Pharmacokinetic comparison of four arbidol hydrochloride preparations in beagle dogs.

This study aimed to compare the pharmacokinetic properties of four preparations (dispersible tablets, ordinary tablets, capsules and granules) of arbidol hydrochloride, a broad-spectrum antiviral drug, in beagle dogs. Briefly, a single dose of 100 mg of the four preparations of arbidol hydrochloride was orally administered to dogs; blood was then collected from the veins of the foreleg at different times after administration to prepare plasma samples. The plasma concentration of arbidol hydrochloride was measured using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results showed that when orally administered with dispersible tablets, ordinary tablets, capsules and granules suspended with water, there were no significant differences in the pharmacokinetic parameters (including peak time, peak concentration, elimination half-life, area under the curve (AUC0-t ), and mean retention time) of arbidol hydrochloride. However, in the case of the dispersible tablets, the pharmacokinetics of arbidol hydrochloride was significantly affected by the mode of administration. Compared with direct feeding, peak time [0.50 (0.13, 0.50) vs. 1.00 (0.50, 2.00)] was significantly shortened (P = 0.033) and the AUC0-48 h (8726.5 ± 2509.3 vs. 3650.8 ± 1536.9 ng h/ml) was significantly increased (P = 0.012) when the dispersible tablets were orally administered as water dispersion. In conclusion, the pharmacokinetics of four preparations of arbidol hydrochloride were not significant different in beagle dogs. However, compared with direct feeding, the absorption of arbidol hydrochloride was faster and the bioavailability was better when the dispersible tablets were orally administered as water dispersion.

Oxidative stress induced by realgar in neurons: p38 MAPK and ERK1/2 perturb autophagy and induce the p62-Keap1-Nrf2 feedback loop to activate the Nrf2 signalling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Due to the modernization of traditional Chinese medicine (TCM) and the influence of traditional medication habits (TCM has no toxicity or side effects), arsenic poisoning incidents caused by the abuse of realgar and realgar-containing Chinese patent medicines have occurred occasionally. However, the potential mechanism of central nervous system toxicity of realgar remains unclear. AIM OF THE STUDY: This study aimed to clarify the specific mechanism of realgar-induced neurotoxicity. MATERIALS AND METHODS: In this study, the roles of ERK1/2 and p38 MAPK in realgar-induced neuronal autophagy and overactivation of the nuclear factor erythroid-derived factor 2-related factor (Nrf2) signalling pathways was investigated in vivo and in vitro. RESULTS: The arsenic in realgar passed through the blood-brain barrier and accumulated in the brain, resulting in damage to neurons, synapses and myelin sheaths in the cerebral cortex and a decrease in the total antioxidant capacity. The specific mechanism is that the excessive activation of Nrf2 is regulated by the upstream signalling molecules ERK1/2 and p38MAPK. At the same time, p38 MAPK and ERK1/2 interfere with autophagy, thereby promoting autophagy initiation but causing subsequent dysfunctional autophagic degradation and inducing the p62-Keap1-Nrf2 feedback loop to promote Nrf2 signalling pathway activation and nerve cell apoptosis. CONCLUSIONS: This study confirmed the role of the signalling molecules p38 MAPK and ERK1/2 in perturbing autophagy and inducing the p62-Keap1-Nrf2 feedback loop to activate the Nrf2 signalling pathway in realgar-induced neurotoxicity.

Simultaneous determination of febuxostat and montelukast in human plasma using fabric phase sorptive extraction and high performance liquid chromatography-fluorimetric detection.

