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1.
Exp Oncol ; 45(4): 399-408, 2024 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-38328850

RESUMO

Today, methotrexate (MTX) is used in combination with other medicines to treat a wide range of malignancies. Despite its proven high efficacy, MTX often causes serious side effects, which may result in the need to reduce the dose of MTX or discontinue the drug altogether. This, in turn, can provoke the development of MTX resistance and cancer progression. Predicting the risk of MTX-induced toxicity is currently difficult due to the variability of pharmacokinetics and pharmacodynamics in different patients, so the scientific literature is intensively searching for potential biomarkers. Based on the data available in the current literature, we analyzed the relationship between variants in the genes encoding the key components of MTX intracellular metabolism and the MTX-induced side effects and drug response. According to the results of our work, the most studied variants are those of the SLC19A1 gene, which encodes the reduced folate carrier protein 1, and the MTHFR gene, which encodes the enzyme methylenetetrahydrofolate reductase. Studies of the effect of methylation of the promoter regions of genes on the therapeutic effect of MTX are also very promising. In conclusion, the study of molecular genetic markers of MTX toxicity is extremely relevant and necessary because it can help to avoid the effect of multidrug resistance and improve the quality of life and survival of patients.


Assuntos
Metotrexato , Neoplasias , Humanos , Metotrexato/efeitos adversos , Metotrexato/farmacocinética , Qualidade de Vida , Neoplasias/tratamento farmacológico , Neoplasias/genética , Polimorfismo de Nucleotídeo Único
2.
Drug Des Devel Ther ; 18: 395-406, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38352172

RESUMO

Purpose: Statins are widely used in combination with omega-3 fatty acids for the treatment of patients with dyslipidemia. The aim of this study was to compare the pharmacokinetic (PK) profiles of atorvastatin and omega-3-acid ethyl esters between fixed-dose combination (FDC) and loose combination in healthy subjects. Methods: A randomized, open-label, single-dose, 2-sequence, 2-treatment, 4-period replicated crossover study was performed. Subjects were randomly assigned to one of the 2 sequences and alternately received four FDC soft capsules of atorvastatin/omega-3-acid ethyl esters (10/1000 mg) or a loose combination of atorvastatin tablets (10 mg × 4) and omega-3-acid ethyl ester soft capsules (1000 mg× 4) for four periods, each period accompanied by a high-fat meal. Serial blood samples were collected for PK analysis of atorvastatin, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). PK parameters were calculated by a non-compartmental analysis. The geometric mean ratio (GMR) and its 90% confidence interval (CI) of the FDC to the loose combination were calculated to compare PK parameters. Results: A total of 43 subjects completed the study as planned. The GMR (90% CI) of FDC to loose combination for maximum concentration (Cmax) and area under the time-concentration curve from zero to the last measurable point (AUClast) were 1.0931 (1.0054-1.1883) and 0.9885 (0.9588-1.0192) for atorvastatin, 0.9607 (0.9068-1.0178) and 0.9770 (0.9239-1.0331) for EPA, and 0.9961 (0.9127-1.0871) and 0.9634 (0.8830-1.0512) for DHA, respectively. The intra-subject variability for Cmax and AUClast of DHA was 30.8% and 37.5%, respectively, showing high variability. Both the FDC and the loose combination were safe and well tolerated. Conclusion: The FDC of atorvastatin and omega-3-acid ethyl esters showed comparable PK characteristics to the corresponding loose combination, offering a convenient therapeutic option for the treatment of dyslipidemia.


Assuntos
Dislipidemias , Ácido Eicosapentaenoico , Humanos , Masculino , Atorvastatina , Ácido Eicosapentaenoico/farmacocinética , Voluntários Saudáveis , Estudos Cross-Over , Ácidos Docosa-Hexaenoicos , República da Coreia , Combinação de Medicamentos , Área Sob a Curva
3.
Int J Mol Sci ; 25(3)2024 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-38338896

