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1.
AAPS J ; 26(3): 56, 2024 04 26.
Article in English | MEDLINE | ID: mdl-38671158

ABSTRACT

Advair Diskus is an essential treatment for asthma and chronic obstructive pulmonary disease. It is a dry powder inhaler with a combination of fluticasone propionate (FP) and salmeterol xinafoate (SX). However, the pharmacokinetics (PK) batch-to-batch variability of the reference-listed drug (RLD) hindered its generic product development. This work developed the PK models for inhaled FP and SX that could represent potential batch variability. Two batches each of the reference and the test product (R1, R2, T1, T2) of Advair Diskus (100 µg FP/50 µg SX inhalation) were administered to 60 healthy subjects in a 4-period, 4-sequence crossover study. The failure of the bioequivalence (BE) between R1 and R2 confirmed the high between-batch variability of the RLD. Non-linear mixed effect modeling was used to estimate the population mean PK parameters for each batch. For FP, a 2-compartment model with a sequential dual zero-order absorption best described the PK profile. For SX, a 2-compartment model with a first-order absorption model best fit the data. Both models were able to capture the plasma concentration, the maximum concentration, and the total exposure (AUCinf) adequately for each batch, which could be used to simulate the BE study in the future. In vitro properties were also measured for each batch, and the batch with a higher fraction of the fine particle (diameter < 1 µm, < 2 µm) had a higher AUCinf. This positive correlation for both FP and SX could potentially assist the batch selection for the PK BE study.


Subject(s)
Bronchodilator Agents , Cross-Over Studies , Dry Powder Inhalers , Fluticasone-Salmeterol Drug Combination , Models, Biological , Therapeutic Equivalency , Humans , Administration, Inhalation , Male , Adult , Fluticasone-Salmeterol Drug Combination/pharmacokinetics , Fluticasone-Salmeterol Drug Combination/administration & dosage , Young Adult , Bronchodilator Agents/pharmacokinetics , Bronchodilator Agents/administration & dosage , Bronchodilator Agents/blood , Female , Middle Aged , Fluticasone/pharmacokinetics , Fluticasone/administration & dosage , Salmeterol Xinafoate/pharmacokinetics , Salmeterol Xinafoate/administration & dosage , Healthy Volunteers
2.
Int Immunopharmacol ; 130: 111706, 2024 Mar 30.
Article in English | MEDLINE | ID: mdl-38382265

ABSTRACT

BACKGROUND: YH35324, a long-acting IgETrap-Fc fusion protein, is a novel therapeutic agent for immunoglobulin E (IgE)-mediated allergic diseases. This randomized, double-blind, placebo/active-controlled, single ascending dose Phase 1 study assessed the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of YH35324 in subjects with atopy. METHODS: Eligible subjects were healthy subjects or atopic adults with mild allergic rhinitis, atopic dermatitis, food allergy, or urticaria, and a serum total IgE level of 30-700 IU/mL (Part A) or > 700 IU/mL (Part B). In Part A, 35 subjects in 5 cohorts received YH35324 (0.3, 1, 3, 6, and 9 mg/kg), 8 received omalizumab (300 mg), and 9 received placebo. In Part B, 8 subjects received YH35324 and 8 received omalizumab. RESULTS: Twenty subjects (38.5 %) in Part A (YH35324: 37.1 %, omalizumab: 50.0 %, placebo: 33.3 %) and 10 subjects (62.5 %) in Part B (YH35324: 100 %; omalizumab: 25.0 %) experienced treatment-emergent adverse events (TEAEs). TEAEs were mostly grade 1/2; no serious AEs, AE-related treatment discontinuation, or anaphylaxis were reported. YH35324 exhibited dose-proportional increase in Cmax and AUClast over the dose range of 0.3-9 mg/kg. YH35324 rapidly suppressed serum-free IgE levels to a significant extent (< 25 and < 82.8 ng/mL, both P < 0.05) and with longer duration than omalizumab. CONCLUSION: This study showed that YH35324 has a favorable safety profile and is effective in reducing serum-free IgE levels in subjects with atopic conditions.


