) were detected by a blood coagulation analyzer, and international normalized ratio (INR) values were calculated. UPLC-MS/MS was conducted to measure concentrations of warfarin enantiomers and pharmacokinetic parameters were calculated by DAS2.0 software.ResultsThe single-dose study demonstrated that SFI alone had no effect on coagulation indices, but significantly decreased PT and INR values of warfarin when the two drugs were co-administered (P < 0.05 or P < 0.01), while APTT values unaffected (P > 0.05). Cmax and AUC of R/S-warfarin decreased but CL increased significantly in presence of SFI (P < 0.01). The multiple-dose study showed that PT, APTT, INR, and concentrations of R/S-warfarin decreased significantly when SFI was co-administered with warfarin (P < 0.01). Warfarin plasma protein binding rate was not significantly changed by SFI (P > 0.05).ConclusionsThe present study implied that SFI could accelerate warfarin metabolism and weaken its anticoagulation intensity in rats.

Pharmacokinetic and pharmacodynamic principles: unique considerations for optimal design of neonatal clinical trials.

Core clinical pharmacology principles must be considered when designing and executing neonatal clinical trials. In this review, the authors discuss important aspects of drug dose selection, pharmacokinetics, pharmacogenetics and pharmacodynamics that stakeholders may consider when undertaking a neonatal or infant clinical trial.

A decade of pyridine-containing heterocycles in US FDA approved drugs: a medicinal chemistry-based analysis.

Heterocyclic scaffolds, particularly, pyridine-containing azaheterocycles, constitute a major part of the drugs approved in the past decade. In the present review, we explored the pyridine ring part of US FDA-approved small molecules (2014-2023). The analysis of the approved drugs bearing a pyridine ring revealed that a total of 54 drugs were approved. Among them, the significant number comprised the anticancer category (18 drugs, 33%), followed by drugs affecting the CNS system (11 drugs, 20%), which include drugs to treat migraines, Parkinsonism disorders, chemotherapeutic-induced nausea, insomnia, and ADHD or as CNS-acting analgesics or sedatives. Next, six drugs (11%) were also approved to treat rare conditions, followed by five drugs that affect the hematopoietic system. The analysis also revealed that drug approval was granted for antibiotics, antivirals, and antifungals, including drugs for the treatment of tropical and sub-tropical diseases. Primary drug targets explored were kinases, and the major metabolizing enzyme was CYP3A4. Further analysis of formulation types revealed that 50% of the approved drugs were tablets, followed by 17% capsules and 15% injections. Elemental analysis showed that most approved drugs contained sulfur, while fluorine was noted in 32 compounds. Therefore, the present review is a concerted effort to cover drugs bearing pyridine rings approved in the last decade and provide thorough discussion and commentary on their pharmacokinetics and pharmacodynamics aspects. Furthermore, in-depth structural and elemental analyses were explored, thus providing comprehensive guidance for medicinal chemists and scientists working in allied science domains.

Nanotechnology for Novel Drug Delivery: A Systematic Review of Classification, Preparation, Characterization, and Applications of Nanoparticles in Drug Delivery

ABSTRACT: The goal of nanotechnology is to develop new nanoscale components by designing, fabricating, and using materials that are atomically, molecularly, and macromolecular organized. For several decades, there has been an abundance of scientific curiosity in the administration of medicines using particle delivery systems as carriers for small and big molecules. Particulate systems, such as nanoparticles, have been utilized as a physical method to modify and improve the pharmacokinetic and pharmacodynamics aspects of numerous pharmaceutical molecules. A typical nanoparticle is between 1 and 100 nm in size and has one or more dimensions. Nanoparticles are usually categorized as inorganic, organic, or carbon-based particles according to their superior characteristics in comparison to larger sizes of the corresponding materials. They have been utilized in vivo to protect the drug entity in the systemic circulation, limiting drug distribution to the targeted areas, and to transport the drug at a controlled and sustained rate to its site of action. The most innovative and promising medication delivery technique at the moment is nanoparticle technology. This methodical research examines the categorization, characteristics, techniques, characterizations, and applications of nanoparticles in the delivery of drug molecules.