RESUMO

A food additive, silicon dioxide (SiO2) is commonly used in the food industry as an anti-caking agent. The presence of nanoparticles (NPs) in commercial food-grade SiO2 has raised concerns regarding their potential toxicity related to nano size. While recent studies have demonstrated the oral absorption and tissue distribution of food-additive SiO2 particles, limited information is available about their excretion behaviors and potential impact on macrophage activation. In this study, the excretion kinetics of two differently manufactured (fumed and precipitated) SiO2 particles were evaluated following repeated oral administration to rats for 28 d. The excretion fate of their intact particles, decomposed forms, or ionic forms was investigated in feces and urine, respectively. Monocyte uptake, Kupffer cell activation, and cytokine release were assessed after the oral administration of SiO2 particles. Additionally, their intracellular fates were determined in Raw 264.7 cells. The results revealed that the majority of SiO2 particles were not absorbed but directly excreted via feces in intact particle forms. Only a small portion of SiO2 was eliminated via urine, predominantly in the form of bioconverted silicic acid and slightly decomposed ionic forms. SiO2 particles were mainly present in particle forms inside cells, followed by ionic and silicic acid forms, indicating their slow conversion into silicic acid after cellular uptake. No effects of the manufacturing method were observed on excretion and fates. Moreover, no in vivo monocyte uptake, Kupffer cell polarization, or cytokine release were induced by orally administered SiO2 particles. These finding contribute to understanding the oral toxicokinetics of food-additive SiO2 and provide valuable insights into its potential toxicity.


Assuntos
Nanopartículas , Dióxido de Silício , Ratos , Animais , Dióxido de Silício/farmacocinética , Ácido Silícico , Aditivos Alimentares , Ativação de Macrófagos , Nanopartículas/toxicidade , Tamanho da Partícula , Citocinas
4.
Ceska Slov Farm ; 72(6): 267-276, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38346904

RESUMO

Current trends in drug design notably consider so-called privileged scaffolds as the core structural fragments with decisive impact on affinity to properly chosen biological targets, potency, selectivity and toxicological characteristics of drugs and prospective drug candidates. Fruquintinib (1) is a novel synthetic selective inhibitor of vascular endothelial growth factor receptor (VEGFR) isoforms, i.e., VEGFR-1, VEGFR-2 and VEGFR-3. The therapeutic agent (1) consists of a flat bicyclic heteroaromatic ring, in which two nitrogens are suitablyincorporated, a core bicyclic heteroaromatic ring - privileged (substituted) benzofuran scaffold, and a pair of hydrogen bond (H-bond) donor and acceptor group, i.e., amide functional moiety. Fruquintinib (1) was first approved in China for the treatment of metastatic colorectal cancer, a severe malignant disease with a high mortality rate. The review article offered a brief insight into the topic of privileged structures, their drug- -like ranges of several parameters, pharmacodynamic characteristics of fruquintinib (1) and various in silico descriptors characterizing drug's structural and physicochemical properties (molecular weight, number of heavy atoms, number of aromatic heavy atoms, fraction of sp3 C-atoms, number of H-bond acceptors, number of H-bond donors, total polar surface area, molar refractivity, molecular volume as well as parameters of lipophilicity and solubility). Some of these descriptors were related to pharmacokinetics and distribution of fruquintinib (1), and, in addition, might help predict its ability to cross passively the blood-brain barrier (BBB). Moreover, a possible connection between the induction potential on cytochrome P450 isoenzymes (CYP1A2 and CYP3A4) and passive transport of a given drug into the central nervous system via BBB was investigated. Current clinical experience and future directions regarding of fruquintinib (1) were also briefly outlined.


Assuntos
Antineoplásicos , Benzofuranos , Quinazolinas , Fator A de Crescimento do Endotélio Vascular , Antineoplásicos/farmacologia , Benzofuranos/farmacocinética , Benzofuranos/uso terapêutico , Relação Estrutura-Atividade , Biotransformação
5.
Drug Des Devel Ther ; 18: 291-306, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38333899

