Tumor-targeting intravenous lipid emulsion of paclitaxel:Characteristics,stability,toxicity,and toxicokinetics

Lipid nanoemulsions are promising nanodrug delivery carriers that can improve the efficacy and safety of paclitaxel(PTX).However,no intravenous lipid emulsion of PTX has been approved for clinical treatment,and systemic safety profiles have not yet been reported.Here we outline the development of a PTXloaded tumor-targeting intravenous lipid emulsion(PTX Emul)and describe its characteristics,colloidal stability,and systemic safety profiles in terms of acute toxicity,long-term toxicity,and toxicokinetics.We also compare PTX Emul with conventional PTX injection.Results showed that PTX Emul exhibited an ideal average particle size(approximately 160 nm)with narrow size distribution and robust colloidal stability under different conditions.Hypersensitivity reaction and hemolysis tests revealed that PTX Emul did not induce hypersensitivity reactions and had no hemolytic potential.In addition,where the alleviated systemic toxicity of PTX Emul may be attributed to the altered toxicokinetic characteristics in beagle dogs,including the decreased AUC and increased plasma clearance and volume of distribution,PTX Emul alleviated acute and long-term toxicity as evidenced by the enhanced the median lethal dose and approximate lethal dose,moderate body weight change,decreased bone marrow suppression and organ toxicity compared with those under PTX injection at the same dose.A fundamental understanding of the systemic safety profiles,high tumor-targeting efficiency,and superior antitumor activity in vivo of PTX Emul can provide powerful evidence of its therapeutic potential as a future treatment for breast cancer.

Diazinon Toxicokinetics, Tissue Distribution and Anticholinesterase Activity in the Rat

The toxicokinetics, tissue distribution, and anticholinesteruse (antiChE ) activity of diazinon were investigated in the rat. Plasma concentrations most adequately fitted a two-compartment open model after iv administration of 10 mg/kg and a one-compartment model after oral administration of 80 mg/kg. Diazinon elimination half-life following iv and oral dosing was 4.70 and 2.86 h, respectively. The oral bioavailabllity was found to be low (35.5%). Hepatic extraction ratios after iv administration of 5 or 10 mg

INFLUENCE OF ETHANOL ON TOXICOKINETICS OF ACONITINE

A reverse-phase High-performance Liquid Chromatography (HPLC) method for the detection of aconitine (AC) in biological samples was used. After orally ingested Aconitum brochypodum Diels (AbD) to rabbits, the toxicokinetics process of AC showed a two-compartment open model.Ka. A and B of which were 1.1629±0. 4053, 0. 6046±0.2574 and 1. 1607±0. 3781 mg/L respectively. The influence of ethanol on this kinetics process was studied. It was indicated that ethanol did not change the model type, but the absorption and distribution of which were improved significantly (P<0. 01), its elimination process was not influenced significantly, the values of Ka. A and B were 2. 4026 ±0. 5376, 1. 205± 0. 5328, 1. 2037 ±0. 4095 mg/L respectively. All these suggest that ethanol increases the toxicity of AbD.

Acute Toxicity and Toxicokinetics of Tongguan Powder in Rats

[Objectives]To evaluate the acute toxicity and toxicokinetics of Tongguan Powder in rats,and provide references for clinical safe medication.[Methods]The classical acute toxicity test method was used,rats were given different doses of Tongguan Powder through the mouth and nasal cavity to observe the symptoms of toxicity,and make a record of the food intake,weight changes,and death.After the medication,blood was taken from each group of rats at different time points,and the plasma levels of benzoyl aconitine(BA),benzoyl hypaconine(BH)and benzoyl mesaconine(BM)were determined by the liquid chromatography tandem-mass spectrometry(LC-MS/MS),and the toxicokinetic parameters were fitted with the aid of DAS software.[Results]Rats were given Tongguan Powder 3.75 g/kg(equivalent to 54 times the human daily dose)in the nasal cavity of rats.Rats were observed with reactions such as scratching and sneezing;rats were given Tongguan Powder LD50 and 95%confidence limit of 4.15(3.53-4.71)g/kg through the oral administration,which is equivalent to 60 times the human daily dose,rats showed slow weight gain,decreased food intake,decreased voluntary activities,prone,black stools,etc.One hour after nasal administration of Tongguan Powder,the plasma concentration of benzoyl aconitine and benzoyl hypaconine was below the lower limit of detection,and benzoyl mesaconine could not be detected at any time point;one hour after the oral administration of Tongguan Powder,the plasma concentration of the three components reached the maximum,the exposure level of benzoyl hypaconine was higher than that of benzoyl aconitine and benzoyl mesaconine;there was no gender difference in the kinetic parameters.[Conclusions]The toxicity of Tongguan Powder in nasal administration is much lower than that of intragastric administration.The target organs and mechanism of toxicity need to be further studied.

