Mannich Curcuminoids as Potent Anticancer Agents.

A series of novel curcuminoids were synthesised for the first time via a Mannich-3CR/organocatalysed Claisen-Schmidt condensation sequence. Structure-activity relationship (SAR) studies were performed by applying viability assays and holographic microscopic imaging to these curcumin analogues for anti-proliferative activity against A549 and H1975 lung adenocarcinoma cells. The TNFα-induced NF-κB inhibition and autophagy induction effects correlated strongly with the cytotoxic potential of the analogues. Significant inhibition of tumour growth was observed when the most potent analogue 44 was added in liposomes at one-sixth of the maximally tolerated dose in the A549 xenograft model. The novel spectrum of activity of these Mannich curcuminoids warrants further preclinical investigations.

Cardioprotection by remote ischemic preconditioning of the rat heart is mediated by extracellular vesicles.

Remote ischemic preconditioning (RIPC) of the heart is exerted by brief ischemic insults affected on a remote organ or a remote area of the heart before a sustained cardiac ischemia. To date, little is known about the inter-organ transfer mechanisms of cardioprotection by RIPC. Exosomes and microvesicles/microparticles are vesicles of 30-100 nm and 100-1000 nm in diameter, respectively (collectively termed extracellular vesicles [EVs]). Their content of proteins, mRNAs and microRNAs, renders EV ideal conveyors of inter-organ communication. However, whether EVs are involved in RIPC, is unknown. Therefore, here we investigated whether (1) IPC induces release of EVs from the heart, and (2) EVs are necessary for cardioprotection by RIPC. Hearts of male Wistar rats were isolated and perfused in Langendorff mode. A group of donor hearts was exposed to 3 × 5-5 min global ischemia and reperfusion (IPC) or 30 min aerobic perfusion, while coronary perfusates were collected. Coronary perfusates of these hearts were given to another set of recipient isolated hearts. A group of recipient hearts received IPC effluent depleted of EVs by differential ultracentrifugation. Infarct size was determined after 30 min global ischemia and 120 min reperfusion. The presence or absence of EVs in perfusates was confirmed by dynamic light scattering, the EV marker HSP60 Western blot, and electron microscopy. IPC markedly increased EV release from the heart as assessed by HSP60. Administration of coronary perfusate from IPC donor hearts attenuated infarct size in non-preconditioned recipient hearts (12.9 ± 1.6% vs. 25.0 ± 2.7%), similarly to cardioprotection afforded by IPC (7.3 ± 2.7% vs. 22.1 ± 2.9%) on the donor hearts. Perfusates of IPC hearts depleted of EVs failed to exert cardioprotection in recipient hearts (22.0 ± 2.3%). This is the first demonstration that EVs released from the heart after IPC are necessary for cardioprotection by RIPC, evidencing the importance of vesicular transfer mechanisms in remote cardioprotection.

Uterine vasculature remodeling in human pregnancy involves functional macrochimerism by endothelial colony forming cells of fetal origin.

The potency of adult-derived circulating progenitor endothelial colony forming cells (ECFCs) is drastically surpassed by their fetal counterparts. Human pregnancy is associated with robust intensification of blood flow and vascular expansion in the uterus, crucial for placental perfusion and fetal supply. Here, we investigate whether fetal ECFCs transmigrate to maternal bloodstream and home to locations of maternal vasculogenesis, primarily the pregnant uterus. In the first instance, endothelial-like cells, originating from mouse fetuses expressing paternal eGFP, were identified within uterine endothelia. Subsequently, LacZ or enhanced green fluorescent protein (eGFP)-labeled human fetal ECFCs, transplanted into immunodeficient (NOD/SCID) fetuses on D15.5 pregnancy, showed similar integration into the mouse uterus by term. Mature endothelial controls (human umbilical vein endothelial cells), similarly introduced, were unequivocally absent. In humans, SRY was detected in 6 of 12 myometrial microvessels obtained from women delivering male babies. The copy number was calculated at 175 [IQR 149-471] fetal cells per millimeter square endothelium, constituting 12.5% of maternal vessel lumina. Cross-sections of similar human vessels, hybridized for Y-chromosome, positively identified endothelial-associated fetal cells. It appears that through ECFC donation, fetuses assist maternal uterine vascular expansion in pregnancy, potentiating placental perfusion and consequently their own fetal supply. In addition to fetal growth, this cellular mechanism holds implications for materno-fetal immune interactions and long-term maternal vascular health.