RESUMO

Growth hormone (GH) replacement therapy for growth hormone deficiency (GHD) in children and adults has for over 25 years, until recently, been administered as daily injections. This daily treatment regimen often incurs a burden to patients and caregivers, leading to high rates of non-adherence and, consequently, decreased treatment efficacy outcomes. To address this shortcoming, long-acting growth hormones (LAGHs) have been developed with the aim of reducing the burden of daily injections, thereby potentially improving treatment adherence and outcomes. Somapacitan (Sogroya®) (Novo Nordisk, Bagsværd, Denmark) is a LAGH currently approved for the treatment of adult and childhood GHD (AGHD and CGHD, respectively) in several countries. Other LAGHs, such as somatrogon (Ngenla®) (Pfizer, New York, United States) and lonapegsomatropin/TransCon GH (Skytrofa®) (Ascendis Pharma, Copenhagen, Denmark), are also currently approved and available for the treatment of CGHD in several countries. In this review, we will consider the method of protraction, pharmacokinetics (PK) and pharmacodynamics (PD), efficacy, and safety results of somapacitan in adult and pediatric trials and how these characteristics differ from those of the other aforementioned LAGHs. Additionally, the administration of somapacitan and timing of measurement of serum insulin-like growth factor-I (IGF-I) levels are summarized. Information on administration, advice on missed doses, and clinical guidelines are discussed, as well as identifying which patients are suitable for somapacitan therapy, and how to monitor and adjust dosing whilst on therapy.


Assuntos
Nanismo Hipofisário , Histidina , Hormônio do Crescimento Humano , Manitol , Fenol , Adulto , Humanos , Criança , Estados Unidos , Hormônio do Crescimento Humano/uso terapêutico , Nanismo Hipofisário/tratamento farmacológico , Hormônio do Crescimento/farmacocinética , Hormônio do Crescimento/uso terapêutico , Resultado do Tratamento , Fator de Crescimento Insulin-Like I
6.
BMC Complement Med Ther ; 24(1): 87, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38355450

RESUMO

BACKGROUND: Herb-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. METHODS: Rats 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. RESULTS: The 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). CONCLUSIONS: The present study implied that SFI could accelerate warfarin metabolism and weaken its anticoagulation intensity in rats.


Assuntos
Ácidos Cumáricos , Espectrometria de Massas em Tandem , Varfarina , Ratos , Animais , Varfarina/farmacocinética , Varfarina/uso terapêutico , Cromatografia Líquida , Coagulação Sanguínea , Anticoagulantes/farmacologia
7.
Biopharm Drug Dispos ; 45(1): 58-68, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38319316

RESUMO

Renal function is an important factor affecting the pharmacokinetics of vancomycin. The renal function in elderly patients gradually decreases with age. An accurate estimated glomerular filtration rate (GFR) is essential in drug dosing. The study aimed to determine the most appropriate renal function estimation equations to describe vancomycin pharmacokinetics in elderly patients using population pharmacokinetic analysis. Data were obtained retrospectively from elderly patients aged ≥65 years who received vancomycin for infection from September 2016 to January 2022. Renal function was estimated using the Cockcroft-Gault equation (CG), Modification of Diet in Renal Disease equation (MDRD), three Chronic Kidney Disease Epidemiology Collaboration equations (CKD-EPIcys-scr , CKD-EPIscr , and CKD-EPIcys ) and two Berlin Initiative Study equations (BIS-1 and BIS-2). The CKD-EPIcys-scr and BIS-2 equations were based on cystatin C (Cys C) and serum creatinine (Scr). The others were based on Cys C or Scr. A nonlinear mixed effects model (NONMEM) was used to develop the population pharmacokinetic model. A total of 471 serum concentrations from 313 elderly patients were used to develop the population pharmacokinetic model. Weight and GFR were identified as significant covariates affecting the pharmacokinetics of vancomycin. Cys C and Scr-based GFR (CKD-EPIcys-scr and BIS-2) yielded significant improvement performance compared with the other equations in model building. The interindividual variability of CL was reduced from 49.4% to 23.6% and 49.4% to 23.7% in CKD-EPIcys-scr and BIS-2 based models, respectively. However, greater interindividual variabilities of CL (from 26.6% to 29.0%) were represented in the other five models which were based on either Cys C or Scr. The GFR estimated by EPIcys-scr and BIS-2 equations and vancomycin CL exhibited a good correlation (r = 0.834 and 0.833). In the external validation with 124 serum concentrations, the predictive performances of the CKD-EPIcys-scr and BIS-2 based models (the mean relative prediction errors were less than 1%, the mean relative absolute prediction errors were about 23%) were also superior to the other five models (the mean relative prediction errors were about 2%, the mean relative absolute prediction errors were greater than 25%) which are based on either Cys C or Scr. In this study, we determined that the equation used to estimate GFR can affect the population pharmacokinetic model fitting result. Population pharmacokinetics model with CKD-EPIcys-scr or BIS-2 can be used to optimize vancomycin dosage in elderly Chinese patients.