Effects of nanoscale quantum dots in male Chinese loaches (Misgurnus anguillicaudatus):Estrogenic interference action,toxicokinetics and oxidative stress

Quantum dots (QDs) have received more and more attention as a novel example of nanocrystals due to their unique fluorescent characteristics. Recently, the toxicity and the potential environmental effects of QDs have become a research hotspot. In this work, in vivo endocrine disrupting effect, toxicokinetics and oxidative stress of QDs were characterized following the intraperitoneal dosing in Chinese loaches. Vitellogenin (Vtg) levels induced by E2 decreased significantly when administrated with the mixture of QDs and E2, which was consistent with the observations of histopathology in testes. The release of free Cd2+ from QDs and the non-specific adsorption of E2 by QDs might be the joint factors contributing to the inhibition of Vtg expression induced by E2 in the male Chinese loaches. In the muscle, bone, intestines, blood and testis, CdSe QDs reached the maximal concentration (Cmax) in approximately 1-h postinjection and subsequently presented downtrend with the prolonged time. Whereas, there were even increasing tendencies of CdSe QDs' concentrations in the liver and kidney. It is educible that CdSe QDs can be persistent at least for 7 days, indicating the overall half-life of CdSe QDs in the fish body is very long. The measurement of hepatic superoxide dismutase (SOD) activity and reduced glutathione (GSH) content indicate that QDs have smaller effects on the antioxidative system of the organisms compared with free Cd2+ due to the effective prevention of the release of Cd by PEG coating of QDs. The comprehensive evaluation of QDs' toxicity in the present study provides an essential and general framework towards more focused research on the elucidation of the biological effects of QDs in vivo.

Toxicokinetics and the related metabolites in rainbow trout(Oncorhynchus mykiss) after exposure to decabromodiphenyl ether

Decabromodiphenyl ether(BDE209) is poorly absorbed by mammals,and little information is available on the toxicokinetics of BDE209 and its metabolites in fish.In the present study,rainbow trout(Oncorhynchus mykiss) were administered to 100 ng/g and 500 ng/g body wet weight of BDE209 via a single intraperitoneal injection and parent BDE209 and its metabolites were sequentially monitored for 28 days.The results showed that toxicokinetic profiles of BDE209 could be described by the one-compartment model.In the higher dose group(500 ng/g wet weight),the calculated half-life(t1/2) and elimination rate(ke) were 17.7 d and 0.039/d in the liver,and 100.3 d and 0.007/d in the muscle,respectively.Three major methoxylated brominated diphenyl ethers(MeO-BDEs) were detected with 2,2',4,4'-tetrabromo-5-methoxydiphenyl ether(5-MeO-BDE47) being detected in all tissue samples.There was no significant temporal change of 5-MeO-BDE47 concentration in the muscle,whereas an exponential increase was observed in the liver.Therefore,the metabolism rate of BDE209 depended on the administered dose.BDE209 was hardly accumulated in the muscle of rainbow trout,while the liver was a primary metabolic organ.MeO-BDEs were formed via metabolism of BDE209,which probably played a significant role in fish toxicology as a potential indicator.

SYNTHESIS OF (~3H-METHYL) TRINITROTOLUENE AND ITS APPLICATION TO TOXICOLOGICAL STUDY

In this paper, (2H- methyl) toluene was prepared by catalysed halogen- tritium substitution method from benzyl bromide, then it was nitrated to produce (8H- methyl) trinitrotoluene. The tritiated product was purified by thin- layer chromatography. At last, the pure 3H- TNT was obtained with specific radioactivity of 3.77 GBq/mmol. Radiochemical purity was over 98% and the ultraviolet absorption spectrum of tritiated TNT was conformed with that of standard sample. Using 3H- TNT as a tracer, its toxicokinetics was sudied in rats. The results showed that the toxicokinetics characteristics of TNT were quickly absorbed into the blood, Vd】2L/kg.h, long T1/2β and fixed accumulation with four routes of administration, TNT and its metabolites were mainly excreted by the urine. The half- life of TNT in the urine were 1,1- 24h. A trace of radioactivity of 3H- TNT and its metabolites could be detected in the urine on 7th day after administration (9.25×106Bq/kg).

