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Role of Modeling and Simulation in Preclinical and Clinical Long-Acting Injectable Drug Development.The AAPS Journal Oct 2023Innovations in the field of long-acting injectable drug development are increasingly being reported. More advanced in vitro and in vivo characterization can improve our... (Review)
Review
Innovations in the field of long-acting injectable drug development are increasingly being reported. More advanced in vitro and in vivo characterization can improve our understanding of the injection space and aid in describing the long-acting injectable (LAI) drug's behavior at the injection site more mechanistically. These innovations may enable unlocking the potential of employing a model-based framework in the LAI preclinical and clinical space. This review provides a brief overview of the LAI development process before delving deeper into the current status of modeling and simulation approaches in characterizing the preclinical and clinical LAI pharmacokinetics, focused on aqueous crystalline suspensions. A closer look is provided on in vitro release methods, available biopharmaceutical models and reported in vitro/in vivo correlations (IVIVCs) that may advance LAI drug development. The overview allows identifying the opportunities for use of model-informed drug development approaches and potential gaps where further research may be most warranted. Continued investment in improving our understanding of LAI PK across species through translational approaches may facilitate the future development of LAI drug products.
Topics: Humans; Antipsychotic Agents; Schizophrenia; Delayed-Action Preparations; Injections; Suspensions
PubMed: 37848754
DOI: 10.1208/s12248-023-00864-9 -
Astrobiology Oct 2023Since the Viking Labeled Release experiments were carried out on Mars in the 1970s, it has been evident that the martian surface regolith has a strong oxidizing capacity...
Since the Viking Labeled Release experiments were carried out on Mars in the 1970s, it has been evident that the martian surface regolith has a strong oxidizing capacity that can convert organic compounds into CO and probably water. While HO was suggested originally for being the oxidizing agent responsible for the outcome of the Viking experiments, recent analyses of the martian regolith by the Phoenix lander and by consecutive missions point toward radiation-mediated decomposition products of perchlorate salts as the primary oxidant. In a series of experiments, we have shown that abrasion and triboelectric charging of basalt by simulated saltation could be an additional way of activating regolith. We have also shown that abraded basalt with a chemical composition close to that of martian regolith is toxic to several bacterial species and thus may affect the habitability of the martian surface. In the present study, we investigated the effect of the quantitatively most important minerals (olivine, augite, and plagioclase) and iron oxides (hematite, magnetite, and maghemite) on the survival of bacterial cells to elucidate whether a specific mineral that constitutes basalt is responsible for our observations. We observed that suspensions of iron-containing minerals olivine and augite in phosphate-buffered saline (1 × PBS) significantly reduce the number of surviving cells of our model organism after 24 h of incubation. In contrast, the iron-free mineral plagioclase showed no effect. We also observed that suspending abraded olivine and augite in 1 × PBS led to a dramatic increase in pH compared to the pH of 1 × PBS alone. The sudden increase in pH caused by the presence of these minerals may partly explain the observed cytotoxicity. The cytotoxic effect of augite could be relieved when a strong buffer (20 × PBS) was used. In contrast, olivine, despite the stronger buffer, maintained its cytotoxicity. Iron oxides have no negative effect on the survival of our test organism. Overall, our experiments confirm the cytotoxicity of basalt and show that no single constituent mineral of the basalt can account for its toxicity. We could show that abraded iron-containing minerals (olivine and augite) change the pH of water when brought into suspension and thereby could affect the habitability of martian regolith.
PubMed: 37672600
DOI: 10.1089/ast.2023.0015 -
Langmuir : the ACS Journal of Surfaces... Aug 2023Portlandite (calcium hydroxide: CH: Ca(OH)) suspensions aggregate spontaneously and form percolated fractal aggregate networks when dispersed in water. Consequently, the...