Assuntos
Taxa de Filtração Glomerular , Insuficiência Renal Crônica , Vancomicina , Idoso , Humanos , China , Creatinina , Cistatina C , Insuficiência Renal Crônica/metabolismo , Estudos Retrospectivos , Vancomicina/farmacocinética
8.
Hematology ; 29(1): 2314871, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38346146

RESUMO

OBJECTIVE: To investigate the influence of the dead space in disposable blood sampling needle on activated partial thromboplastin time (APTT), FVIII level and pharmacokinetic (PK) profiles in children with hemophilia. METHODS: Children (<18 years) with severe hemophilia A were enrolled. After three days' washout-period, blood samples were collected at pre-dose, 1 h, 3 h, 9 h, 24 h and 48 h post-infusion. At each timepoint, two 2 mL vacuum tubes with 3.2% trisodium citrate were used. The first tube was signed as 'non-standard' (NS) and the second tube was signed as 'standard' (S). FVIII activities were evaluated by one-stage assay. WAPPS-Hemo was used to generate PK profiles like half-life time (t1/2), clearance (CL), trough level and time to 1, 2 and 5IU/dL after a dose of 50 ± 10IU/dL. The FVIII activities at 9 h and 24 h post-infusion were put into WAPPS and thus brought four combinations by true or biased FVIII level that used. RESULT: Compared with standard-collected blood samples, prolonged APTT results (P-values < 0.01) and decreased FVIII activity (P-values < 0.05) were revealed in those non-standard blood samples. The corresponding bias was in positive relation to both APTT-S (r = 0.44, P < 0.0001) and FVIII-S level(r = 0.68, P < 0.001). The FVIII bias percentage got larger as FVIII-S level reduced (r = -0.24, P < 0.01). During the four combinations of FVIII activity at 9 h and 24 h, statistically longer t1/2, lower CL and longer time to 1, 2 or 5IU/dL were observed in 9H-S&24H-S group and 9H-NS&24H-S group. CONCLUSION: While using vacuum tubes for clotting indicators and PK profiles, the dead space of blood sampling needle should be eliminated in advance.


Assuntos
Coleta de Amostras Sanguíneas , Fator VIII , Hemofilia A , Tempo de Tromboplastina Parcial , Criança , Humanos , Coagulação Sanguínea , Fator VIII/farmacocinética , Meia-Vida , Hemofilia A/sangue , Hemofilia A/diagnóstico , Agulhas , Tempo de Tromboplastina Parcial/normas , Coleta de Amostras Sanguíneas/normas
9.
AAPS PharmSciTech ; 25(3): 39, 2024 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-38366149

RESUMO

Quantitative in silico tools may be leveraged to mechanistically predict the dermato-pharmacokinetics of compounds delivered from topical and transdermal formulations by integrating systems of rate equations that describe permeation through the formulation and layers of skin and pilo-sebaceous unit, and exchange with systemic circulation via local blood flow. Delivery of clobetasol-17 propionate (CP) from DermovateTM cream was simulated using the Transdermal Compartmental Absorption & Transit (TCATTM) Model in GastroPlus®. The cream was treated as an oil-in-water emulsion, with model input parameters estimated from publicly available information and quantitative structure-permeation relationships. From the ranges of values available for model input parameters, a set of parameters was selected by comparing model outputs to CP dermis concentration-time profiles measured by dermal open-flow microperfusion (Bodenlenz et al. Pharm Res. 33(9):2229-38, 2016). Predictions of unbound dermis CP concentrations were reasonably accurate with respect to time and skin depth. Parameter sensitivity analyses revealed considerable dependence of dermis CP concentration profiles on drug solubility in the emulsion, relatively less dependence on dispersed phase volume fraction and CP effective diffusivity in the continuous phase of the emulsion, and negligible dependence on dispersed phase droplet size. Effects of evaporative water loss from the cream and corticosteroid-induced vasoconstriction were also assessed. This work illustrates the applicability of computational modeling to predict sensitivity of dermato-pharmacokinetics to changes in thermodynamic and transport properties of a compound in a topical formulation, particularly in relation to rate-limiting steps in skin permeation. Where these properties can be related to formulation composition and processing, such a computational approach may support the design of topically applied formulations.