Liquid chromatography-mass spectrometry method for the quantification of an anti-sclerostin monoclonal antibody in cynomolgus monkey serum

Liquid chromatography tandem mass spectrometry(LC-MS/MS)has gradually become a promising alternative to ligand binding assay for the bioanalysis of biotherapeutic molecules,due to its rapid method development and high accuracy.In this study,we established a new LC-MS/MS method for the determination of the anti-sclerostin monoclonal antibody(SHR-1222)in cynomolgus monkey serum,and compared it to a previous electrochemiluminescence method.The antibody was quantified by detecting the surrogate peptide obtained by trypsin digestion.The surrogate peptide was carefully selected by investigating its uniqueness,stability and MS response.The quantitative range of the proposed method was 2.00-500μg/mL,and this verified method was successfully applied to the toxicokinetic assessment of SHR-1222 in cynomolgus monkey serum.It was found that the concentrations of SHR-1222 in cynomolgus monkeys displayed an excellent agreement between the LC-MS/MS and electrochemiluminescence methods(ratios of drug exposure,0.8-1.0).Notably,two monkeys in the60 mg/kg dose group had abnormal profiles with a low detection value of SHR-1222 in their individual sample.Combining the high-level anti-drug antibodies(ADAs)in these samples and the consistent quantitative results of the two methods,we found that the decreased concentration of SHR-1222 was due to the accelerated clearance mediated by ADAs rather than the interference of ADAs to the detection platform.Taken together,we successfully developed an accurate,efficient and cost-effective LC-MS/MS method for the quantification of SHR-1222 in serum samples,which could serve as a powerful tool to improve the preclinical development of antibody drugs.

Case Study: Suicide Attempt by Intentional Ingestion of Chlormequat

Chlormequat is a quaternary ammonium and choline chlorinated derivated is used as plant growth regulating agent. There are very few documented cases of poisoning in humans. We reported a case of non-fatal suicide attempt by chlormequat in France. A 34-year-old woman was admitted to hospital after deliberate consumption of plant growth regulator, C5 SUN, containing chlormequat chloride (460 g/L) and choline chloride (320 g/L). Immediately, she developed symptoms of respiratory distress and a cardiac massage was begun by her father. In this case report, we described the method for an accurate and reliable screening of chlormequat which was based on the combination of Target Analysis powerful software and a high performance TOF-MS (Impact HD from Bruker). After forced diuresis, the kinetic of elimination of chlormequat is biphasic: vascular phase diffusion (half-life of 5.6 hr) followed by a phase of free elimination (half-life of 16.2 h). Although chlormequat poisoning is clinically similar to that observed with anticholinesterase compounds, chlormequat chloride is not an acetylcholinesterase inhibitor. Chlormequat seems to be a weak substrat competitor for cholinesterase leading to acetylcholine accumulation and prolonged depolarization in muscular junction. Cardiac massage, artificial respiration and forced diuresis have significantly improved the prognosis of our patient.

Assessing comparable bioconcentration potentials for nanoparticles in aquatic organisms via combined utilization of machine learning and toxicokinetic models

The toxicokinetic(TK)model‐derived kinetic bioconcentration factor(BCFk)provides a quantitatively comparable index to estimate the bioaccumulation potential of nanoparticles(NPs)that barely reach thermodynamic equilibrium in aquatic organisms,but experimental data are limited for various NPs.In the present study,a machine learning model was applied to offer reliable in silico predictions for the dynamic body burden of diverse NPs to derive corresponding parameters for the TK model.The developed eXtreme Gradient Boosting‐derived TK(XGB‐TK)model was applied to predict BCFk results for a broad range of metallic or carbonaceous NPs,with an appreciable prediction R2 of 0.96.The BCFk values were predicted based on a random combination of selected variable features,revealing that their bioaccumulation potential showed an overall negative correlation with NP density or organism size.By applying importance analysis and partial dependence plots,NP density and organism size were revealed to be the top essential features that impact the bioaccumulation potential.The conjunctively used XGB‐TK model enabled a prior comparison for diverse NPs and straightforward derivation on the dependency of features,which could also guide the bioaccumulation mechanism exploration and experimental condition formulation.