Portlandite (calcium hydroxide: CH: Ca(OH)) suspensions aggregate spontaneously and form percolated fractal aggregate networks when dispersed in water. Consequently, the viscosity and yield stress of portlandite suspensions diverge at low particle loadings, adversely affecting their processability. Even though polycarboxylate ether (PCE)-based comb polyelectrolytes are routinely used to alter the particle dispersion state, water demand, and rheology of similar suspensions (e.g., ordinary portland cement suspensions) that feature a high pH and high ionic strength, their use to control portlandite suspension rheology has not been elucidated. This study combines adsorption isotherms and rheological measurements to elucidate the role of PCE composition (i.e., charge density, side chain length, and grafting density) in controlling the extent of PCE adsorption, particle flocculation, suspension yield stress, and thermal response of portlandite suspensions. We show that longer side-chain PCEs are more effective in affecting suspension viscosity and yield stress, in spite of their lower adsorption saturation limit and fractional adsorption. The superior steric hindrance induced by the longer side chain PCEs results in better efficacy in mitigating particle aggregation even at low dosages. However, when dosed at optimal dosages (i.e., a dosage that induces a dynamically equilibrated dispersion state of particle aggregates), different PCE-dosed portlandite suspensions exhibit identical fractal structuring and rheological behavior regardless of the side chain length. Furthermore, it is shown that the unusual evolution of the rheological response of portlandite suspensions with temperature can be tailored by adjusting the PCE dosage. The ability of PCEs to modulate the rheology of aggregating charged particle suspensions can be generally extended to any colloidal suspension with a strong screening of repulsive electrostatic interactions.
PubMed: 37462925
DOI: 10.1021/acs.langmuir.3c00704 -
Environmental Science and Pollution... Nov 2023This study aims to formulate bacterial tablets of cadmium (Cd)-resistant Micrococcus sp. MU1, an indole-3-acetic acid-producer, for soil inoculation to improve Cd...
This study aims to formulate bacterial tablets of cadmium (Cd)-resistant Micrococcus sp. MU1, an indole-3-acetic acid-producer, for soil inoculation to improve Cd phytoremediation by Chlorophytum comosum (Thunb.) Jacques. The viability of Micrococcus sp. MU1 in tablets after storage at room temperature and 4 °C was determined. The ability of Micrococcus sp. tablets and cell suspensions on stimulating growth and Cd accumulation in C. comosum was compared. The results found that the viability of Micrococcus sp. tablets stored at room temperature and 4 °C for 2 months were 29.2 and 97.9%, respectively. After 2 months of growth in pots, the dry biomass weights of C. comosum amended with Micrococcus sp. tablet and cell suspension were greater than that of uninoculated control by 1.4- and 1.3-fold, respectively. Cd concentrations in the roots and shoots of C. comosum inoculated with bacterial tablet and bacterial suspension were not significantly different (p < 0.05) and were greater than that of the uninoculated plants. In addition, plants inoculated with Micrococcus sp. tablet and cell suspension exhibited superior phytoextraction performance, bioaccumulation factor, and translocation factor, indicating equal performance of both bacterial forms on boosting Cd phytoremediation efficiency in C. comosum. These findings suggest that soil inoculation with Micrococcus sp. tablet as a ready-to-use inoculum is a novel approach to promote phytoremediation of C. comosum in Cd-contaminated agricultural soil.
Topics: Cadmium; Biodegradation, Environmental; Soil Pollutants; Plant Roots; Soil; Asparagaceae; Micrococcus
PubMed: 37847368
DOI: 10.1007/s11356-023-30382-2 -
Sensors (Basel, Switzerland) Jun 2024In this study, we have developed an electrostatically suspended accelerometer (ESA) specifically designed for ground use. To ensure sufficient overload capacity and...
In this study, we have developed an electrostatically suspended accelerometer (ESA) specifically designed for ground use. To ensure sufficient overload capacity and minimize noise resulting from high suspension voltage, we introduced a proof mass design featuring a hollow, thin-walled cylinder with a thin flange fixed at the center, offering the highest surface-area-to-mass ratio compared to various typical proof mass structures. Preload voltage is directly applied to the proof mass via a golden wire, effectively reducing the maximum supply voltage for suspension. The arrangement of suspension electrodes, offering five degrees of freedom and minimizing cross-talk, was designed to prioritize simplicity and maximize the utilization of electrode area for suspension purposes. The displacement detection and electrostatic suspension force were accurately modeled based on the structure. A controller incorporating an inverse winding mechanism was developed and simulated using Simulink. The simulation results unequivocally demonstrate the successful completion of the stable initial levitation process and suspension under ±1g overload.