In the present work, a new sensitive and selective high-performance liquid chromatography-fluorimetric detection (HPLC-FLD) method was developed and validated to quantify febuxostat (FBX) and montelukast (MON) in human plasma. The developed procedure was successfully applied to a study aimed at evaluating the pharmacokinetic profiles of febuxostat and montelukast in human plasma. A sol-gel poly (caprolactone)-block-poly(dimethylsiloxane)-block-poly(caprolactone) (sol-gel PCAP-PDMS-PCAP) extraction sorbent coated fabric phase sorptive extraction membrane was used in the extraction process. The entire chromatographic analysis was performed with isocratic elution of the composition of the mobile phase (acetonitrile:water, 60:40, v:v, 0.032% glacial acetic acid) on the C18 column. The flow rate is varied during the analysis, particularly from 0.5 mL min-1 at the start and linearly increased to 1.5 mL min-1 in 7 min. The detection and quantification of the analytes was carried out by means of a fluorimetric detector at 320 nm and 350 nm as absorption wavelengths and at 380 and 400 nm as emission wavelengths for FBX and MON, respectively. The calibration curves demonstrated linearity in the range 0.3-10 ng mL-1 and 5-100 ng mL-1 for FBX and MON, respectively, while the LOD and LOQ values were 0.1 and 0.3 ng mL-1 for FBX and 1.5 and 5 ng mL-1 for MON. Intraday and interday RSD% values were found lower than 5.79%. As reported, the method was applied to real plasma samples obtained from a volunteer who was co-administered both the drugs. Pharmacokinetic data reveal that the concentration of both the drugs reaches the plateau approximately at the same time, but exhibits an elimination phase at different rates. This study demonstrated the usefulness of the new method and its applicability in therapeutic drug monitoring (TDM).

Case Study 5: Predicting the Drug Interaction Potential for Inhibition of CYP2C8 by Montelukast.

Predicting drug-drug interactions (DDIs) from in vitro data is made difficult by not knowing concentrations of substrate and inhibitor at the target site. For in vivo targets, this is understandable, since intracellular concentrations can differ from extracellular concentrations. More vexing is that the concentration of the drug at the target for some in vitro assays can also be unknown. This uncertainty has resulted in standard in vitro practices that cannot accurately predict human pharmacokinetics. This case study highlights the impact of drug distribution, both in vitro and in vivo, with the example of the drug interaction potential of montelukast.

A New Workflow for Drug Metabolite Profiling by Utilizing Advanced Tribrid Mass Spectrometry and Data-Processing Techniques.

Drug metabolite profiling utilizes liquid chromatography with tandem mass spectrometry (LC/MS/MS) to acquire ample information for metabolite identification and structural elucidation. However, there are still challenges in detecting and characterizing all potential metabolites that can be masked by a high biological background, especially the unknown and uncommon ones. In this work, a novel metabolite profiling workflow was established on a platform using a state-of-the-art tribrid high-resolution mass spectrometry (HRMS) system. Primarily, an instrumental method was developed based on the novel design of the tribrid system that facilitates in-depth MSn scans with two fragmentation devices. Additionally, different advanced data acquisition techniques were assessed and compared, and automatic background exclusion and deep-scan approaches were adopted to promote assay efficiency and metabolite coverage. Finally, different data-analysis techniques were explored to fully extract metabolite data from the information-rich MS/MS data sets. Overall, a workflow combining tribrid mass spectrometry and advanced acquisition methodology has been developed for metabolite characterization in drug discovery and development. It maximizes the tribrid HRMS platform's utility and enhances the coverage, efficiency, quality, and speed of metabolite profiling assays.

Montelukast microsuspension with hypromellose for improved stability and oral absorption.

Oral montelukast (MTK) is prescribed to treat asthma or rhinitis, and is clinically investigated as new medication in the treatment of Alzheimer's dementia. Herein, in order to better patient's compliance, microsuspensions (MSs)-based oral liquid preparations of montelukast (MTK) were formulated with polymeric suspending agents including hypromellose (HPMC), and those drug-polymer interaction, physicochemical stability, dissolution, and in vivo pharmacokinetic profile was evaluated. When amorphous MTK particle was suspended in aqueous vehicle, it was readily converted into crystalline form and grown into aggregates, drastically lowering dissolution rate. However, the addition of HPMC polymer markedly suppressed the crystal growth, providing both improved drug stability and profound dissolution profile. Raman spectrometry denoted the inter-molecular hydrogen boding between MTK particle and HPMC polymer. The crystal growth or dissolution profile of MSs was markedly affected by pharmaceutical additives (sucrose or simethicone) in the preparations or storage temperature. The optimized HPMC-based MS exhibited over 80% higher bioavailability, compared to marketed granule (Singulair®) in rats. Therefore, novel MTK-loaded MS can be a promising liquid preparation, bettering oral absorption and patient's compliance.

Europium sulfide nanoprobes predict antiretroviral drug delivery into HIV-1 cell and tissue reservoirs.

