Time-dependent Action Research Articles

Analysis of a high-dimensional free boundary problem on tumor growth with time-dependent nutrient supply and inhibitor action

This paper is concerned with a free boundary problem modeling tumor growth with time-dependent nutrient supply and inhibitor action. We highlight in this paper that the spatial domain occupied by the tumor is set to be n-dimensional for any n⩾3, and it is taken into account that the nutrient supply ϕ(t) and the inhibitor injection ψ(t) on the tumor surface are time-varying in this problem. The high-dimensional setting of the problem makes the proof of the existence of radial stationary solutions and the accurate determination of their numbers highly nontrivial, in which we have developed a new method that is different from the previous work by Cui and Friedman [11]. We can give a complete classification of the radial stationary solutions to this problem under different parameter conditions, and also explore the asymptotic behavior of the transient solution for small c:=c1+c2 in the case that ϕ(t) and ψ(t) have finite limits as t→∞.

Residue depletion profiles and withdrawal intervals of florfenicol and its metabolite florfenicol amine in plasma and milk of lactating goats after repeated subcutaneous administrations

Florfenicol is a broad-spectrum and bacteriostatic antibiotic with a time-dependent killing action. It is commonly used to treat respiratory diseases in goats in an extra-label manner. This study aimed to determine the plasma pharmacokinetics and milk residue depletion profiles and calculate the milk withdrawal interval (WDI) of florfenicol and its main metabolite florfenicol amine in lactating goats. Five healthy lactating goats were administered with 40 mg/kg florfenicol by subcutaneous injection, twice, 96 h apart. Plasma and milk samples were collected up to 864 h post the first injection. Non-compartmental analysis was used to estimate the plasma pharmacokinetic parameters. Milk WDIs were calculated using the U.S. Food and Drug Administration (FDA) method and European Medicines Agency (EMA) method. A Monte Carlo simulation was performed to generate simulated data for five virtual animals to meet the data requirement of the FDA method. The calculated milk WDIs based on florfenicol, florfenicol amine, and the combined (the sum of florfenicol and florfenicol amine) were 720.28, 690.45, and 872.69 h after the last injection using the FDA method. In conclusion, this study improves our understanding on the plasma pharmacokinetics and milk residue depletion kinetics of florfenicol and florfenicol amine in lactating ruminants after subcutaneous injections.

Substrate Affinity Is Not Crucial for Therapeutic L-Asparaginases: Antileukemic Activity of Novel Bacterial Enzymes.

L-asparaginases are used in the treatment of acute lymphoblastic leukemia. The aim of this work was to compare the antiproliferative potential and proapoptotic properties of novel L-asparaginases from different structural classes, viz. EcAIII and KpAIII (class 2), as well as ReAIV and ReAV (class 3). The EcAII (class 1) enzyme served as a reference. The proapoptotic and antiproliferative effects were tested using four human leukemia cell models: MOLT-4, RAJI, THP-1, and HL-60. The antiproliferative assay with the MOLT-4 cell line indicated the inhibitory properties of all tested L-asparaginases. The results from the THP-1 cell models showed a similar antiproliferative effect in the presence of EcAII, EcAIII, and KpAIII. In the case of HL-60 cells, the inhibition of proliferation was observed in the presence of EcAII and KpAIII, whereas the proliferation of RAJI cells was inhibited only by EcAII. The results of the proapoptotic assays showed individual effects of the enzymes toward specific cell lines, suggesting a selective (time-dependent and dose-dependent) action of the tested L-asparaginases. We have, thus, demonstrated that novel L-asparaginases, with a lower substrate affinity than EcAII, also exhibit significant antileukemic properties in vitro, which makes them interesting new drug candidates for the treatment of hematological malignancies. For all enzymes, the kinetic parameters (Km and kcat) and thermal stability (Tm) were determined. Structural and catalytic properties of L-asparaginases from different classes are also summarized.