Pest management systems affect composition but not abundance of phytoseiid mites (Acari: Phytoseiidae) in apple orchards.

We examined the faunal composition and abundance of phytoseiid mites (Acari: Phytoseiidae) in apple orchards under different pest management systems in Hungary. A total of 30 apple orchards were surveyed, including abandoned and organic orchards and orchards where integrated pest management (IPM) or broad spectrum insecticides (conventional pest management) were applied. A total of 18 phytoseiid species were found in the canopy of apple trees. Species richness was greatest in the organic orchards (mean: 3.3 species/400 leaves) and the least in the conventional orchards (1.4), with IPM (2.1) and abandoned (2.7) orchards showing intermediate values. The phytoseiid community's Rényi diversity displayed a similar pattern. However, the total phytoseiid abundance in the orchards with different pest management systems did not differ, with abundance varying between 1.8 and 2.6 phytoseiids/10 leaves. Amblyseius andersoni, Euseius finlandicus, and Typhlodromus pyri were the three most common species. The relative abundance of A. andersoni increased with the pesticide load of the orchards whereas the relative abundance of E. finlandicus decreased. The abundance of T. pyri did not change in the apple orchards under different pest management strategies; regardless of the type of applied treatment, they only displayed greater abundance in five of the orchards. The remaining 15 phytoseiid species only occurred in small numbers, mostly from the abandoned and organic orchards. We identified a negative correlation between the abundance of T. pyri and the other phytoseiids in the abandoned and organic orchards. However, we did not find any similar link between the abundance of A. andersoni and E. finlandicus.

Probabilistic modeling and risk characterization of the chronic aflatoxin M1 exposure of Hungarian consumers.

Aflatoxin contamination can appear in various points of the food chain. If animals are fed with contaminated feed, AFB1 is transformed-among others-to aflatoxin M1 (AFM1) metabolite. AFM1 is less toxic than AFB1, but it is still genotoxic and carcinogenic and it is present in raw and processed milk and all kinds of milk products. In this article, the chronic exposure estimation and risk characterization of Hungarian consumers are presented, based on the AFM1 contamination of milk and dairy products, and calculated with a probabilistic method, the two-dimensional Monte-Carlo model. The calculations were performed using the R plugin (mc2d package) integrated into the KNIME (Konstanz Information Miner) software. The simulations were performed using data from the 2018-2020 food consumption survey. The AFM1 analytical data were derived from the Hungarian monitoring survey and 1,985 milk samples were analyzed within the framework of the joint project of the University of Debrecen and the National Food Chain Safety Office of Hungary (NÉBIH). Limited AFM1 concentrations were available for processed dairy products; therefore, a database of AFM1 processing factors for sour milk products and various cheeses was produced based on the latest literature data, and consumer exposure was calculated with the milk equivalent of the consumed quantities of these products. For risk characterization, the calculation of hazard index (HI), Margin of Exposure, and the hepatocellular carcinoma incidence were used. The results indicate that the group of toddlers that consume a large amount of milk and milk products are exposed to a certain level of health risk. The mean estimated daily intake of toddlers is in the range of 0.008-0.221 ng kg-1 bw day-1; the 97.5th percentile exposure of toddlers is between 0.013 ng kg-1 bw day-1 and 0.379 ng kg-1 bw day-1, resulting in a HI above 1. According to our study, the exposure of older age groups does not pose an emergent health risk. Nevertheless, the presence of carcinogenic compounds should be kept to a minimum in the whole population.

Biological Control and Mitigation of Aflatoxin Contamination in Commodities.