Subject(s)
Anaphylaxis , Dermatitis, Atopic , Adult , Humans , Omalizumab/adverse effects , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Anaphylaxis/chemically induced , Dermatitis, Atopic/drug therapy , Dermatitis, Atopic/chemically induced , Immunoglobulin E , Double-Blind Method , CD40 Ligand
3.
Org Lett ; 25(24): 4445-4450, 2023 06 23.
Article in English | MEDLINE | ID: mdl-37310879

ABSTRACT

This study presents a DNA-compatible synthesis of diverse 5-arylimidazo[1,2-a]pyridin-3-amine derivatives using the Suzuki-Miyaura reaction, followed by a Groebke-Blackburn-Bienaymé (GBB) reaction. The GBB reaction demonstrates a wide substrate scope, mild one-pot reaction conditions, and compatibility with subsequent enzymatic ligation, highlighting its potential in DNA-encoded library technology.


Subject(s)
Amines , DNA , Cyclization , Gene Library , Pyridines/chemical synthesis , Pyridines/chemistry
4.
Ecotoxicol Environ Saf ; 262: 115119, 2023 Jun 14.
Article in English | MEDLINE | ID: mdl-37327520

ABSTRACT

Eicosanoids play important roles in inflammation, allergy, fever, and immune responses. In the eicosanoid pathway, cyclooxygenase (COX) catalyzes the conversion of arachidonic acid to prostaglandins and is a crucial target of nonsteroidal anti-inflammatory drugs (NSAIDs). Thus, toxicological studies on the eicosanoid pathway are important for drug discovery and the evaluation of adverse health outcomes due to environmental contaminants. However, experimental models are limited owing to concerns regarding ethical standards. Thus, new alternative models for evaluating toxic effects on the eicosanoid pathway must be developed. To this end, we adopted an invertebrate species, Daphnia magna, as an alternative model. D. magna was exposed to ibuprofen, a major NSAID, for 6 and 24 h. Transcription of eicosanoid-related genes (pla2, cox, pgd synthase, pgd2r2, ltb4dh, and lox) was analyzed by qPCR, eicosanoids (arachidonic acid, prostaglandin F2, dihydroxy prostaglandin F2, and 5-hydroxyeicosatetraenoate) were quantified by multiple reaction monitoring, and enzyme-linked immunosorbent assay was used to determine protein levels of arachidonic acid and prostaglandin E2 (PGE2). After 6 h of exposure, transcription of the pla2 and cox genes was downregulated. In addition, the whole-body level of arachidonic acid, an upstream of COX pathway, increased by over 1.5-fold. The levels of PGE2, a downstream of COX pathway, decreased after 24 h of exposure. According to our results, it is expected that the eicosanoid pathway might be conserved in D. magna, at least partially. This indicates the plausibility of D. magna as an alternative model for the screening of new drugs or chemical toxicity.

5.
Food Res Int ; 167: 112665, 2023 05.
Article in English | MEDLINE | ID: mdl-37087250

ABSTRACT

Bacteriophages, bacterial viruses, are now being re-highlighted as one of the promising alternative antimicrobial agents to control bacterial pathogens in various fields, including the food industry. However, wild-type (WT) phages isolated from nature are vulnerable to external stresses such as heat, limiting the usability of phages in thermal processing. Here, we applied an adaptive laboratory evolution approach to improving the heat stability of newly isolated Salmonella-infecting lytic phage ΦYMFM0293 and examined its application in the poultry scalding process. After 15 cycles of exposure to sub-lethal temperature, the obtained adaptively evolved (AE) phages maintained approximately 3-log more infectious particles at 73 or 74 °C than the WT and non-heat-treated control phages. Missense mutations mainly concentrated in the genes related to the phage tail module were identified from the independently obtained heat-challenged phages, regardless of host Salmonella's heat-shock protein chaperone induction. These results demonstrated the necessity and sufficiency of the phage exposures to heat for thermal adaptation and suggested the involvement of the phage tail in heat stability. No significant physiological or morphological changes except the mutually offsetting phage replication parameters were observed in the AE phages. Accordingly, hot water supplemented with the AE phages significantly reduced the number of artificially contaminated Salmonella cells on chicken and duck skin in the mimicked scalding process. The AE strategy used here could be applied to other WT phages to improve their usability as more feasible antimicrobials for food safety.