Pharmacodynamic and pharmacokinetic aspects of combined use of glycyrrhizinic acid

Glycyrrhizinic acid is a triterpenoid plant-derived compound with potent antisteatotic, anticytolitic, anti-inflammatory, antifibrotic, anticholestatic as well as antiapoptotic, antineoplastic and some other effects. Recent studies have demonstrated glycyrrhizinic acid to form supramolecular self-associates and micelles, which makes it a pharmacokinetic, and, hence, a pharmacodynamic enhancer. Thus, the prospects and possibilities of combined use of glycyrrhizinic acid in liver disease and other pathologies arise due to the pharmacological properties of the molecule itself as well as its function as drug carrier and delivery enhancer. The present review is focused on the pharmacodynamic and pharmacokinetic features of glycyrrhizinic acid combinations with essential phospholipids and ursodeoxycholic acid.

Mutant CYP3A4/5 Correlated with Clinical Outcomes by Affecting Rivaroxaban Pharmacokinetics and Pharmacodynamics in Patients with Atrial Fibrillation.

This study was designed to investigate the impact of single-nucleotide polymorphism-encoded cytochrome P450 enzymes (CYP3A4/5) on clinical outcomes of rivaroxaban in patients with non-valvular atrial fibrillation (NVAF) based on pharmacokinetics and pharmacodynamics (PK/PD) aspects. A prospective study enrolling 165 rivaroxaban-treated patients with NVAF was conducted. Genotyping of CYP3A4 (rs2242480, rs2246709, rs3735451, and rs4646440) and CYP3A5 (rs776746) was performed to explore their impact on the trough plasma concentrations (Ctrough) of rivaroxaban, coagulation indicators at the Ctrough including activated partial thromboplastin time (APTT) and prothrombin time (PT), and clinical outcomes. Patients with mutant genotype CYP3A4 (rs2242480, rs2246709, and rs3735451) and CYP3A5 (rs776746) had higher levels of rivaroxaban Ctrough, PT values than that of wild-type. Furthermore, a positive relationship was revealed between Ctrough and PT (r = 0.212, p = 0.007), while no significant correlation was found between Ctrough and APTT. Regarding the clinical outcomes, the minor allele carriers on rs3735451 and the minor allele (A) carriers on rs2246709 were associated with higher incidence of minor bleeding (p = 0.028 and p = 0.038, respectively) and were identified as the independent risk factors of minor bleeding treated with rivaroxaban (p = 0.024 and p = 0.036, respectively), with the receiver operating characteristic (ROC) curve validated (AUC = 0.8956, 95% CI: 0.829-0.962). The CYP3A4 polymorphisms (rs2242480, rs2246709, and rs3735451) and CYP3A5 rs776746 were associated with variations in rivaroxaban PK/PD. The minor allele (C) carriers on rs3735451 and the minor allele (A) carriers on rs2246709 were correlated with clinical outcomes.

A COMPREHENSIVE META-ANALYSIS AND REVIEW ON THE ANTIARTHRITIC EFFECTS OF CAMPESTEROL: INSIGHTS INTO MECHANISTIC ACTION

Delving into the potential therapeutic benefits of Campesterol, a plant-derived sterol, this comprehensive metaanalysis and review systematically dissect its role in combating arthritis. The focus is primarily on the reported ability of Campesterol to suppress vital proinflammatory markers such as TNF-α, IL1β, IL-6, NFκ-B, MMP-3, COX-I, and COX-II, and its potential to stimulate the anti-inflammatory cytokine IL-4. Rheumatoid arthritis (RA) is a chronic inflammatory condition recognized for deleterious impact on joint structures. This meta-analysis and review aim to elucidate the potential therapeutic advantages of Campesterol, a phytosterol renowned for its anti-inflammatory properties, in managing rheumatoid arthritis (RA). Through the systematic compilation of evidence from various studies, our objective is to elucidate the precise mechanism of action by which Campesterol exerts its antiarthritic effects. This meta-analysis, conducted in adherence to the PRISMA guidelines, encompasses studies until July 2023. The primary objective is to comprehend the function of Campesterol in regulating both pro and anti-inflammatory indicators in rheumatoid arthritis (RA). The reliability of the studies included in the analysis was assessed using standardized evaluation instruments. A noteworthy study conducted on a rat model with arthritis induced by CFA (Complete Freund's Adjuvant) presents compelling evidence supporting the antiarthritic properties of Campesterol. Administration of Campesterol resulted in a notable decrease in arthritic scores, paw edema, and levels of proinflammatory cytokines, including TNF-α, NFκ-B, IL-6, COX-II, and IL-1. Additionally, the levels of PGE-2 were also reduced. Moreover, it elicited an increase in anti-inflammatory interleukin4 (IL-4) levels and restored homeostasis in blood and biochemical parameters, indicating a comprehensive amelioration in the pathology of arthritis. These findings were further supported by additional studies, highlighting the potential of Campesterol as a potent therapeutic agent in managing rheumatoid arthritis (RA). This meta-analysis strongly supports the therapeutic potential of Campesterol in treating arthritis. However, additional research, particularly involving human trials, is required to substantiate these findings and gain a comprehensive understanding of the therapeutic potential of Campesterol in the management of arthritis. Further investigations are warranted to explore the intricate aspects of Campesterol's pharmacokinetics and pharmacodynamics and its enduring safety profile. Additionally, it is imperative to examine the potential synergistic interactions that may arise when Campesterol is combined with established treatments for rheumatoid arthritis (RA). It is imperative to investigate Campesterol's precise molecular targets further.