PubMed: 38931812
DOI: 10.3390/s24124029 -
PloS One 2023The purpose of this study was to assess the differences in muscle activation (EMG) and body weight distribution (%BW) between suspension (TRX™ push-up and TRX™...
The purpose of this study was to assess the differences in muscle activation (EMG) and body weight distribution (%BW) between suspension (TRX™ push-up and TRX™ inverted row) and conventional exercises (bench press and lying barbell row) using different contraction types (isometric and isotonic) and position variations (feet on the ground [FG] and feet on suspension device [FD]). It was also used to determine the intensity of the force applied to the straps of the suspension device corresponding to one repetition maximum (1-RM). Twelve male athletes (ages-24.5±4.2 years (mean±standard deviation [SD]); Height-181.0±6.8 cm; body mass-83.08±6.81 kg) participated in this study. Two suspension devices were used, one for the FD variation and one for the FG variation pectoralis major (PM) and triceps brachii (TRI) activations were assessed during the TRX™ push-up and bench press exercises. Transversus trapezius (TRA) and biceps brachii (BB) activations were assessed during the TRX™ inverted row and lying barbell row exercises. The results showed significant differences between exercises (FG and FD variations of TRX™ push-up and bench press) in PM activities (isometric and isotonic) (p≤0.05). However, these differences were only observed during isometric TRI activation (p≤0.05). In the FG and FD variations of the TRX™ inverted row and lying barbell row exercises, there were only differences in the isometric contractions of the TRA and BB (p≤0.05). In the suspension device of push-ups and inverted row for the FD variations, 70.5% and 72.64% of 1-RM intensity were obtained, respectively. Similar responses to training intensities and muscle activations can be obtained in suspension exercises and conventional exercises. FD variations of suspension exercises can be more effective in terms of muscle activations than FG variations, and isotonic suspension exercises increase exercise intensity more than isometric suspension exercises.
Topics: Male; Humans; Exercise; Exercise Therapy; Foot; Pectoralis Muscles; Isometric Contraction; Suspensions
PubMed: 37738266
DOI: 10.1371/journal.pone.0291608 -
International Journal of Antimicrobial... Dec 2023To investigate the potential impact of clinical characteristics and the Chinese race on posaconazole pharmacokinetics in patients using an integrated population...
Meta-pharmacokinetic analysis of posaconazole following dosing of oral suspension, delayed-release tablet, and intravenous infusion in patients vs. healthy volunteers: Impact of clinical characteristics and race.
OBJECTIVES
To investigate the potential impact of clinical characteristics and the Chinese race on posaconazole pharmacokinetics in patients using an integrated population pharmacokinetic model for posaconazole oral suspension (SUS), delayed-release tablet (DR-tablet), and intravenous (IV) infusion that was developed in healthy volunteers (HV).
METHODS
1046 concentrations from 105 prospectively studied Caucasian patients receiving either of the three posaconazole formulations were pooled with 3898 concentrations from 182 HV. Clinical characteristics were tested for significance. The impact of Chinese race was assessed using 292 opportunistic samples from 80 Chinese patients receiving SUS.
RESULTS
Bioavailability of SUS (F) in patients decreased from 38.2% to 24.6% when the dose was increased from 100 mg to 600 mg. Bioavailability of DR-tablet (F) was 59% regardless of dose. Mucositis, diarrhoea, administration through a nasogastric tube, and concomitant use of proton pump inhibitors or metoclopramide reduced F by 61%, 36%, 44%, 48%, and 29%, respectively, putting patients with these characteristics at increased risk of inadequate exposure. Clearance decreased from 7.0 to 5.1 L/h once albumin levels were <30 g/L. Patients showed an 84.4% larger peripheral volume of distribution (V) and 67.5% lower intercompartmental clearance (Q) compared with HV. No racial difference could be identified.
CONCLUSIONS
Pharmacokinetics of posaconazole in patients differ considerably to those in HV, with altered F that is also impacted by clinical covariates, an F similar to fasted conditions in HV, and altered parameters for clearance, V, and Q. There was no evidence to indicate that Chinese patients require a different dose to Caucasian patients.