Aflatoxins (AFs) are toxic secondary metabolites produced mostly by Aspergillus species. AF contamination entering the feed and food chain has been a crucial long-term issue for veterinarians, medicals, agroindustry experts, and researchers working in this field. Although different (physical, chemical, and biological) technologies have been developed, tested, and employed to mitigate the detrimental effects of mycotoxins, including AFs, universal methods are still not available to reduce AF levels in feed and food in the last decades. Possible biological control by bacteria, yeasts, and fungi, their excretes, the role of the ruminal degradation, pre-harvest biocontrol by competitive exclusion or biofungicides, and post-harvest technologies and practices based on biological agents currently used to alleviate the toxic effects of AFs are collected in this review. Pre-harvest biocontrol technologies can give us the greatest opportunity to reduce AF production on the spot. Together with post-harvest applications of bacteria or fungal cultures, these technologies can help us strictly reduce AF contamination without synthetic chemicals.

Physical and Chemical Methods for Reduction in Aflatoxin Content of Feed and Food.

Aflatoxins (AFs) are among the most harmful fungal secondary metabolites imposing serious health risks on both household animals and humans. The more frequent occurrence of aflatoxins in the feed and food chain is clearly foreseeable as a consequence of the extreme weather conditions recorded most recently worldwide. Furthermore, production parameters, such as unadjusted variety use and improper cultural practices, can also increase the incidence of contamination. In current aflatoxin control measures, emphasis is put on prevention including a plethora of pre-harvest methods, introduced to control Aspergillus infestations and to avoid the deleterious effects of aflatoxins on public health. Nevertheless, the continuous evaluation and improvement of post-harvest methods to combat these hazardous secondary metabolites are also required. Already in-use and emerging physical methods, such as pulsed electric fields and other nonthermal treatments as well as interventions with chemical agents such as acids, enzymes, gases, and absorbents in animal husbandry have been demonstrated as effective in reducing mycotoxins in feed and food. Although most of them have no disadvantageous effect either on nutritional properties or food safety, further research is needed to ensure the expected efficacy. Nevertheless, we can envisage the rapid spread of these easy-to-use, cost-effective, and safe post-harvest tools during storage and food processing.

Type 1 diabetes associated with Hashimoto's thyroiditis and juvenile rheumatoid arthritis: a case report with clinical and genetic investigations.

Autoimmune diseases are initiated by interaction between genetic and environmental factors and caused by the loss of immunologic tolerance to self-antigens. They cluster within families and individuals, but the aggregation in a triad is quite rare. We report a case of a young girl affected by three organ-specific autoimmune disorders, from which type 1 diabetes developed first, then Hashimoto's thyroiditis and juvenile rheumatoid arthritis were diagnosed. Hitherto unreported detailed genetic studies included genotyping of HLA class II, CTLA4, and PTPN22 gene regions. These genes have been associated with autoimmunity in general and some of their variants confer increased risk to all three diseases. Our results - with the limitation of reporting only on a single patient - contribute to the complex genetic background of these clustering organ-specific autoimmune diseases and the analysis of further similar cases might help to reveal how the major and minor genetic factors determine the individual clinical phenotype.

Fat rich diet-induced steatosis and changes in the gut­liver axis / A zsírdús étrend indukálta steatosis és a bél-máj tengely változásai.

INTRODUCTION: Fatty liver can develop as a result of diseases, surgical procedures, medicaments, malnutrition or excessive alcohol consumption, however, fat and poor fiber feeding can be attributed as the primary cause. Non-alcoholic fatty liver can be found in 20-30% of the population. Generally, alimentary-induced fatty liver in early state is described as uncomplicated liver injury. AIM: The aim of our research was to study the effect of fat rich nutrition on the gut-liver axis by routine laboratory, analytical and histological methods in rats. METHODS: We also examined the redox parameters of the liver and of the bowel. Fatty acid composition and element content of liver were measured. RESULTS: Significant changes were found in parameters of redox homeostasis as well as alterations in liver enzymes and metabolites. The changes could be detected in the liver, blood and bowel parts. The development of fatty liver is associated with the decrease of transmethylation capacity. Fatty acid composition and metal ion homeostasis were also altered in liver. Histological examinations showed that hepatocytes were swollen in the central part of the liver lobules, showed droplets and pycnotic nuclei, which were characterized by fatty degeneration. Small and large bowel enterocytes were damaged, sometimes pushed from the surface, and sometimes inflammatory reactions in the mucous membrane were observed. CONCLUSION: Our results suggest that alimentary fatty liver in early state is not considered simply as a reversible alteration because it alters the entire body's redox homeostasis and establishes heart and serious metabolic diseases as well as hasten the development of gastrointestinal tumors. Orv Hetil. 2020; 161(35): 1456-1465.