Subject(s)
Anti-Infective Agents , Bacteriophages , Animals , Bacteriophages/genetics , Poultry , Salmonella , Chickens , Food Safety/methods
6.
Anal Chim Acta ; 1239: 340708, 2023 Jan 25.
Article in English | MEDLINE | ID: mdl-36628715

ABSTRACT

Developing a ready-to-use miniaturized thermosensor is a great challenge due to its individual use on a large scale for daily business such as food industry and healthcare. Herein, a polyethylene glycol (PEG)-modified graphene oxide (GO)-based hydrogel thermosensor was established with a fluorescent dye-labeled peptide nucleic acid (F-PNA). The size-tunable hydrogel with high water content and sufficient solidity allowed free movement of the oligonucleotides through the pores and improved usability for handling the sensor. In the PEG-GO hydrogel, the DNA/F-PNA duplex could be denatured by increasing the temperature, followed by selective PNA capture on the PEG-GO. Using this principle, the PEG-GO hydrogel exhibited a change in the fluorescence signal of F-PNA in a temperature-dependent manner, allowing real-time visualization of temperature on a large scale. The temperature detection range of this system can be adjusted by designing the PNA strands based on the melting temperature of the DNAzyme/PNA duplex. Its sensing specificity and detection range could be increased and broadened by observing multi-color detection using PNA probes labeled with different fluorescent dyes of different lengths in a single hydrogel. In addition, the hydrogel platform is easy to store for long time periods via dehydration and can be restored with the addition of water, allowing easy transport, storage, and use of the thermosensor in everyday life.


Subject(s)
Peptide Nucleic Acids , Peptide Nucleic Acids/chemistry , Hydrogels , Water , Polyethylene Glycols/chemistry , Nucleic Acid Hybridization
7.
AAPS J ; 24(5): 98, 2022 09 02.
Article in English | MEDLINE | ID: mdl-36056223

ABSTRACT

Accurately predicting the spread of the SARS-CoV-2, the cause of the COVID-19 pandemic, is of great value for global regulatory authorities to overcome a number of challenges including medication shortage, outcome of vaccination, and control strategies planning. Modeling methods that are used to simulate and predict the spread of COVID-19 include compartmental model, structured metapopulations, agent-based networks, deep learning, and complex network, with compartmental modeling as one of the most widely used methods. Compartmental model has two noteworthy features, a flexible framework that allows users to easily customize the model structure and its high adaptivity that allows well-matured approaches (e.g., Bayesian inference and mixed-effects modeling) to improve parameter estimation. We retrospectively evaluated the prediction performances of the compartmental models on the CDC COVID-19 Mathematical Modeling webpage based on data collected between August 2020 and February 2021, and subsequently discussed in detail their corresponding model enhancement. Finally, we presented examples using the compartmental models to assist policymaking. By evaluating all models in parallel, we systemically evaluated the performance and evolution of using compartmental models for COVID-19 pandemic prediction. In summary, as a 100-year-old epidemic approach, the compartmental model presents a powerful tool that is extremely adaptive and can be readily customized and implemented to address new data or emerging needs during a pandemic.


Subject(s)
COVID-19 , Aged, 80 and over , Bayes Theorem , COVID-19/epidemiology , Disease Outbreaks , Epidemiological Models , Humans , Pandemics , Retrospective Studies , SARS-CoV-2
8.
RSC Adv ; 12(25): 15652-15657, 2022 May 23.
Article in English | MEDLINE | ID: mdl-35685716

ABSTRACT

Biomolecule detection based on the localized surface plasmon resonance (LSPR) phenomenon has advantages in label-free detection, good sensitivity, and measurement simplicity and reproducibility. However, in order to ultimately be used for actual diagnosis, the ability to detect trace amounts of biomarkers is necessary, which requires the development of signal enhancement strategies that enable ultrasensitive detection. In this paper, we provide a straightforward and efficient route to boost LSPR sensitivity based on multiple sample washings. We found that repeated washing and drying cycles lead to a shift in the LSPR peak in a concentration-dependent manner, where this process drives the accumulation of a precipitate, formed by an enzyme reaction with target specificity, in the sample's LSPR active plasmonic nano-valley structure. Results show that the washing and drying process leads to a signal enhancement of more 200 times compared to a sensor with only enzyme-based amplification. To maximize this effect, optimization of the plasmonic nanostructure was also carried out to finally achieve atto-molar detection of miRNA with a distinguishable LSPR peak shift.