Background: Delivery of long-acting nanoformulated antiretroviral drugs (ARVs) to human immunodeficiency virus type one cell and tissue reservoirs underlies next generation antiretroviral therapeutics. Nanotheranostics, comprised of trackable nanoparticle adjuncts, can facilitate ARV delivery through real-time drug tracking made possible through bioimaging platforms. Methods: To model HIV-1 therapeutic delivery, europium sulfide (EuS) nanoprobes were developed, characterized and then deployed to cells, tissues, and rodents. Tests were performed with nanoformulated rilpivirine (NRPV), a non-nucleoside reverse transcriptase inhibitor (NNRTI) used clinically to suppress or prevent HIV-1 infection. First, CD4+ T cells and monocyte-derived macrophages were EuS-treated with and without endocytic blockers to identify nanoprobe uptake into cells. Second, Balb/c mice were co-dosed with NRPV and EuS or lutetium177-doped EuS (177LuEuS) theranostic nanoparticles to assess NRPV biodistribution via mass spectrometry. Third, single photon emission computed tomography (SPECT-CT) and magnetic resonance imaging (MRI) bioimaging were used to determine nanotheranostic and NRPV anatomic redistribution over time. Results: EuS nanoprobes and NRPV entered cells through dynamin-dependent pathways. SPECT-CT and MRI identified biodistribution patterns within the reticuloendothelial system for EuS that was coordinate with NRPV trafficking. Conclusions: EuS nanoprobes parallel the uptake and biodistribution of NRPV. These data support their use in modeling NRPV delivery to improve treatment strategies.

No association between pyrite content and lung cell responses to coal particles.

There has been an increase in the identification of cases of coal workers' pneumoconiosis (CWP) in recent years around the world. While there are a range of possible explanations for this, studies have implicated the pyrite content of coal as a key determinant of CWP risk. However, experimental studies to support this link are limited. The aim of this study was to assess the association between the pyrite content, and subsequent release of bioavailable iron, in coal particles and the response of lung cells involved in the pathogenesis of CWP (epithelial cells, macrophages and fibroblasts). Using real-world Australian coal samples, we found no evidence of an association between the pyrite content of the coal and the magnitude of the detrimental cell response. We did find evidence of an increase in IL-8 production by epithelial cells with increasing bioavailable iron (p = 0.01), however, this was not linked to the pyrite content of the coal (p = 0.75) and we did not see any evidence of a positive association in the other cell types. Given the lack of association between the pyrite content of real-world coal particles and lung cell cytotoxicity (epithelial cells and macrophages), inflammatory cytokine production (epithelial cells, macrophages and fibroblasts), and cell proliferation (fibroblasts) our data do not support the use of coal pyrite content as a predictor of CWP risk.

Pharmacokinetics and Bioequivalence Evaluation of Two Montelukast Sodium Chewable Tablets in Healthy Chinese Volunteers Under Fasted and Fed Conditions.

PURPOSE: The aim of this study was to assess and compare the pharmacokinetic (PK) properties and bioequivalence of montelukast sodium chewable tablets prepared by two different manufacturers in healthy Chinese volunteers to obtain adequate PK evidence for the registration approval of the test formulation. PATIENTS AND METHODS: A randomized-sequence, single-dose, open-label, 2-period crossover study was conducted in fasted and fed healthy Chinese volunteers (Chinese Clinical Trials Registry identifier: CTR20182362). Eighteen subjects each were selected for a fasted study and a fed study. Eligible participants were randomly assigned in a 1:1 ratio to receive a single dose of the reference formulation or the test formulation, followed by a 5-day washout period and the administration of the alternate formulation. Plasma samples were collected over a 24-hour period following tablet administration and analyzed for montelukast contents by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The PK parameters, such as maximum serum concentration (Cmax), area under the curve (AUC) from t = 0 to the last quantifiable concentration (AUC0-t), AUC from t = 0 to infinity (AUC0-∞), half-life (t1/2), time to Cmax (Tmax), and terminal elimination rate constant (λz), were evaluated. The safety assessment included changes in vital signs (blood pressure, pulse, and temperature) or laboratory tests (hematology, blood biochemistry, hepatic function, and urinalysis) and the incidence of adverse events (AEs). RESULTS: The geometric mean ratios (GMRs) between the two formulations for the primary pharmacokinetic parameters (Cmax, AUC0-24, and AUC 0-∞) and the corresponding 90% confidence intervals (Cis) were all within the range of 80.00-125.00% for both the fasting and fed states. The safety profiles for both treatments were comparable. CONCLUSION: The PK analysis revealed that the test and reference formulations of montelukast sodium chewable tablets were bioequivalent and well-tolerated by healthy Chinese subjects.