Antibacterial mechanism of action and in silico molecular docking studies of Cupressus funebris essential oil against drug resistant bacterial strains

The primary objective of this research work was to study the antibacterial effects of Cupressus funebris essential oil (EO) against various drug resistant bacterial pathogens along with studying the molecular docking interactions of the major components of the EO with the key bacterial proteins/enzymes. Gas chromatography-mass spectrometry was used to analyse the chemical composition of the Cupressus funebris EO. The initial antibacterial screening was performed by using disc diffusion and microdilution methods. Scanning electron microscopy was also performed in order to study effects of the EO on bacterial cell morphology. Further, molecular docking studies were performed using Autodock Vina and results were visualised by BIOVIA Discovery Studio. The chemical composition of the EO showed the presence of 15 components with citronellal, terpinene-4-ol, α-phellandrene and 1,8-cineole as the major components of the EO. Results indicated that the EO of Cupressus funebris exhibited dose-dependent as well as time dependent antibacterial effects. The scanning electron microscopy indicated that the Cupressus funebris EO led to membrane rupture and permeabilization of the bacterial cells. Molecular docking studies indicated that the major compounds of the EO (citronellal and terpinene-4ol) showed strong interactions with the active site of the bacterial DNA gyrase enzyme explaining the antibacterial mode of action of the EO. Ciprofloxacin was also used for docking which showed stronger interactions with the target protein than citronellal or terpinene-4-ol. In conclusion, the major findings of the current study were that the EO of Cupressus funebris causes bacterial membrane rupture and permeabilization, shows time-dependent and dose-dependent antibacterial action, along with interacting with crucial bacterial enzyme viz., DNA gyrase as indicated by molecular docking studies.

In Vitro Combination of Ascorbic and Ellagic Acids in Sperm Oxidative Damage Inhibition

It is known that an altered redox balance interferes with normal spermatic functions. Exposure to genotoxic substances capable of producing oxidative stress (OS) can cause infertility in humans. The use of antioxidants to reduce oxidative stress contributes to the improvement in reproductive function. This study focused on an antigenotoxic evaluation of ellagic acid (EA) and ascorbic acid (AA) in combination against benzene genotoxic action on human spermatozoa in vitro. In addition to the evaluation of sperm parameters, damage in sperm genetic material and intracellular ROS quantification were assessed after AA, EA and benzene co-exposure using the TUNEL technique and DCF assay. The results showed that the combination of the two antioxidants generates a greater time-dependent antigenotoxic action, reducing both the sperm DNA fragmentation index and the oxidative stress. The genoprotective effect of AA and EA association in sperm cells lays the foundations for a more in-depth clinical study on the use of antioxidants as a therapy for male infertility.

Radiative cooling of polyyne anions: C4H- and C6H.

Time-dependent photodetachment action spectra for the linear hydrocarbon anions C4H- and C6H- are investigated using the cryogenic Double ElectroStatic Ion Ring ExpEriment. The radiative cooling characteristics of these ions on the millisecond to seconds timescale are characterized by monitoring changes in their spectra as the ions cool by spontaneous infrared (IR) emission. The average cooling rates, extracted using Non-negative Matrix Factorization, are fit with 1/e lifetimes of 19 ± 2 and 3.0 ± 0.2s for C4H- and C6H-, respectively. The cooling rates are successfully reproduced using a simple harmonic cascade model of IR emission. The ultraslow radiative cooling dynamics determined in this work provide important data for understanding the thermal cooling properties of linear hydrocarbon anions and for refining models of the formation and destruction mechanisms of these anions in astrochemical environments.

A Modular Approach to Atropisomeric Bisphosphines of Diversified Electronic Density on Phosphorus Atoms.

The series of C2-symmetric biaryl core-based non-racemic bisphosphines possessing substituents of different electronic properties: both EDG and EWG were obtained in a short sequence of good yielding transformations, started from commercial 1,3-dimethyl-2-nitrobenzene. Several different approaches leading to the desirable ligands were practically evaluated. Notably, the synthesis of the entire series of ligands could be performed with the utilization of a single early-stage precursor DIDAB (6,6′-diiodo-2,2′,4,4′-tetramethylbiphenyl-3,3′-diamine), which could be easily obtained in enantiomerically pure form. The obtained compounds at concentrations of 50 and 200 µM showed various biological activity against normal human dermal fibroblast, ranging from inactivity through time-dependent action and ending up with high toxicity.

Operatorial formulation of the ghost rotationally invariant slave-boson theory

We propose an operatorially exact formalism for describing the equilibrium and quantum-dynamical properties of many-electron systems interacting locally on a lattice, called ``ghost rotationally invariant slave-boson theory'' (g-RISB). We demonstrate that our theoretical framework reduces to the recently developed ghost Gutzwiller approximation (g-GA) at the mean-field level. Furthermore, we introduce the time-dependent mean-field g-RISB action, generalizing the time-dependent GA theory. Since the g-RISB is based on exact reformulation of the many-body problem, it may pave the way to the development of practical implementations for adding systematically quantum-fluctuation corrections towards the exact solution, in arbitrary dimension.