9.
CPT Pharmacometrics Syst Pharmacol ; 11(7): 833-842, 2022 07.
Article in English | MEDLINE | ID: mdl-35411692

ABSTRACT

The coronavirus disease 2019 (COVID-19) has presented unprecedented challenges to the generic drug development, including interruptions in bioequivalence (BE) studies. Per guidance published by the US Food and Drug Administration (FDA) during the COVID-19 public health emergency, any protocol changes or alternative statistical analysis plan for COVID-19-interrupted BE study should be accompanied with adequate justifications and not lead to biased equivalence determination. In this study, we used a modeling and simulation approach to assess the potential impact of study outcomes when two different batches of a Reference Standard (RS) were to be used in an in vivo pharmacokinetic BE study due to the RS expiration during the COVID-19 pandemic. Simulations were performed with hypothetical drugs under two scenarios: (1) uninterrupted study using a single batch of an RS, and (2) interrupted study using two batches of an RS. The acceptability of BE outcomes was evaluated by comparing the results obtained from interrupted studies with those from uninterrupted studies. The simulation results demonstrated that using a conventional statistical approach to evaluate BE for COVID-19-interrupted studies may be acceptable based on the pooled data from two batches. An alternative statistical method which includes a "batch" effect to the mixed effects model may be used when a significant "batch" effect was found in interrupted four-way crossover studies. However, such alternative method is not applicable for interrupted two-way crossover studies. Overall, the simulated scenarios are only for demonstration purpose, the acceptability of BE outcomes for the COVID19-interrupted studies could be case-specific.


Subject(s)
COVID-19 Drug Treatment , Cross-Over Studies , Humans , Pandemics , Pharmaceutical Preparations , Therapeutic Equivalency
10.
Clin Pharmacol Ther ; 112(5): 982-989, 2022 11.
Article in English | MEDLINE | ID: mdl-35133652

ABSTRACT

Herein, we present the US Food and Drug Administration (FDA) Office of Research and Standards' current thinking, challenges, and opportunities for comparative clinical endpoint bioequivalence (BE) studies of orally inhaled drug products (OIDPs). Given the product-associated complexities of OIDPs, the FDA currently uses an aggregate weight-of-evidence approach to demonstrate that a generic OIDP is bioequivalent to its reference listed drug. The approach utilizes comparative clinical endpoint BE or pharmacodynamic BE studies, pharmacokinetic BE studies, and in vitro BE studies to demonstrate equivalence, in addition to formulation sameness and device similarity. For the comparative clinical endpoint BE studies, metrics based on forced expiratory volume in the first second (FEV1 ) are often the recommended clinical endpoints. However, the use of FEV1 can pose a challenge due to its large variability and a relatively flat dose-response relationship for most OIDPs. The utility of applying dose-scale analysis was also investigated by the FDA but often not recommended, due to either flat dose-response relationships or insufficient clinical study data. As a potential way to reduce sample size, we found adapting covariate analysis only explained a limited portion of the variation based on further investigation. The FDA continues to develop alternative methods to make BE assessment of OIDPs more cost- and time-efficient. Prospective generic drug applicants and academia are encouraged to participate in this effort by proposing new approaches in pre-abbreviated new drug application meeting requests and collaborating in the form of grants and contracts under the Generic Drug User Fee Amendments (GDUFA) Regulatory Science and Research Program.