Design of Thioether Cyclic Peptide Scaffolds with Passive Permeability and Oral Exposure.

Advances in the design of permeable peptides and in the synthesis of large arrays of macrocyclic peptides with diverse amino acids have evolved on parallel but independent tracks. Less precedent combines their respective attributes, thereby limiting the potential to identify permeable peptide ligands for key targets. Herein, we present novel 6-, 7-, and 8-mer cyclic peptides (MW 774-1076 g·mol-1) with passive permeability and oral exposure that feature the amino acids and thioether ring-closing common to large array formats, including DNA- and RNA-templated synthesis. Each oral peptide herein, selected from virtual libraries of partially N-methylated peptides using in silico methods, reflects the subset consistent with low energy conformations, low desolvation penalties, and passive permeability. We envision that, by retaining the backbone N-methylation pattern and consequent bias toward permeability, one can generate large peptide arrays with sufficient side chain diversity to identify permeability-biased ligands to a variety of protein targets.

A Review of Different Analytical Techniques for Fexofenadine Hydrochloride and Montelukast Sodium in Different Matrices.

Fexofenadine hydrochloride is an antihistamine agent used for the treatment of allergic disorders like rhinitis. It is a second generation antihistamine. Montelukast sodium is an anti-asthmatic agent and leukotriene receptor antagonist used in the treatment of respiratory disorders. This article exemplifies the reported analytical methods like electrometric methods, ultraviolet spectroscopy, mass spectroscopy, thin layer chromatography, high performance liquid chromatography, high performance thin layer chromatography and tandem spectroscopy for determination of fexofenadine HCl and montelukast sodium in dosage form and in biological matrices. This review covers almost all the analytical methods for fexofenadine hydrochloride and montelukast sodium form 1968-2018 years. Complete analytical validation parameters reported are discussed in this review for both analytes. Among various analytical methods, HPLC and UV-visible spectrophotometry were found to be the most extensively used methods by the researchers.

Pilot Study of Peak Plasma Concentration After High-Dose Oral Montelukast in Children With Acute Asthma Exacerbations.

Acute asthma exacerbations are primarily due to airway inflammation and remain one of the most frequent reasons for childhood hospitalizations. Although systemic corticosteroids remain the mainstay of therapy because of their anti-inflammatory properties, not all inflammatory pathways are responsive to systemic corticosteroids, necessitating hospital admission for further management. Cysteinyl leukotrienes (LTs) are proinflammatory mediators that play an important role in systemic corticosteroids non-responsiveness. Montelukast is a potent LT-receptor antagonist, and an intravenous preparation caused rapid, sustained improvement of acute asthma exacerbations in adults. We hypothesized that a 30-mg dose of oral montelukast achieves peak plasma concentrations (Cmax ), comparable to the intravenous preparation (1700 ng/mL) and would be well tolerated in 15 children aged 5 to 12 years with acute asthma exacerbations. After administration of montelukast chewable tablets, blood samples were collected at 0, 15, 30, 45, 60, 120, 180, and 240 minutes. Plasma was separated and frozen at -80°C until analysis for montelukast concentration using liquid chromatography- tandem mass spectrometry. Median time to Cmax (tmax ) was 3.0 hours. Six participants (40%) achieved Cmax of 1700 ng/mL or higher. However, there was high interindividual variability in peak plasma concentration (median Cmax of 1378 ng/mL; range, 16-4895 ng/mL). No participant had side effects or adverse events. Plasma concentrations from this pilot study support the design of a weight-based dose-finding study aimed at selecting an optimal dose for future clinical trials to assess the efficacy of high-dose oral montelukast in children with moderate to severe asthma exacerbations.

LP2, the first lanthipeptide GPCR agonist in a human pharmacokinetics and safety study.