Patency of uterine wall in pregnancies following assisted and spontaneous conception with antecedent laparoscopic and abdominal myomectomies - a difficult case and systematic review.

A case of uterine rupture at 24 weeks in a pregnancy succeeding myomectomy and triple embryo transfer is described and literature is reviewed systematically to evaluate the importance of uterine rupture in pregnancies after myomectomy in general and some important sub-populations. Systematic search identified 179 papers and following a strategical selection process 45 studies were analyzed in detail, including 6 cohort and 19 observational studies, 3 case series and 17 case reports. Comparison of risk of uterine rupture after abdominal and laparoscopic myomectomy is made. In pregnancies after IVF number of embryos transferred are determined. Optimal contraceptive intervals and surgical techniques are discussed. The consequences of these observations are analyzed and conclusions are made which can assist individualizing treatment options and improve patient selection.

Adverse Effects, Transformation and Channeling of Aflatoxins Into Food Raw Materials in Livestock.

Aflatoxins are wide-spread harmful carcinogenic secondary metabolites produced by Aspergillus species, which cause serious feed and food contaminations and affect farm animals deleteriously with acute or chronic manifestations of mycotoxicoses. On farm, both pre-harvest and post-harvest strategies are applied to minimize the risk of aflatoxin contaminations in feeds. The great economic losses attributable to mycotoxin contaminations have initiated a plethora of research projects to develop new, effective technologies to prevent the highly toxic effects of these secondary metabolites on domestic animals and also to block the carry-over of these mycotoxins to humans through the food chain. Among other areas, this review summarizes the latest findings on the effects of silage production technologies and silage microbiota on aflatoxins, and it also discusses the current applications of probiotic organisms and microbial products in feeding technologies. After ingesting contaminated foodstuffs, aflatoxins are metabolized and biotransformed differently in various animals depending on their inherent and acquired physiological properties. These mycotoxins may cause primary aflatoxicoses with versatile, species-specific adverse effects, which are also dependent on the susceptibility of individual animals within a species, and will be a function of the dose and duration of aflatoxin exposures. The transfer of these undesired compounds from contaminated feed into food of animal origin and the aflatoxin residues present in foods become an additional risk to human health, leading to secondary aflatoxicoses. Considering the biological transformation of aflatoxins in livestock, this review summarizes (i) the metabolism of aflatoxins in different animal species, (ii) the deleterious effects of the mycotoxins and their derivatives on the animals, and (iii) the major risks to animal health in terms of the symptoms and consequences of acute or chronic aflatoxicoses, animal welfare and productivity. Furthermore, we traced the transformation and channeling of Aspergillus-derived mycotoxins into food raw materials, particularly in the case of aflatoxin contaminated milk, which represents the major route of human exposure among animal-derived foods. The early and reliable detection of aflatoxins in feed, forage and primary commodities is an increasingly important issue and, therefore, the newly developed, easy-to-use qualitative and quantitative aflatoxin analytical methods are also summarized in the review.

Oxidative stress with altered element content and decreased ATP level of erythrocytes in hepatocellular carcinoma and colorectal liver metastases.