Olutasidenib: A ray of hope in the treatment of acute myeloid leukaemia

Acute myeloid leukaemia (AML) or Myelodysplastic syndrome (MDS) is one of the most common and life-threatening forms of blood cancer spreading worldwide. AML is characterized by some common sign and symptoms including fever, fatigue, easy bruising/bleeding, and sometimes with major differentiation syndrome. The pathogenesis of AML is attributed to the extreme differentiation of abnormally proliferated myeloid cell i.e., myeloblasts. Due to the cytotoxic potential of available chemical agents towards healthy cell, there is emerging need to develop target based selective medication with least adverse effects. Olutasidenib, is a quinoline-2-one analogue that selectively binds to mutated isocitrate dehydrogenase-1 to resist the formation of oncometabolite 2-hydroxyglutarate (2-HG) and hence, leads to cancerous cell apoptosis. Olutasidenib was approved on December 1, 2022, by FDA with the brand name Rezlidhea as one of the effective treatments against acute myeloid leukaemia via targeting IDH1m gene. In this review, a comprehensive report has been derived on olutasidenib with keen emphasis on pathophysiology of AML, mechanism of action, adverse effects along with pharmacokinetics and pharmacodynamics aspects of olutasidenib. Also, this review is focused on different clinical trials associated with the drug. Olutasidenib is a mutant IDH1 (Isocitrate dehydrogenase-1) inhibitor with significant potential in the management of acute myeloid leukaemia.

Insights into Pharmacological Potential of Apigenin through various Pathways on a Nanoplatform in Multitude of Diseases.

Apigenin is a natural polyphenolic compound widely distributed as a glycoside in fruits and vegetables. Apigenin belongs to BCS class II with low solubility, which leads to poor absorption and bioavailability. It is mostly absorbed from the small intestine and extensively metabolized through glucuronidation and sulfation processes. Apigenin is known for its antioxidant and anti-inflammatory properties. It is also used as a chemopreventive drug in the management of various cancers. Pharmacological effects of apigenin have a wide range, from neuroprotective to treating renal disorders. Apigenin is non-toxic in nature and acts through various pathways (JAK/STAT, Wnt/β-catenin, MAPK/ERK, PI3K/Akt, and NF-κB) to exert its therapeutic efficacy. Numerous formulations have been researched to enhance the bioavailability and pharmacological effects of apigenin. Combinatorial therapies are also researched to minimize the side-effects of chemotherapeutic drugs. The review presents pharmacokinetic and pharmacodynamic aspects of apigenin. Apigenin is safe for the treatment and management of numerous diseases. It can be easily incorporated into nanoformulation alone or in combination with other active ingredients to widen the therapeutic window. This review intends to help in drug optimization and therapeutic efficacy maximization for future studies.

Herbal infusion – processing techniques, bioactivity, quality, and safety

Botanical remedy, including herbal infusion or tisane, is getting attention from the healthconscious consumer to provide dietary polyphenol/dietary antioxidants. However, some quality and pharmacological aspects of dried herbs used in the tisane or herbal tea are taken for granted and can place the consumer's health and safety at risk. The purpose of this review is to investigate pre-harvesting and post-harvesting aspects of herbal tea that implicate the quality, i.e., therapeutic properties and safety, i.e., toxicity. Selection of botanical origin, agricultural practice, and pharmacological background (pharmacodynamic and pharmacokinetic aspects) of botanical material are the identified vital factors in the pre-harvesting aspects that should be considered before introducing the monoherbal or polyherbal preparation to ensure optimum benefits and safety. Besides the herbal blending preparation, the tea processing standard and drying technique are vital in ensuring the stability of herbal tea and consequently determining the quality of herbal infusion. The variation of processing techniques used and the pharmacological factors of herbal sources have laced on the quality and authenticity issues of herbal infusion and still need further studies to identify the potential health risks to the consumer.