Subject(s)
Drugs, Generic , Humans , United States , Therapeutic Equivalency , Drugs, Generic/pharmacokinetics , Forced Expiratory Volume , Pharmaceutical Preparations , United States Food and Drug Administration
11.
Int J Soc Robot ; 14(1): 193-211, 2022.
Article in English | MEDLINE | ID: mdl-33841588

ABSTRACT

Is it true that parents always prioritize educational effectiveness when selecting childcare services? The current study identified the potential requirements of dual-income parents toward social robots' diverse childcare functions (e.g., socialization, education, entertainment, and consultation). The results revealed that parental attitudes toward robots were made more positive by all the childcare functions of robots except for their educational features. Furthermore, parents' expectations of childcare functions varied based on their parenting characteristics. Spectral clustering analysis identified distinctive parenting styles (e.g., family-oriented, work-oriented, noninterventional, and dominant), and multigroup structural equation modeling suggested that the impact of robots' socialization function was significant in all parent groups, while other childcare functions exerted limited influence according to specific parenting styles. In addition, children's characteristics were found to alter parents' preferences for each childcare function. These results offer practical implications for the early adoption of childcare robots through predetermining parents' acceptability based on their specific parenting characteristics.

12.
J Hazard Mater ; 424(Pt B): 127524, 2022 Feb 15.
Article in English | MEDLINE | ID: mdl-34879518

ABSTRACT

The chemiresistive response of metal-oxide gas sensors depends on ambient conditions. Humidity is a strongly influential parameter and causes large deviations in signals and, consequently, an inaccurate detection of target gases. Developing sensors unaffected by humidity, as documented by extensive works of research, comes at the cost of response - a significant drop in sensor response inevitably accompanies an increase in humidity-independence. This trade-off between humidity-independence and gas response is one of the major obstacles that limit practical applications of metal-oxide gas sensors. This study presents a novel approach to improve both the features by incorporating the rare-earth element, yttrium, into the host SnO2 sensor. The Y-doped SnO2 nanofibers are highly stable across relative humidity values ranging from 0% to 87%, and show improved selectivity and sensitivity in the detection of up to 20 ppb of NO2 target gas with the limit of detection at 103.71 ppt. Based on experimental results and van der Waals (vdW)-corrected DFT calculations, these improvements can be attributed to the synergistic effect of oxygen vacancy created by the introduction of aliovalent Y and the formation of Y2O3 nanoparticles that play a critical role in making the sensor surface hydrophobic.

13.
Mikrochim Acta ; 189(1): 35, 2021 12 23.
Article in English | MEDLINE | ID: mdl-34940914

ABSTRACT

MicroRNAs (miRNAs), found in blood and body fluids, have emerged as potential non-invasive biomarkers for disease and injury. miRNAs are quantitatively evaluated using typical RNA analysis methods such as the quantitative reverse transcription polymerase chain reaction, microarrays, and Northern blot, all of which require complex procedures and expensive reagents. To utilize miRNAs as practical biomarkers, it will be helpful to develop simple and user-friendly sensors. In this study, a paper-based miRNA sensor was developed by combining two methods: (1) target-recycled DNAzyme (Dz) amplification and (2) graphene oxide-assisted Dz blotting on paper. The Dz spots on paper caused a miRNA-dependent color change in presence of colorimetric reagents and facilitated the quantification of absolute amount of the target miRNA, irrespective of the volume, with high reproducibility. This approach is technologically straightforward and enables quantification of as low as 7.75 fmol miRNA using a portable smartphone.


Subject(s)
Colorimetry/methods , Graphite/chemistry , MicroRNAs/analysis , Paper , Benzothiazoles/chemistry , Colorimetry/instrumentation , DNA, Catalytic/chemistry , Hemin/chemistry , Hydrogen Peroxide/chemistry , Indicators and Reagents/chemistry , Limit of Detection , MicroRNAs/chemistry , Reproducibility of Results , Smartphone , Sulfonic Acids/chemistry
14.
J Med Chem ; 64(18): 13766-13779, 2021 09 23.
Article in English | MEDLINE | ID: mdl-34519505

ABSTRACT

5-HT7R belongs to a family of G protein-coupled receptors and is associated with a variety of physiological processes in the central nervous system via the activation of the neurotransmitter serotonin (5-HT). To develop selective and biased 5-HT7R ligands, we designed and synthesized a series of pyrazolyl-diazepanes 2 and pyrazolyl-piperazines 3, which were evaluated for binding affinities to 5-HTR subtypes and functional selectivity for G protein and ß-arrestin signaling pathways of 5-HT7R. Among them, 1-(3-(3-chlorophenyl)-1H-pyrazol-4-yl)-1,4-diazepane 2c showed the best binding affinity for 5-HT7R and selectivity over other 5-HTR subtypes. It was also revealed as a G protein-biased antagonist. The self-grooming behavior test was performed with 2c in vivo with Shank3-/- transgenic (TG) mice, wherein 2c significantly reduced self-grooming duration time to the level of wild-type mice. The results suggest that 5-HT7R could be a potential therapeutic target for treating autism spectrum disorder stereotypy.