Assuntos
Clobetasol , Pele , Humanos , Clobetasol/farmacocinética , Emulsões/farmacologia , Simulação por Computador , Água
10.
Int J Mol Sci ; 25(4)2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38396908

RESUMO

Rosmarinic acid (RA) is a phenolic compound with antiviral properties, often encountered in dietary supplements and herbal drugs. Data on the pharmacokinetics of RA are lacking in cases of the chronic use of supplements containing this compound, and only limited data on the metabolism and distribution of RA are available. The aim of the study was to investigate the plasma levels of RA after 12 weeks of use and determine potential interactions of RA and selected antiretroviral drugs. Patients infected with human immunodeficiency virus took a supplement containing RA for 12 weeks, after which the RA concentrations in the plasma samples were analyzed. A detailed in silico analysis was conducted in order to elucidate the potential interactions between RA and the drugs efavirenz, darunavir and raltegravir. It was found that RA can be detected in patients' plasma samples, mainly in the form of sulphoglucuronide. The potential interactions are suggested on the level of liver metabolizing enzymes and efflux P-glycoprotein, with RA competing with antiretroviral drugs as a substrate in metabolism and distribution systems. The present study suggests that the simultaneous use of RA and antiretroviral therapy (containing efavirenz, darunavir or raltegravir) may affect the plasma levels of RA after prolonged supplementation.


Assuntos
Alcinos , Fármacos Anti-HIV , Benzoxazinas , Ciclopropanos , Infecções por HIV , Humanos , Raltegravir Potássico/uso terapêutico , Darunavir/farmacocinética , Darunavir/uso terapêutico , Infecções por HIV/tratamento farmacológico , Antirretrovirais/uso terapêutico , Fármacos Anti-HIV/uso terapêutico
11.
Nucl Med Biol ; 128-129: 108880, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38330637

RESUMO

Patients with HER2-positive and triple negative breast cancer (TNBC) are associated with increased risk to develop metastatic disease including reoccurring disease that is resistant to standard and targeted therapies. The αVß3 has been implicated in BC including metastatic disease. The aims of this study were to investigate the potential of αVß3-targeted peptides to deliver radioactive payloads to BC tumors expressing αVß3 on the tumor cells or limited to the tumors' neovascular. Additionally, we aimed to assess the pharmacokinetic profile of the targeted α-particle therapy (TAT) agent [225Ac]Ac-DOTA-cRGDfK dimer peptide and the in vivo generated decay daughters. The expression of αVß3 in a HER2-positive and a TNBC cell line were evaluated using western blot analysis. The pharmacokinetics of [111In]In-DOTA-cRGDfK dimer, a surrogate for the TAT-agent, was evaluated in subcutaneous mouse tumor models. The pharmacokinetic of the TAT-agent [225Ac]Ac-DOTA-cRGDfK dimer and its decay daughters were evaluated in healthy mice. Selective uptake of [111In]In-DOTA-cRGDfK dimer was shown in subcutaneous tumor models using αVß3-positive tumor cells as well as αVß3-negative tumor cells where the expression is limited to the neovasculature. Pharmacokinetic studies demonstrated rapid accumulation in the tumors with clearance from non-target organs. Dosimetric analysis of [225Ac]Ac-DOTA-cRGDfK dimer showed the highest radiation absorbed dose to the kidneys, which included the contributions from the free in vivo generated decay daughters. This study shows the potential of delivering radioactive payloads to BC tumors that have αVß3 expression on the tumor cells as well as limited expression to the neovascular of the tumor. Furthermore, this work determines the radiation absorbed doses to normal organs/tissues and identified key organs that act as suppliers and receivers of the actinium-225 free in vivo generated α-particle-emitting decay daughters.


Assuntos
Neoplasias de Mama Triplo Negativas , Camundongos , Humanos , Animais , Oligopeptídeos/farmacocinética , Peptídeos , Integrina alfaVbeta3/metabolismo
12.
Exp Neurol ; 374: 114718, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38336285