Effect of decision to delivery interval on perinatal outcomes during emergency cesarean deliveries in Ethiopia: A prospective cohort study.

BackgroundThe National guidelines of most developed countries suggest a target of 30 minutes of the decision to delivery interval for emergency cesarean section. Such guidelines may not be feasible in poorly resourced countries and busy obstetric settings. It is generally accepted that the decision to delivery interval should be kept to the minimum time achievable to prevent adverse outcomes. Therefore, this study aimed to determine the average decision to delivery interval and its effect on perinatal outcomes in emergency cesarean section.MethodsA prospective cohort study was conducted from May to July 2020 at Bahir Dar City Public Hospitals. A total of 182 participants were enrolled, and data were collected using a structured and pre-tested questionnaire. A systematic sampling technique was applied to select the study subjects. Data were cleaned and entered into Epi-Data version 4.6 and exported to SPSS version 25 software for analysis. Logistic regression analysis was performed to identify predictors of outcome variables, and variables with a p-value of <0.05 were considered statistically significant.ResultsThe average decision to delivery interval was 43.73 ±10.55 minutes. Anesthesia time [AOR = 2.1, 95%CI = (1.3–8.4)], and category of emergency cesarean section [AOR = 3, 95% CI = (2.1–11.5)] were predictors of decision to delivery interval. The prolonged decision to delivery interval had a statistically significant association with composite adverse perinatal outcomes (odds ratio [OR] = 1.8, 95% confidence interval [CI] = (1.2–6.5).ConclusionThe average decision to delivery interval was longer than the recommended time. It should always be considered an important factor contributing to perinatal outcomes. Therefore, to prevent neonatal morbidity and mortality, a time-dependent action is needed.

Ginzburg-Landau effective action for a fluctuating holographic superconductor

Under holographic prescription for Schwinger-Keldysh closed time contour for non-equilibrium system, we consider fluctuation effect of the order parameter in a holographic superconductor model. Near the critical point, we derive the time-dependent Ginzburg-Landau effective action governing dynamics of the fluctuating order parameter. In a semi-analytical approach, the time-dependent Ginzburg-Landau action is computed up to quartic order of the fluctuating order parameter, and first order in time derivative.

Conservation laws in coupled cluster dynamics at finite temperature.

We extend the finite-temperature Keldysh non-equilibrium coupled cluster theory (Keldysh-CC) [A. F. White and G. K.-L. Chan, J. Chem. Theory Comput. 15, 6137-6253 (2019)] to include a time-dependent orbital basis. When chosen to minimize the action, such a basis restores local and global conservation laws (Ehrenfest's theorem) for all one-particle properties while remaining energy conserving for time-independent Hamiltonians. We present the time-dependent Keldysh orbital-optimized coupled cluster doubles method in analogy with the formalism for zero-temperature dynamics, extended to finite temperatures through the time-dependent action on the Keldysh contour. To demonstrate the conservation property and understand the numerical performance of the method, we apply it to several problems of non-equilibrium finite-temperature dynamics: a 1D Hubbard model with a time-dependent Peierls phase, laser driving of molecular H2, driven dynamics in warm-dense silicon, and transport in the single impurity Anderson model.

Trans-chalcone induces death by autophagy mediated by p53 up-regulation and β-catenin down-regulation on human hepatocellular carcinoma HuH7.5 cell line

BackgroundHepatocellular Carcinoma (HCC) is extremely aggressive and presents low rates of response to the available chemotherapeutic agents. Many studies have focused on the search for alternative low-cost natural compounds with antiproliferative potential that selectively respond to liver cancer cells. PurposeThis study assessed the in vitro direct action of trans-chalcone (TC) on cells of the human HCC HuH7.5 cell line. MethodsWe subjected the HuH7.5 tumor cells to TC treatment at increasing concentrations (12.5–100 µM) for 24 and 48 h. Cell viability was verified through MTT and 50% inhibitory concentration of cells (IC50 23.66 µM) was determined within 48 h. We quantified trypan blue proliferation and light microscopy, ROS production, mitochondrial depolarization and autophagy, cell cycle analysis, and apoptosis using Muse® cell analyzer and immunocytochemical markings of p53 and β-catenin. ResultsData showed an effective dose- and time-dependent TC-cytotoxic action at low micromolar concentrations without causing toxicity to non-cancerous cells, such as erythrocytes. TC-treatment caused mitochondrial membrane damage and cell cycle G0/G1 phase arrest, increasing the presence of the p53 protein and decreasing β-catenin, in addition, to inducing cell death by autophagy. Additionally, TC decreased the metastatic capacity of HuH7.5, which affected the migration/invasion of this type of cell. ConclusionIn vitro TC activity in the human HCC HuH7.5 tumor cell line is shown to be a potential molecule to develop new therapies to repair the p53 pathway and prevent the overexpression of Wnt/β-catenin tumor development inducing autophagy cell death and decreasing metastatic capacity of HuH7.5 cell line.