Introduction of a lanthionine into a peptide may enhance target affinity, target specificity and proteolytic resistance. This manuscript reports preclinical safety studies and the first-in-human study with the lanthipeptide AT2R agonist LP2, a structural analog of cAng-(1-7), whose N-terminus was protected against aminopeptidases by the presence of a d-lysine. None of the preclinical studies, including an in vitro multitarget panel, behavioral, respiratory and cardiovascular measurements, genotoxicity and toxicity studies in rat and dog, posed any safety concern. Due to lack of toxicity the maximum tolerated dose was not reached neither in rat nor in dog. In the human dose escalation study, healthy male volunteers received a single 1 mL subcutaneous injection (0.001 mg, 0.01 mg or 0.1 mg) of LP2 or matching placebo. In contrast to angiotensin II which has a T1/2 in plasma of < 1 min, LP2 has a T1/2 of approximately 2.1-2.6 hours. The fraction of the dose excreted unchanged in urine ranged from 84.73 ± 10.4 % at a dose of 0.001 mg to 66.4 ± 3.9 % at 0.1 mg. There were no deaths, serious adverse events or subject withdrawals as a result of an adverse event. The incidence of adverse events was 16.7 %; each was mild in severity. One adverse event, peripheral coldness, was considered to be possibly related to LP2 at 0.001 mg LP2. None of the results was considered to pose a clinically relevant safety concern. This study supports the potential for the therapeutic use of lanthipeptides.

Nephrotoxicity Evaluation of Indium Phosphide Quantum Dots with Different Surface Modifications in BALB/c Mice.

InP QDs have shown a great potential as cadmium-free QDs alternatives in biomedical applications. It is essential to understand the biological fate and toxicity of InP QDs. In this study, we investigated the in vivo renal toxicity of InP/ZnS QDs terminated with different functional groups-hydroxyl (hQDs), amino (aQDs) and carboxyl (cQDs). After a single intravenous injection into BALB/c mice, blood biochemistry, QDs distribution, histopathology, inflammatory response, oxidative stress and apoptosis genes were evaluated at different predetermined times. The results showed fluorescent signals from QDs could be detected in kidneys during the observation period. No obvious changes were observed in histopathological detection or biochemistry parameters. Inflammatory response and oxidative stress were found in the renal tissues of mice exposed to the three kinds of QDs. A significant increase of KIM-1 expression was observed in hQDs and aQDs groups, suggesting hQDs and aQDs could cause renal involvement. Apoptosis-related genes (Bax, Caspase 3, 7 and 9) were up-regulated in hQDs and aQDs groups. The above results suggested InP/ZnS QDs with different surface chemical properties would cause different biological behaviors and molecular actions in vivo. The surface chemical properties of QDs should be fully considered in the design of InP/ZnS QDs for biomedical applications.

Water dispersible ZnSe/ZnS quantum dots: Assessment of cellular integration, toxicity and bio-distribution.

Quantum dots (QDs) comprise an emerging group of materials with innumerable number of possibilities in biological research including cellular labelling. Among the leading members in this category, ZnSe/ZnS quantum dots (QDs) hold greater attractive possibilities in imaging primarily due to their higher biocompatibility and dispersibility. Nevertheless, the inherent toxicity of ZnSe/ZnS QDs is not yet completely explored which largely compromise most of their biomedical application potential. Strong blue emitting water soluble QDs effectively synthesized by aqueous phase route. Synthesized QDs further subjected to various optical and physicochemical characterization. Approximately 5-6 nm sized ZnSe/ZnS QDs illuminated bluish green fluorescence under UV lamp. Present study addresses possible adverse effects of ZnSe/ZnS QDs in hepatic system using HepG2 cells; which is the routinely employed in vitroliver cell model. A bundle of assays wasperformed out to reveal the cytotoxic nature of ZnSe/ZnS QDs and the mechanism behind it. Herein, absorption, distribution, metabolism, excretion and toxicity (ADME and T) of ZnSe/ZnS in mice were profiled in detail followed by intravenous (i.v.) and intraperitoneal (i.p.) administration at a dose of 10 mg/kg body weight. In a short review, it could be state that ZnSe/ZnS QDs did not exhibit any significant in vivo toxicity outcome in mice.

CC12 Induces Apoptotic Cell Death and Cell Cycle Arrest in Human Glioblastoma Cell Lines and Mouse Xenograft Model.