RESUMO

Executive function, including working memory, attention and inhibitory control, is crucial for decision making, thinking and planning. Lisdexamfetamine, the prodrug of d-amphetamine, has been approved for treating attention-deficit hyperactivity disorder and binge eating disorder, but whether it improves executive function under non-disease condition, as well as the underlying pharmacokinetic and neurochemical properties, remains unclear. Here, using trial unique non-matching to location task and five-choice serial reaction time task of rats, we found lisdexamfetamine (p.o) enhanced spatial working memory and sustained attention under various cognitive load conditions, while d-amphetamine (i.p) only improved these cognitive performances under certain high cognitive load condition. Additionally, lisdexamfetamine evoked less impulsivity than d-amphetamine, indicating lower adverse effect on inhibitory control. In vivo pharmacokinetics showed lisdexamfetamine produced a relative stable and lasting release of amphetamine base both in plasma and in brain tissue, whereas d-amphetamine injection elicited rapid increase and dramatical decrease in amphetamine base levels. Microdialysis revealed lisdexamfetamine caused lasting release of dopamine within the medial prefrontal cortex (mPFC), whereas d-amphetamine produced rapid increase followed by decline to dopamine level. Moreover, lisdexamfetamine elicited more obvious efflux of noradrenaline than that of d-amphetamine. The distinct neurochemical profiles may be partly attributed to the different action of two drugs to membranous catecholamine transporters level within mPFC, detecting by Western Blotting. Taken together, due to its certain pharmacokinetic and catecholamine releasing profiles, lisdexamfetamine produced better pharmacological action to improving executive function. Our finding provided valuable evidence on the ideal pharmacokinetic and neurochemical characteristics of amphetamine-type psychostimulants in cognition enhancement.


Assuntos
Estimulantes do Sistema Nervoso Central , Dimesilato de Lisdexanfetamina , Ratos , Animais , Dimesilato de Lisdexanfetamina/farmacologia , Função Executiva , Dopamina , Estimulantes do Sistema Nervoso Central/efeitos adversos , Dextroanfetamina/efeitos adversos , Dextroanfetamina/farmacocinética , Anfetamina/farmacologia , Catecolaminas , Cognição
13.
BMC Anesthesiol ; 24(1): 70, 2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38395779

RESUMO

BACKGROUND: Propofol formulated with medium- and long-chain triglycerides (MCT/LCT propofol) has rapidly replaced propofol formulated with long-chain triglycerides (LCT propofol). Despite this shift, the modified Marsh and Schnider pharmacokinetic models developed using LCT propofol are still widely used for target-controlled infusion (TCI) of propofol. This study aimed to validate the external applicability of these models by evaluating their predictive performance during TCI of MCT/LCT propofol in general anesthesia. METHODS: Adult patients (n = 48) undergoing elective surgery received MCT/LCT propofol via a TCI system using either the modified Marsh or Schnider models. Blood samples were collected at various target propofol concentrations and at specific time points, including the loss of consciousness and the recovery of consciousness (13 samples per patient). The actual plasma concentration of propofol was determined using high-performance liquid chromatography. The predictive performance of each pharmacokinetic model was assessed by calculating four parameters: inaccuracy, bias, divergence, and wobble. RESULTS: Both the modified Marsh and Schnider models demonstrated predictive performances within clinically acceptable ranges for MCT/LCT propofol. The inaccuracy values were 24.4% for the modified Marsh model and 26.9% for the Schnider model. Both models showed an overall positive bias, 16.4% for the modified Marsh model and 16.6% for the Schnider model. The predictive performance of MCT/LCT propofol was comparable to that of LCT propofol, suggesting formulation changes might exert only a minor impact on the reliability of the TCI system during general anesthesia. Additionally, both models exhibited higher bias and inaccuracy at target concentrations ranging from 3.5 ~ 5 ug/ml than at concentrations between 2 ~ 3 ug/ml. CONCLUSIONS: The modified Marsh and Schnider models, initially developed for LCT propofol, remain clinically acceptable for TCI with MCT/LCT propofol. TRIAL REGISTRATION: This study was registered at the Clinical Research Information Service of the Korean National Institute of Health ( https://cris.nih.go.kr ; registration number: KCT0002191; 06/01/2017).