Radiative cooling of carbon cluster anions C2n+1\u2212 (n\xa0=\xa03\u20135)

Radiative cooling of carbon cluster anions C2n+1− (n = 3–5) is investigated using the cryogenic electrostatic ion storage ring DESIREE. Two different strategies are applied to infer infrared emission on slow (milliseconds to seconds) and ultraslow (seconds to minutes) timescales. Initial cooling of the ions over the millisecond timescale is probed indirectly by monitoring the decay in the yield of spontaneous neutralization by thermionic emission. The observed cooling rates are consistent with a statistical model of thermionic electron emission in competition with infrared photon emission due to vibrational de-excitation. Slower cooling over the seconds to minutes timescale associated with infrared emission from low-frequency vibrational modes is probed using time-dependent action spectroscopy. For C9− and C11−, cooling is evidenced by the time-evolution of the yield of photo-induced neutralization following resonant excitation of electronic transitions near the detachment threshold. The cross-section for resonant photo-excitation is at least two orders of magnitude greater than for direct photodetachment. In contrast, C7− lacks electronic transitions near the detachment threshold.Graphical abstract

Pharmacokinetics and pharmacodynamics in extracorporeal renal replacement therapy

Intermittent hemodialysis, continuous hemofiltration and prolonged daily dialysis are used for renal replacement therapy in the intensive care units. Independent of the replacement modality, antibiotic therapy must start with ahigh loading dose. Dose adjustment to the kidneys must follow 48 h later to prevent toxic accumulation. Dose recommendations on product labels are often underdosed. On continuous hemofiltration, meanwhile many intensivists administer anormal standard dose because the high filtration rate corresponds to ahalf-normal glomerular filtration rate. After intermittent hemodialysis, adose similar to the loading dose will be needed. On day off dialysis, the maintenance dose must be adjusted to the failing kidney function. Immediately after prolonged daily dialysis, aloading dose should be given; with twice daily dosing the maintenance dose needs to be adjusted to kidney function. Therapeutic drug monitoring is recommended for gentamicin, vancomycin, piperacillin, meropenem and voriconazole. Due to pharmacodynamic reasons, the target concentration corresponds to the concentration producing the half-maximum effect. Accordingly, the target concentration is the normal peak for concentration-dependent action with bolus dosing. The target is the average steady-state concentration for antibiotics with time-dependent action and continuous infusion.

A Simulation Study to Assess the Effect of Analytic Error on Neonatal Glucose Measurements Using the Canadian Pediatric Society Position Statement Action Thresholds.

The Canadian Pediatric Society (CPS) has endorsed an algorithm for the screening and immediate management of babies at risk of neonatal hypoglycemia that provides time-dependent glucose concentration action thresholds. The objective of this study was to evaluate the impact of glucose analytic error (bias and imprecision) on the misclassification of glucose meter results from a neonatal intensive care unit (NICU) using the CPS guidelines. A simulation dataset of true glucose values (N = 100 000) was derived by finite mixture model analysis of NICU glucose data (N = 23 749). Bias and imprecision were added to create measured glucose values. The percentages of measured glucose values that were misclassified at CPS action thresholds were determined by Monte Carlo simulation. Measurement biases ranging from -20 to +20 mg/dL combined with coefficients of variation 0% to 20% were evaluated to predict misclassification rates at 32, 36, and 47 mg/dL. The models demonstrated low risk of false normoglycemia-at 5% CV and +10 mg/dL bias: 0.8% to 5% misclassification at the 32 and 47 mg/dL thresholds due to bias. The models demonstrated risk of false hypoglycemia-at 5% CV and -10 mg/dL bias: 3% to 12.5% misclassification at 32 and 47 mg/dL thresholds due to both bias and imprecision. Using CPS action thresholds, the simulation model predicted the proportion of neonates at risk of inappropriate clinical action-both of omission or "failure to treat" and commission or "overtreatment" in response to NICU glucose meter results at specific bias and imprecision values.