Subject(s)
Autistic Disorder/drug therapy , Pyrazoles/therapeutic use , Receptors, Serotonin/metabolism , Serotonin Antagonists/therapeutic use , Animals , Drug Design , Grooming/drug effects , Male , Mice, Transgenic , Microfilament Proteins/deficiency , Microfilament Proteins/genetics , Molecular Docking Simulation , Nerve Tissue Proteins/deficiency , Nerve Tissue Proteins/genetics , Pyrazoles/chemical synthesis , Pyrazoles/metabolism , Receptors, Serotonin/chemistry , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/metabolism
15.
Molecules ; 26(11)2021 Jun 02.
Article in English | MEDLINE | ID: mdl-34199418

ABSTRACT

Since neurodevelopmental disorders (NDDs) influence more than 3% of children worldwide, there has been intense investigation to understand the etiology of disorders and develop treatments. Although there are drugs such as aripiprazole, risperidone, and lurasidone, these medications are not cures for the disorders and can only help people feel better or alleviate their symptoms. Thus, it is required to discover therapeutic targets in order to find the ultimate treatments of neurodevelopmental disorders. It is suggested that abnormal neuronal morphology in the neurodevelopment process is a main cause of NDDs, in which the serotonergic system is emerging as playing a crucial role. From this point of view, we noticed the correlation between serotonin receptor subtype 7 (5-HT7R) and NDDs including autism spectrum disorder (ASD), fragile X syndrome (FXS), and Rett syndrome (RTT). 5-HT7R modulators improved altered behaviors in animal models and also affected neuronal morphology via the 5-HT7R/G12 signaling pathway. Through the investigation of recent studies, it is suggested that 5-HT7R could be a potential therapeutic target for the treatment of NDDs.


Subject(s)
Molecular Targeted Therapy/methods , Neurodevelopmental Disorders/metabolism , Receptors, Serotonin/metabolism , Animals , Humans , Neurodevelopmental Disorders/drug therapy , Serotonin Antagonists/pharmacology , Serotonin Antagonists/therapeutic use , Serotonin Receptor Agonists/pharmacology , Serotonin Receptor Agonists/therapeutic use , Signal Transduction/drug effects
16.
J Med Chem ; 64(11): 7453-7467, 2021 06 10.
Article in English | MEDLINE | ID: mdl-34032427

ABSTRACT

There has been significant attention concerning the biased agonism of G protein-coupled receptors (GPCRs), and it has resulted in various pharmacological benefits. 5-HT7R belongs to a GPCR, and it is a promising pharmaceutical target for the treatment of neurodevelopmental and neuropsychiatric disorders. Based on our previous research, we synthesized a series of 6-chloro-2'-methoxy biphenyl derivatives 1, 2, and 3 with a variety of amine scaffolds. These compounds were evaluated for their binding affinities to 5-HTR subtypes and their functional selectivity toward the Gs protein and the ß-arrestin signaling pathways of 5-HT7R. Among them, 2-(6-chloro-2'-methoxy-[1,1'-biphenyl]-3-yl)-N-ethylethan-1-amine, 2b, was found to be a G-protein-biased ligand of 5-HT7R. In an in vivo study with Shank3 transgenic mice, the self-grooming behavior test was performed with 2b, which increased the duration of self-grooming. The experiments further suggested that 5-HT7R is associated with autism spectrum disorders (ASDs) and could be a therapeutic target for the treatment of stereotypy in ASDs.