Topics: Humans; Infusions, Intravenous; Antifungal Agents; Tablets; Triazoles; Biological Availability; Suspensions; Administration, Oral
PubMed: 37806462
DOI: 10.1016/j.ijantimicag.2023.106995 -
Tissue & Cell Dec 2023Circulating tumor cells (CTCs) are considered an important factor involved in tumor metastasis and can overcome mechanical interactions to gain the ability to distant...
Circulating tumor cells (CTCs) are considered an important factor involved in tumor metastasis and can overcome mechanical interactions to gain the ability to distant metastasis. The previous study had shown that the suspension state could regulate the stemness of breast cancer cells (BCCs). However, the specific molecular mechanisms involved have not yet been explored clearly. In this study, MCF-7 and MDA-MBA-231 BCCs were cultured in suspension and adherent. The effect of suspension state on BCCs was further elucidated by observing suspension cell clusters, sorting CD44/CD24 cell subpopulation and detecting self-renewal ability. Furthermore, it was found that glycogen synthase kinase-3β (GSK-3β) was significantly down-regulated in MCF-7 suspension cells along with the activation of the Wnt/β-catenin signaling, but the converse was true for MDA-MB-231 cells. Subsequently, GSK-3β was differentially expressed in MCF-7 suspension cells. The activation of the Wnt/β-catenin signaling, epithelial-mesenchymal transition (EMT) and stemness were all inhibited when GSK-3 was overexpressed in suspension MCF-7 cells. While GSK-3β was down-regulated, it further promoted the Wnt/β-catenin signaling, mesenchymal characteristic and stemness of MCF-7 cells. This study demonstrated that suspension state could activate the Wnt/β-catenin signaling by inhibiting GSK-3β to promote the stemness of epithelial BCCs, providing a therapeutic strategy for targeted CTCs.
Topics: Female; Humans; beta Catenin; Breast Neoplasms; Cell Line, Tumor; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Wnt Signaling Pathway
PubMed: 37683322
DOI: 10.1016/j.tice.2023.102208 -
Soft Matter Feb 2024Autonomous out-of-equilibrium agents or cells in suspension are ubiquitous in biology and engineering. Turning chemical energy into mechanical stress, they generate...
Autonomous out-of-equilibrium agents or cells in suspension are ubiquitous in biology and engineering. Turning chemical energy into mechanical stress, they generate activity in their environment, which may trigger spontaneous large-scale dynamics. Often, these systems are composed of multiple populations that may reflect the coexistence of multiple species, differing phenotypes, or chemically varying agents in engineered settings. Here, we present a new method for modeling such multi-population active fluids subject to confinement. We use a continuum multi-scale mean-field approach to represent each phase by its first three orientational moments and couple their evolution with those of the suspending fluid. The resulting coupled system is solved using a parallel adaptive level-set-based solver for high computational efficiency and maximal flexibility in the confinement geometry. Motivated by recent experimental work, we employ our method to study the spatiotemporal dynamics of confined bacterial suspensions and swarms dominated by fluid hydrodynamic effects. Our explorations reproduce observed emergent collective patterns, including features of active dissolution in two-population active-passive swarms, with results clearly suggesting that hydrodynamic effects dominate dissolution dynamics. Our work lays the foundation for a systematic characterization and study of collective phenomena in natural or synthetic multi-population systems such as bacteria colonies, bird flocks, fish schools, colloid swimmers, or programmable active matter.
Topics: Animals; Models, Biological; Hydrodynamics; Suspensions; Bacteria
PubMed: 38305767
DOI: 10.1039/d3sm01196h -
Physical Review Letters Nov 2023We consider a suspension of noninteracting flat elastic particles in a Newtonian fluid. We model a flat shape as three beads, carried along by the flow according to...
We consider a suspension of noninteracting flat elastic particles in a Newtonian fluid. We model a flat shape as three beads, carried along by the flow according to Stokes law, and connected by nonlinear springs, chosen such that the energy is quadratic in the area. In analogy with common dumbbell models involving two beads connected by linear springs, we solve the stochastic equations of motion exactly to compute the constitutive law for the stress tensor of a flat elastic particle suspension. A lower convected time derivative naturally arises as part of the constitutive law, but surprisingly the rheological response in strong extensional and strong contracting flows is similar to that of the classical Oldroyd-B model associated with dumbbell suspensions.
PubMed: 38000428
DOI: 10.1103/PhysRevLett.131.194002