Assuntos
Propofol , Adulto , Humanos , Propofol/farmacocinética , Anestésicos Intravenosos/farmacocinética , Reprodutibilidade dos Testes , Áreas Alagadas , Infusões Intravenosas , Anestesia Geral/métodos , Triglicerídeos
14.
Clin Transl Sci ; 17(2): e13729, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38380703

RESUMO

CYP3A4 activity shows considerable interindividual variability. Although studies indicate 60%-80% is heritable, common single nucleotide variants (SNVs) in CYP3A4 together only explain ~10%. Transcriptional factors, such as the testis-specific Y-encoded-like proteins (TSPYLs) family, have been reported to regulate the expression of CYP enzymes including CYP3A4 in vitro. Here, we investigated the effect of genetic variants in TSPYL on CYP3A4 activity using data from a clinical study and a human liver bank. Five SNVs (rs3828743, rs10223646, rs6909133, rs1204807, and rs1204811) in TSPYL were selected because of a reported effect on CYP3A4 expression in vitro or suggested clinical effect. For the clinical study, whole blood concentrations, clinical data, and DNA were available from 295 kidney transplant recipients participating in the prospective MECANO study. A multivariate pharmacokinetic model adjusted for body weight, steroid treatment, and CYP3A4 genotype was used to assess the effect of the genetic variants on cyclosporine clearance. In multivariate analysis, homozygous carriers of rs3828743 had a 18% lower cyclosporin clearance compared to the wild-type and heterozygous patients (28.72 vs. 35.03 L/h, p = 0.018) indicating a lower CYP3A4 activity and an opposite direction of effect compared to the previously reported increased CYP3A4 expression. To validate, we tested associations between rs3828743 and CYP3A4 mRNA and protein expression as well as enzyme activity with data from a liver bank (n = 150). No association with any of these end points was observed. In conclusion, the totality of evidence is not in support of a significant role for TSPYL SNV rs3828743 in explaining variability in CYP3A4 activity.


Assuntos
Ciclosporina , Transplante de Rim , Masculino , Humanos , Ciclosporina/farmacocinética , Citocromo P-450 CYP3A/genética , Imunossupressores/farmacocinética , Fatores de Transcrição/genética , Transplante de Rim/efeitos adversos , Estudos Prospectivos , Genótipo , Polimorfismo de Nucleotídeo Único
15.
ACS Nano ; 18(8): 6162-6175, 2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38359902

RESUMO

Nanomedicines exhibit multifaceted performances, yet their biopharmaceutics remain poorly understood and present several challenges in the translation from preclinical to clinical research. To address this issue and promote the production of high-quality nanomedicines, a systematic screening of the design space and in vivo performance is necessary. Establishing formulation performance specifications early on enables an informed selection of candidates and promotes the development of nanosimilars. The deconvolution of the pharmacokinetics enables the identification of key characteristics that influence their performances and disposition. Using an in vitro-in vivo rank-order relationship for doxorubicin nanoformulations, we defined in vitro release specifications for Doxil/Caelyx-like follow-on products. Additionally, our model predictions were used to establish the bioequivalence of Lipodox, a nanosimilar of Doxil/Caelyx. Furthermore, a virtual safe space was established, providing crucial insights into expected disposition kinetics and informing formulation development. By addressing bottlenecks in biopharmaceutics and formulation screening, our research advances the translation of nanomedicine from bench to bedside.


Assuntos
Doxorrubicina , Doxorrubicina/análogos & derivados , Polietilenoglicóis , Doxorrubicina/farmacocinética , Polietilenoglicóis/farmacocinética
16.
Med Eng Phys ; 123: 104092, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38365330

RESUMO

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is widely used to assess tissue vascularization, particularly in oncological applications. However, the most widely used pharmacokinetic (PK) models do not account for contrast agent (CA) diffusion between neighboring voxels, which can limit the accuracy of the results, especially in cases of heterogeneous tumors. To address this issue, previous works have proposed algorithms that incorporate diffusion phenomena into the formulation. However, these algorithms often face convergence problems due to the ill-posed nature of the problem. In this work, we present a new approach to fitting DCE-MRI data that incorporates CA diffusion by using Physics-Informed Neural Networks (PINNs). PINNs can be trained to fit measured data obtained from DCE-MRI while ensuring the mass conservation equation from the PK model. We compare the performance of PINNs to previous algorithms on different 1D cases inspired by previous works from literature. Results show that PINNs retrieve vascularization parameters more accurately from diffusion-corrected tracer-kinetic models. Furthermore, we demonstrate the robustness of PINNs compared to other traditional algorithms when faced with noisy or incomplete data. Overall, our results suggest that PINNs can be a valuable tool for improving the accuracy of DCE-MRI data analysis, particularly in cases where CA diffusion plays a significant role.