Subject(s)
Biphenyl Compounds/chemistry , Ligands , Receptors, Serotonin/metabolism , Animals , Behavior, Animal/drug effects , Biphenyl Compounds/metabolism , Biphenyl Compounds/pharmacology , Drug Evaluation, Preclinical , Drug Stability , Half-Life , Humans , Male , Mice , Mice, Inbred ICR , Mice, Transgenic , Microfilament Proteins/genetics , Microfilament Proteins/metabolism , Microsomes/metabolism , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Protein Isoforms/chemistry , Protein Isoforms/metabolism , Receptors, G-Protein-Coupled/chemistry , Receptors, G-Protein-Coupled/metabolism , Receptors, Serotonin/chemistry , Structure-Activity Relationship
17.
Int J Mol Sci ; 22(7)2021 Mar 29.
Article in English | MEDLINE | ID: mdl-33805345

ABSTRACT

Acrylamide is a commonly used industrial chemical that is known to be neurotoxic to mammals. However, its developmental toxicity is rarely assessed in mammalian models because of the cost and complexity involved. We used zebrafish to assess the neurotoxicity, developmental and behavioral toxicity of acrylamide. At 6 h post fertilization, zebrafish embryos were exposed to four concentrations of acrylamide (10, 30, 100, or 300 mg/L) in a medium for 114 h. Acrylamide caused developmental toxicity characterized by yolk retention, scoliosis, swim bladder deficiency, and curvature of the body. Acrylamide also impaired locomotor activity, which was measured as swimming speed and distance traveled. In addition, treatment with 100 mg/L acrylamide shortened the width of the brain and spinal cord, indicating neuronal toxicity. In summary, acrylamide induces developmental toxicity and neurotoxicity in zebrafish. This can be used to study acrylamide neurotoxicity in a rapid and cost-efficient manner.


Subject(s)
Acrylamide/toxicity , Embryo, Nonmammalian/drug effects , Neurotoxicity Syndromes/physiopathology , Zebrafish/growth & development , Acrylamide/pharmacology , Air Sacs/pathology , Animals , Animals, Genetically Modified , Disease Models, Animal , Embryo, Nonmammalian/physiopathology , Embryonic Development/drug effects , Neurotoxicity Syndromes/etiology , Scoliosis/etiology , Swimming , Zebrafish/physiology
18.
J Clin Pharmacol ; 61(6): 782-788, 2021 06.
Article in English | MEDLINE | ID: mdl-33460193

ABSTRACT

The key parameters necessary to predict drug-drug interactions (DDIs) are intrinsic clearance (CLint ) and fractional contribution of the metabolizing enzyme toward total metabolism (fm ). Herein, we summarize the accumulated knowledge from 53 approved new drug applications submitted to the Office of Clinical Pharmacology, US Food and Drug Administration, from 2016 to 2018 that contained physiologically based pharmacokinetic (PBPK) models to understand how in vitro data are used in PBPK models to assess drug metabolism and predict DDIs. For evaluation of CLint and fm , 29 and 20 new drug applications were included for evaluation, respectively. For CLint , 86.2% of the PBPK models used modified values based on in vivo data with modifications ranging from -82.5% to 2752.5%. For fm , 45.0% of the models used modified values with modifications ranging from -28% to 178.6%. When values for CLint were used from in vitro testing without modification, the model resulted in up to a 14.3-fold overprediction of the area under the concentration-time curve of the substrate. When values for fm from in vitro testing were used directly, the model resulted in up to a 2.9-fold underprediction of its DDI magnitude with an inducer, and up to a 1.7-fold overprediction of its DDI magnitude with an inhibitor. Our analyses suggested that the in vitro system usually provides a reasonable estimation of fm when the drug metabolism by a given CYP pathway is more than 70% of the total clearance. In vitro experiments provide important information about basic PK properties of new drugs and can serve as a starting point for building a PBPK model. However, key PBPK parameters such as CLint and fm still need to be optimized based on in vivo data.