Cytotoxic and Genotoxic Activities of Alkaloids from the Bulbs of Griffinia gardneriana and Habranthus itaobinus (Amaryllidaceae).

Amaryllidaceae plants are known to be a great source of alkaloids, which are considered an extensive group of compounds encompassing a wide range of biological activities. The remarkable cytotoxic activities observed in most of the Amaryllidaceae alkaloids derivatives have prompt the chemical and biological investigations in unexplored species from Brazil. To evaluate the cytotoxic and genotoxic properties of alkaloids of Griffinia gardneriana and Habranthus itaobinus bulbs and study the role of caspase-3 as a molecular apoptosis mediator. Methanolic crude extracts of Griffinia gardneriana and Habranthus itaobinus bulbs were submitted to acid-base extraction to obtain alkaloid-enriched fractions. The obtained fractions were fractionated using chromatographic techniques leading to isolation and identification of some alkaloids accomplished via HPLC and 1H-NMR, respectively. Molecular docking studies assessed the amount of free binding energy between the isolated alkaloids with the caspase-3 protein and also calculated the theoretical value of Ki. Studies have also been developed to evaluate in vitro cytotoxicity and genotoxicity in such alkaloids and apoptosis activation via the caspase pathway using both tumor and normal cell lines. Seven alkaloids were isolated and identified. Among these, 11-hydroxyvittatine and 2-α-7- dimethoxyhomolycorine were not cytotoxic, whereas tazettine, trisphaeridine, and sanguinine only showed activity against the fibroblast lineage. Lycorine and pretazettine were 10 to 30 folds more cytotoxic than the other alkaloids, including cancerous lines, and were genotoxic and capable of promoting apoptosis via the caspase-3 pathway. This result supports data obtained in docking studies wherein these two compounds exhibited the highest free energy values. The cytotoxicity assay revealed that, among the seven alkaloids isolated, only lycorine and pretazettine were active against different cell lines, exhibiting concentration- and time-dependent cytotoxic actions alongside genotoxic action and the ability to induce apoptosis by caspase-3, a result consistent with those obtained in docking studies.

Data on Evaluation of the Corrosion Inhibition Effect of L-alpha-aminoisocaproate on High Carbon Steel Corrosion in Dilute Acid Media

Corrosion inhibition performance of l-alpha-aminoisocaproate on high carbon steel in 1 M HCl solution has been studied by weight loss measurement, open circuit potential measurement, optical microscopy and ATF-FTIR spectral analysis. The results showed the inhibition performance of l-alpha-aminoisocaproate is time dependent attaining an optimal value of 85.88 % at 5.63 % l-alpha-aminoisocaproate concentration (highest concentration) after 288 h of exposure. The corrosion potential plots of the high carbon steel at 0.91 % (lowest concentration) and 5.63 % l-alpha-aminoisocaproate concentration were more electropositive than the plots at 0% l-alpha-aminoisocaproate concentration due to the effective inhibition performance of l-alpha-aminoisocaproate in counteracting the oxidation of the carbon steel in the presence of chloride anions. Identified functional groups of alcohols, phenols, primary and secondary amines and amides, carboxylic acids, alkynes, aromatics, alkenes and alkanes consisting of O–H stretch, free hydroxyl, H–bonded, N–H stretch, –C(triple bond)C–H: C–H stretch, C–H stretch and =C–H stretch bonds where responsible for the corrosion inhibition. The optical morphology of the carbon steel after 7200 s of exposure in the acid solution without l-alpha-aminoisocaproate was severely corroded in contrast to the morphology of the steel in the presence of l-alpha-aminoisocaproate which underwent minor deterioration due to the time dependent action of the inhibitor.