Turn On, Tune In, Turnover! Target Biology Impacts In Vivo Potency, Efficacy, and Clearance.

Even though significant efforts have been spent in recent years to understand and define the determinants of in vivo potency and clearance, important pieces of information are still lacking. By introducing target turnover into the reasoning, we open up to further the understanding of central factors important to the optimization of translational dose-concentration-response predictions. We describe (i) new (open model) expressions of the in vivo potency and efficacy parameters, which embody target turnover, binding, and complex kinetics, also capturing full, partial, and inverse agonism and antagonism; (ii) a detailed examination of open models to show what potency and efficacy parameters have in common and how they differ; and (iii) a comprehensive literature review showing that target turnover rate varies with age, species, tissue/subregion, treatment, disease state, hormonal and nutritional state, and day-night cycle. The new open model expression, which integrates system and drug properties, shows the following. Fractional turnover rates rather than the absolute target or ligand-target complex expression determine necessary drug exposure via in vivo potency. Absolute ligand-target expression determines the need of a drug, based on the transduction ρ and in vivo efficacy parameters. The free enzyme concentration determines clearance and maximum metabolic rate. The fractional turnover rate determines time to equilibrium between substrate, free enzyme, and complex.The properties of substrate, target, and the complex demonstrate nonsaturable metabolic behavior at equilibrium. Nonlinear processes, previously referred to as capacity- and time-dependent kinetics, may occasionally have been disequilibria. Finally, the open model may pinpoint why some subjects differ in their demand of drug. SIGNIFICANCE STATEMENT: Understanding the target turnover is a central tenet in many translational dose-concentration-response predictions. New open model expressions of in vivo potency, efficacy parameter, and clearance are derived and anchored onto a comprehensive literature review showing that target turnover rate varies with age, species, tissue/subregion, treatment, disease, hormonal and nutritional state, day-night cycle, and more. Target turnover concepts will therefore significantly impact fundamental aspects of pharmacodynamics and pharmacokinetics, thereby also the basics of drug discovery, development, and optimization of clinical dosing.

Pharmacokinetics and Pharmacodynamic of Alpelisib

Advanced breast cancers are frequently hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative. Some of them harbor a mutation in PIK3CA, a gene encoding the PI3K catalytic subunit α of phosphatidyl-inositol 3-kinase (PI3K), which confers resistance to hormone therapy. Alpelisib is the first oral selective p110 [Formula: see text] PI3K inhibitor approved by FDA and EMA, in association with fulvestrant, based on PFS improvement as compared to fulvestrant alone. The aim of this review is to summarize and critically review the key aspects of alpelisib pharmacokinetics (PK) and pharmacodynamics (PD). Preclinical data have shown that alpelisib IC50 was 50 times lower for the α enzyme than for the β, δ and γ PI3K enzymes, leading to a decrease in intra-tumoral AKT phosphorylation. The PK properties of alpelisib are somehow favorable, with a rapid and important absorption, a limited CYP P450-mediated metabolism and a predominant biliary excretion, with a half-life of 17.5 ± 5.9 h. Only limited drug-drug interactions are expected and there is no need for dose adaptation in mild and moderate renal impaired and mild to severe hepatic impaired patients. Pharmacokinetic/pharmacodynamic relationships were evidenced during drug development for exposure/efficacy, but also exposure/safety. Main adverse events are hyperglycemia, rash, and diarrhea. The first, if not fully contra-indicated in (pre-)diabetic patients, warrants a close follow up when treatment is started and a potential dose reduction when needed. Because of its safety profile, alpelisib require stringent patient selection and close follow-up.

Arylcyclohexylamine Derivatives: Pharmacokinetic, Pharmacodynamic, Clinical and Forensic Aspects.

Since the 2000s, an increasing number of new psychoactive substances (NPS) have appeared on the drug market. Arylcyclohexylamine (ACH) compounds such as ketamine, phencyclidine and eticyclidine derivatives are of particular concern, given their rapidly increasing use and the absence of detailed toxicity data. First used mainly for their pharmacological properties in anesthesia, their recreational use is increasing. ACH derivatives have an antagonistic activity against the N-methyl-D-aspartate receptor, which leads to dissociative effects (dissociation of body and mind). Synthetic ketamine derivatives produced in Asia are now arriving in Europe, where most are not listed as narcotics and are, thus, legal. These structural derivatives have pharmacokinetic and pharmacodynamic properties that are sometimes very different from ketamine. Here, we describe the pharmacology, epidemiology, chemistry and metabolism of ACH derivatives, and we review the case reports on intoxication.