Subject(s)
Drug Interactions/physiology , In Vitro Techniques/statistics & numerical data , Models, Biological , United States Food and Drug Administration/statistics & numerical data , Area Under Curve , Computer Simulation , Drug Approval/statistics & numerical data , Humans , In Vitro Techniques/standards , Metabolic Clearance Rate , United States
19.
Drug Metab Pharmacokinet ; 36: 100374, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33348239

ABSTRACT

Intestinal cytochrome P450 3A (CYP3A) plays an important role in oral drug metabolism, but only endogenous metabolic markers for measuring hepatic CYP3A activity were identified. Our study evaluated whether hepatic CYP3A markers reflected intestinal CYP3A activity. An open-label, three-period, six-treatment, one-sequence clinical trial was performed in 16 healthy Korean males. In the control phase, all subjects received a single dose of intravenous (IV) and oral midazolam (1 mg and 5 mg, respectively). Clarithromycin (500 mg) was administered twice daily for 4 days to inhibit hepatic and intestinal CYP3A, and 500 mL of grapefruit juice was given to inhibit intestinal CYP3A. Clarithromycin significantly inhibited total CYP3A activity, and the clearance of IV and apparent clearance of oral midazolam decreased by 0.15- and 0.32-fold, respectively. Grapefruit juice only reduced the apparent clearance of oral midazolam by 0.84-fold, which indicates a slight inhibition of intestinal CYP3A activity. Urinary markers, including 6ß-OH-cortisol/cortisol and 6ß-OH-cortisone/cortisone, were significantly decreased 0.5-fold after clarithromycin administration but not after grapefruit juice. The fold changes in 6ß-OH-cortisol/cortisol and 6ß-OH-cortisone/cortisone did not correlate to changes in intestinal availability but did correlate to hepatic availability. In conclusion, endogenous metabolic markers are only useful to measure hepatic, but not intestinal, CYP3A activity.


Subject(s)
Citrus paradisi/metabolism , Clarithromycin/urine , Cytochrome P-450 CYP3A/urine , Intestinal Mucosa/metabolism , Liver/metabolism , Midazolam/urine , Administration, Intravenous , Administration, Oral , Adult , Biomarkers/blood , Biomarkers/urine , Clarithromycin/administration & dosage , Clarithromycin/blood , Cytochrome P-450 CYP3A/blood , Cytochrome P-450 CYP3A/genetics , Food-Drug Interactions/physiology , Healthy Volunteers , Humans , Intestinal Mucosa/drug effects , Liver/drug effects , Male , Metabolic Clearance Rate/drug effects , Metabolic Clearance Rate/physiology , Midazolam/administration & dosage , Midazolam/blood
20.
Drug Metab Pharmacokinet ; 36: 100368, 2021 Feb.
Article in English | MEDLINE | ID: mdl-33348240

ABSTRACT

Cytochrome P450 (CYP) 3A-related drug-drug interaction (DDI) studies are needed during drug development to determine clinical interaction effects. We aimed to evaluate DDI between sildenafil and two CYP3A inhibitors, clarithromycin and itraconazole, regarding the changes in pharmacokinetics and endogenous markers. An open-label, one-sequence, one-period, two-treatment parallel study was conducted in 32 healthy Korean subjects. Each of 16 subjects were randomly assigned to the clarithromycin and itraconazole groups. Both groups received a single dose of sildenafil 25 mg as a control, and either clarithromycin 250 mg or itraconazole 100 mg was administered four times to inhibit CYP3A activity. Pharmacokinetics of sildenafil showed the similar magnitude of inhibitory effects of the two inhibitors on total CYP3A activity; both inhibitors similarly increased systemic exposure of sildenafil by 2-fold. Urinary 6ß-OH-cortisone/cortisone and plasma 4ß-OH-cholesterol were significantly decreased after clarithromycin administration but not after itraconazole. A significant correlation between sildenafil CL/F and metabolic markers of CYP3A activity was observed after clarithromycin administration. We confirmed that sildenafil has moderate pharmacokinetic interaction with clarithromycin and itraconazole. Endogenous markers well reflected the CYP3A inhibition of clarithromycin, suggesting possible utility in DDI study with moderate to strong CYP3A inhibition; however, there are limitations in predicting intestinal CYP3A mediated DDI.


Subject(s)
Cytochrome P-450 CYP3A Inhibitors/metabolism , Cytochrome P-450 CYP3A/metabolism , Phosphodiesterase 5 Inhibitors/metabolism , Sildenafil Citrate/metabolism , Adult , Cytochrome P-450 CYP3A Inhibitors/administration & dosage , Drug Interactions/physiology , Healthy Volunteers , Humans , Male , Middle Aged , Phosphodiesterase 5 Inhibitors/administration & dosage , Sildenafil Citrate/administration & dosage
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