Among central nervous system tumors, glioblastoma (GBM) is the most common and the most malignant type. Even under current standard treatments, the overall survival rate is still low and the recurrence rate is high. Therefore, developing novel and effective therapy is urgently needed. CC12, a synthesized small molecule, was evaluated for the potential anti-GBM effects in two GBM cell lines, U87MG and U118MG. The observations of cell morphology, MTT assay, flow cytometry-based apoptosis after CC12 treatment, were conducted. Western blot was performed for the investigation of the apoptotic mechanism. Positron emission tomography scan analysis and bioluminescent imaging assay using a mouse xenograft model were performed for the effect of CC12 in vivo. After treated by 10 µM CC12 for 24 h, both U118MG and U87MG cells showed tumor cell death. MTT assay results showed that the survival rates decreased when the CC12 concentrations or the treatment periods increased. Ki-67 expression and flow cytometry results indicated that the proliferation was inhibited in GBM cells, and G1 phase arrest was shown. The results of 7-AAD, Br-dUTP, and JC-1 staining all showed the apoptosis of GBM cells after CC12 treatment. Increased γH2AX, caspase-3, and poly (ADP-ribose) polymerase (PARP) levels meant the DNA damage, and increased Bcl2 family proteins after CC12 treatment indicated the intrinsic apoptotic pathway was involved in CC12 induced apoptosis. Furthermore, CC12 can induce the decrease of tumor prognostic marker DcR3. In vivo experiment results showed the effect of CC12 on tumor size reduction of CC12. In addition, the ability to cross the brain-blood barrier of CC12 was also confirmed. CC12 may have anti-tumor ability through the regulation of cell cycle and apoptosis in vitro and in vivo.

Synthesis and evaluation of 2-(2'-((dimethylamino)methyl)-4'-(2-fluoroethoxy-substituted)phenylthio)benzenamine derivatives as potential positron emission tomography imaging agents for serotonin transporters.

A series of diphenylsulfide derivatives with various substitutions at the 4-position on phenyl ring A and different lengths of the 2-fluoroethoxy-substituted side-chain at the 4'-position on ring B were synthesized and evaluated as potential positron emission tomography (PET) imaging agents for serotonin transporters (SERT). These ligands exhibited high SERT binding affinities (Ki = 0.11-1.3 nM) and the 4-methyl-substituted (4-Me) compounds 7a and 8a displayed excellent selectivity for SERT versus norepinephrine transporters (NET) (392- and 700-fold, respectively). In the parallel artificial membrane permeability assay (PAMPA), these ligands demonstrated moderate to high brain penetration, and the 4-Me analogs showed higher BBB permeability than the corresponding 4-F analogs. The 2-fluoroethoxy-substituted ligands showed higher metabolic stability and lower lipophilicity than 4-F-ADAM. [18F]7a-c were readily prepared using an automatic synthesizer and exhibited significant uptake and slow washout in rat brains. At 120 min after iv injection, [18F]7a exhibited the highest uptake in the midbrain, whereas [18F]7b exhibited the highest uptake in the hypothalamus and midbrain. After treatment with citalopram, a SERT-selective ligand, the uptake of [18F]7a in the hypothalamus and striatum was significantly decreased. The potent and highly selective SERT binding and the selective and reversible accumulation in SERT-rich brain regions suggested that [18F]7a is a promising lead for the further development of novel [18F]-labeled PET imaging agents for SERT binding sites in the brain.

Shell-Free Copper Indium Sulfide Quantum Dots Induce Toxicity in Vitro and in Vivo.

Semiconductor quantum dots (QDs) are attractive fluorescent contrast agents for in vivo imaging due to their superior photophysical properties, but traditional QDs comprise toxic materials such as cadmium or lead. Copper indium sulfide (CuInS2, CIS) QDs have been posited as a nontoxic and potentially clinically translatable alternative; however, previous in vivo studies utilized particles with a passivating zinc sulfide (ZnS) shell, limiting direct evidence of the biocompatibility of the underlying CIS. For the first time, we assess the biodistribution and toxicity of unshelled CIS and partially zinc-alloyed CISZ QDs in a murine model. We show that bare CIS QDs breakdown quickly, inducing significant toxicity as seen in organ weight, blood chemistry, and histology. CISZ demonstrates significant, but lower, toxicity compared to bare CIS, while our measurements of core/shell CIS/ZnS are consistent with literature reports of general biocompatibility. In vitro cytotoxicity is dose-dependent on the amount of metal released due to particle degradation, linking degradation to toxicity. These results challenge the assumption that removing heavy metals necessarily reduces toxicity: indeed, we find comparable in vitro cytotoxicity between CIS and CdSe QDs, while CIS caused severe toxicity in vivo compared to CdSe. In addition to highlighting the complexity of nanotoxicity and the differences between the in vitro and in vivo outcomes, these unexpected results serve as a reminder of the importance of assessing the biocompatibility of core QDs absent the protective ZnS shell when making specific claims of compositional biocompatibility.