Assuntos
Algoritmos , Redes Neurais de Computação , Meios de Contraste/farmacocinética , Imageamento por Ressonância Magnética/métodos
18.
BMC Pharmacol Toxicol ; 25(1): 4, 2024 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-38167223

RESUMO

This study aimed to develop a physiologically-based pharmacokinetic (PBPK) model to predict changes in the pharmacokinetics (PK) and pharmacodynamics (PD, PDE4 inhibition) of roflumilast (ROF) and ROF N-oxide when co-administered with eight CYP3A4/1A2 perpetrators. The population PBPK model of ROF and ROF N-oxide has been successfully developed and validated based on the four clinical PK studies and five clinical drug-drug interactions (DDIs) studies. In PK simulations, every ratio of prediction to observation for PK parameters fell within the range 0.7 to 1.5. In DDI simulations, except for tow peak concentration ratios (Cmax) of ROF with rifampicin (prediction: 0.63 vs. observation: 0.19) and with cimetidine (prediction: 1.07 vs. observation: 1.85), the remaining predicted ratios closely matched the observed ratios. Additionally, the PBPK model suggested that co-administration with the three perpetrators (cimetidine, enoxacin, and fluconazole) may use with caution, with CYP3A4 strong inhibitor (ketoconazole and itraconazole) or with dual CYP3A41A2 inhibitor (fluvoxamine) may reduce to half-dosage or use with caution, while co-administration with CYP3A4 strong or moderate inducer (rifampicin, efavirenz) should avoid. Overall, the present PBPK model can provide recommendations for adjusting dosing regimens in the presence of DDIs.


Assuntos
Citocromo P-450 CYP3A , Rifampina , Rifampina/farmacologia , Cimetidina , Inibidores do Citocromo P-450 CYP3A/farmacocinética , Interações Medicamentosas , Óxidos , Modelos Biológicos
19.
J Breath Res ; 18(2)2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-38211315

RESUMO

The correlation between propofol concentration in exhaled breath (CE) and plasma (CP) has been well-established, but its applicability for estimating the concentration in brain tissues (CB) remains unknown. Given the impracticality of directly sampling human brain tissues, rats are commonly used as a pharmacokinetic model due to their similar drug-metabolizing processes to humans. In this study, we measuredCE,CP, andCBin mechanically ventilated rats injected with propofol. Exhaled breath samples from the rats were collected every 20 s and analyzed using our team's developed vacuum ultraviolet time-of-flight mass spectrometry. Additionally, femoral artery blood samples and brain tissue samples at different time points were collected and measured using high-performance liquid chromatography mass spectrometry. The results demonstrated that propofol concentration in exhaled breath exhibited stronger correlations with that in brain tissues compared to plasma levels, suggesting its potential suitability for reflecting anesthetic action sites' concentrations and anesthesia titration. Our study provides valuable animal data supporting future clinical applications.


Assuntos
Propofol , Humanos , Animais , Ratos , Propofol/análise , Propofol/farmacocinética , Testes Respiratórios/métodos , Expiração
20.
J Agric Food Chem ; 72(3): 1745-1755, 2024 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-38214270

RESUMO

Phellopterin (PLP) is a linear furanocoumarin widely found in citrus fruits and herbal medicines. The study aims to comprehensively investigate the mechanism of inhibition of CYP2D6 enzyme activity by PLP and its alteration of metoprolol pharmacokinetics. PLP was found to irreversibly inhibit CYP2D6 in time-, concentration-, and nicotinamide adenine dinucleotide phosphate-dependent manners. Coincubation with quinidine, which is a competitive inhibitor of CYP2D6, attenuated this time-dependent inhibition. Glutathione (GSH) and catalase/superoxide dismutase failed to reverse the PLP-induced CYP2D6 inactivation. GSH trapping experiments provided strong evidence that PLP metabolic activation produces epoxide or γ-ketoaldehyde intermediates. In addition, pretreatment with PLP resulted in significant increases in Cmax and area under curve of plasma metoprolol in rats.


Assuntos
Cumarínicos , Citocromo P-450 CYP2D6 , Metoprolol , Ratos , Animais , Metoprolol/farmacocinética , Metoprolol/uso terapêutico , Citocromo P-450 CYP2D6/metabolismo , Inibidores do Citocromo P-450 CYP2D6/farmacologia , Interações Medicamentosas
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