Incorporation of shRNA in bioactive glass coated SS316L implant material and its role in inhibition of the osteoclast activity for better post implantation fixation

The possibility of the use of small non-coding RNAs as therapeutics in targeted treatment of damaged hard tissue are presently being explored largely and for the same, a good understanding of the underlying molecular mechanisms of osteoblast and osteoblast differentiation is necessary, which would lead to better fixation of the implant. In the present communication, we made an attempt to incorporate a model non coding RNA viz. short hairpin RNA (shRNA), in the form of shRNA-plasmid, in a porous bioactive coating of phosphate free bioactive glass (PFBG) on surgical grade SS316L implant material, used as reservoir/carrier of the biomolecule and evaluated its time dependent inhibitory action on the osteoclastogenic cytokine, tumor necrosis factor alpha (TNFα), that in turn aids in growth and differentiation of osteoblast cells, for faster remodelling, repair and healing of the damaged hard tissue at the implanted site. Upon treatment with the shRNA-plasmid, results exhibited significant downregulation (approximately 12-fold) of the TNFα, as evidenced from the sandwich ELISA assay and confirmed by quantitative reverse transcription–polymerase chain reaction (qRT–PCR) analysis, followed by upregulation of alkaline phosphatase (approximately 4-fold), corresponding to osteoblast formation, on the contrary, confirming a pivotal role of the same in osteoblast formation. The flow cytometry data showed significant cellular uptake (16.04%) of the shRNA-plasmid into osteoclast cells at a time period of 24h, that was in turn corroborated by confocal imaging.

Metabolic Analyses Revealed Time-Dependent Synergistic Killing by Colistin and Aztreonam Combination Against Multidrug-Resistant Acinetobacter baumannii.

Background: Polymyxins are a last-line class of antibiotics against multidrug-resistant Acinetobacter baumannii; however, polymyxin resistance can emerge with monotherapy. Therefore, synergistic combination therapy is a crucial strategy to reduce polymyxin resistance.Methods: This study conducted untargeted metabolomics to investigate metabolic responses of a multidrug-resistant (MDR) A. baumannii clinical isolate, AB090342, to colistin and aztreonam alone, and their combination at 1, 4, and 24 h. Metabolomics data were analyzed using univariate and multivariate statistics; metabolites showing ≥ 2-fold changes were subjected to bioinformatics analysis.Results: The synergistic action of colistin-aztreonam combination was initially driven by colistin via significant disruption of bacterial cell envelope, with decreased phospholipid and fatty acid levels at 1 h. Cell wall biosynthesis was inhibited at 4 and 24 h by aztreonam alone and the combination as shown by the decreased levels of two amino sugars, UDP-N-acetylglucosamine and UDP-N-acetylmuramate; these results suggested that aztreonam was primarily responsible for the synergistic killing at later time points. Moreover, aztreonam alone and the combination significantly depleted pentose phosphate pathway, amino acid, peptide and nucleotide metabolism, but elevated fatty acid and key phospholipid levels. Collectively, the combination synergy between colistin and aztreonam was mainly due to the inhibition of cell envelope biosynthesis via different metabolic perturbations.Conclusion: This metabolomics study is the first to elucidate multiple cellular pathways associated with the time-dependent synergistic action of colistin-aztreonam combination against MDR A. baumannii. Our results provide important mechanistic insights into optimizing synergistic colistin combinations in patients.

Combination delivery of two oxime-loaded lipid nanoparticles: Time-dependent additive action for prolonged rat brain protection

A novel approach for brain protection against poisoning by organophosphorus agents is developed based on the combination treatment of dual delivery of two oximes. Pralidoxime chloride (2-PAM) and a novel reactivator, 6-(5-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)pentyl)-3-hydroxy picolinaldehyde oxime (3-HPA), have been loaded in solid-lipid nanoparticles (SLNs) to offer distinct release profile and systemic half-life for both oximes. To increase the therapeutic time window of both oximes, SLNs with two different compartments were designed to load each respective drug. Oxime-loaded SLNs of hydrodynamic diameter between 100 and 160 nm and negative zeta potential (−30 to −25 mV) were stable for a period of 10 months at 4 °C. SLNs displayed longer circulation time in the bloodstream compared to free 3-HPA and free 2-PAM. Oxime-loaded SLNs were suitable for intravenous (iv) administration. Paraoxon-poisoned rats (0.8 × LD50) were treated with 3-HPA-loaded SLNs and 2-PAM+3-HPA-loaded SLNs at the dose of 3-HPA and 2-PAM of 5 mg/kg. Brain AChE reactivation up to 30% was slowly achieved in 5 h after administration of 3-HPA-SLNs. For combination therapy with two oximes, a time-dependent additivity and increased reactivation up to 35% were observed.