Study of the accumulation and distribution of arsenic species and association with arsenic toxicity in rats after 30 days of oral realgar administration.

AIM OF THE STUDY: Because the toxicity and efficacy of arsenic is closely related to its chemical species, we conducted examinations of arsenic species accumulation and distribution in the rat body after one-time and 30-day realgar administration and then elucidated the probable roles of different arsenic species in the short-term toxicity of realgar. MATERIALS AND METHODS: According to ICH M3 guidelines for non-clinical repeated dose toxicity studies and OECD Test guideline TG407 "Repeated Dose 28-Day oral Toxicity Study in Rodents, the doses of realgar set were 10.6 mg/kg, 40.5 mg/kg and 170 mg/kg. Rats were orally administered with realgar for one-tme and 30 days, respectively. Thereafter, biological samples (plasma, urine, liver, kidney, and brain) were obtained from rats and analyzed using high-performance liquid chromatography-inductively coupled plasma-mass spectrometry (HPLC-ICP-MS) to determine realgar metabolism, arsenic species accumulation and distribution. Additionally, the toxicity of realgar in rats was evaluated. RESULTS: The absorption, distribution and elimination half-life of total arsenic species in realgar were 3.33 hs, 16.08 hs and 24.65 hs, respectively. After 30 days of oral administration of realgar in rats, no significant drug-related toxicity occurred in the rats. Dimethylarsenic acid (DMA) is the most abundant arsenic species. The DMA contents of the liver and kidney of the high-dose realgar group were approximately 40-fold and 50-fold higher than those in the corresponding tissues of the control group, respectively. The arsenic species (III) was mainly detected in the liver and its content was about 40-fold higher than that of the control group. MMA was mainly detected in rat kidney, and the MMA content of the realgar treatment group was more than 2000 times higher than that of the control group. CONCLUSIONS: Arsenic is rapidly absorbed and distributed over the liver, kidneys and brain, and the distribution and elimination of arsenic in the blood is slow. The realgar doses corresponded to human equivalent doses (HED) of 1.7, 6.4 and 27.2 mg/kg, respectively. Considering that humans are 10 times more sensitive than animals, the realgar dose is equivalent to 0.17, 0.64 and 2.7 mg/kg HED. It can be considered that if patients take no more than 2.7 mg/kg realgar for 2 weeks, there will be no adverse reactions.

Lack of effect of Imrecoxib, an innovative and moderate COX-2 inhibitor, on pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers.

Imrecoxib is a registered treatment for osteoarthritis pain symptoms in China. This study aims to assess the effect of imrecoxib on the pharmacodynamics and pharmacokinetics of warfarin. 12 healthy male volunteers with CYP2C9*3 AA and VKORC1 AA genotypes took a 5 mg dose of warfarin both alone and concomitantly with steady-state imrecoxib. Both warfarin alone and concomitantly with imrecoxib have safey and good tolerance across the trial. Following warfarin and imrecoxib co-administration, neither Cmax, AUC0-t and t1/2 of warfarin enantiomers nor AUC of international normalized ratio (INR) were markedly different from those of warfarin alone. The geometric mean ratios (GMRs) (warfarin + imrecoxib: warfarin alone) of INR(AUC) was 1 (0.99, 1.01). The GMRs of warfarin AUC0-∞ (90% confidence interval, CIs) for warfarin + imrecoxib: warfarin alone were 1.12 (1.08, 1.16) for R-warfarin and 1.13 (1.07, 1.18) for S- warfarin. The 90% CIs of the GMRs of AUC0-∞, Cmax and INR (AUC) were all within a 0.8-1.25 interval. The combination of warfarin and imrecoxib did not impact the pharmacodynamics and pharmacokinetics of single-dose warfarin; therefore, when treating a patient with imrecoxib and warfarin, it is not required to adjust the dosage of warfarin.