Our aim was to study the possible alterations of redox status (enzymatic and nonenzymatic parameters and metal elements) in erythrocytes of patients with hepatocellular carcinoma (HCC), colorectal liver metastases (CRLM) and benign liver neoplasms. The function of redox homeostasis is closely connected to the energy level of erythrocytes, therefore, the ATP level was also determined. Antioxidant parameters, enzyme activities of superoxide dismutase and glutathione peroxidase were estimated in the erythrocytes of 11 patients with benign tumour, 23 patients with primary malignant and 37 metastatic liver tumour patients and 30 age-matched and sex-matched healthy controls. Element content with inductively coupled plasma optical emission spectrometer and ATP level by the chemiluminometric method were also determined from the samples. Free radical intensity was significantly increased, whereas erythrocyte glutathione peroxidase and superoxide dismutase activities were significantly decreased in the HCC and CRLM groups versus benign groups and controls. Se, Mn and Zn levels were lowered in HCC and CRLM groups versus benign and control groups. The content of Cu, Mg, Se and Zn changed significantly between HCC and CRLM groups. Similarly, ATP concentration decreased in HCC and CRLM versus controls and benign groups. The lowest levels of ATP and antioxidant enzyme activities were found in the case of CRLM patients. These results reveal an alteration in the ATP level of erythrocytes with concomitant changes in the antioxidant defence system in hepatic cancer patients. Altered redox homeostasis (oxidative damage) may lead to decreased ATP level and consequently may play an important role in primary carcinogenesis and generation of metastases, as well.

An assessment of the interactions between diclofenac sodium and ammonio methacrylate copolymer using thermal analysis and Raman spectroscopy.

The objective of the work was to assess the possible interactions between the model drug diclofenac sodium (DS) and the water-insoluble ammonio methacrylate copolymer (AMC). Films with different drug/polymer ratios were therefore prepared by the solvent casting method and investigated as a preformulation study towards sustained release microparticles. Differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were used to investigate the dispersed/dissolved state of the DS in the preparation, the thermal stability and the properties of DS-containing AMC films; and Raman spectroscopy was used to confirm the possible interactions between DS and AMC. Thermoanalytical studies confirmed that the DS could behave as a plasticizer, which was indicated by decreasing glass transition temperature (Tg) of the AMC, depending on its dispersity level in the AMC matrix. Partially solid solutions were formed at DS/AMC ratios of 1:12, 1:8 and 1:6. The DS was mainly crystalline at DS/AMC ratio of 1:4, while it remained crystalline at a ratio of 1:2. The Raman spectra confirmed that none of the major structural changes revealed any significant difference, which can indicate a strong ionic interaction between the DS and the AMC. The investigations provided good facilities for the selection of a DS/AMC ratio, in the preformulation study of the microsphere preparation process, in conformity with the therapeutic aim.

Sorption of copper, zinc and lead on soil mineral phases.

Soil mineral phases play a significant role in controlling heavy metal mobility in soils. The effective study of their relation needs the integrated use of several analytical methods. In this study, analytical electron microscopy analyses were combined with sequential chemical extractions on soils spiked with Cu, Zn and Pb. Our aims were to study the metal sorption capacity of soil mineral phases and the effect of presence of iron oxide and carbonate on this property of soil minerals. Copper and Pb were found to be characterized by higher and stronger sorption on the studied samples than Zn. Only the former two metals showed significant differences in their immobilized metal amounts on the studied samples and soil mineral particles. Highest metal amounts were sorbed on the swelling clay mineral particles (smectites and vermiculites), but iron-oxide phases may also have similar lead sorption capacity. Alkaline conditions due to the carbonate content of soils resulted both in increased sorption on the mineral particles for Cu and in enhanced role of precipitation for all the studied metals. On the other hand, the intimate association of phyllosilicates and iron resulted in significant increase in metal sorption capacity of the given particle. The results of sequential extractions could be successfully completed by the analytical electron microscopy analyses for studying the sorption capacity of discrete mineral particles. Their integrated use helps us in better understanding the heavy metal-mineral interactions in soils.

[Laparoscopic knot tying]. / Laparoscopos csomózás.

Wound closure with sutures has been routinely used as a result of the technical and surgical development since the 20th Century. Knot tying in open surgery can be easily learned and performed; however, knot tying becomes challenging and frustrating when performed laparoscopically. Laparoscopic vessel ligation, suturing and performing anastomosis opened up a new horizon for laparoscopy. Laparoscopic knots can be performed extracorporally or intraabdominally. The most common intracorporal knots are the tumble square, Dundee, Aberdeen, midship and blood knots. Inherent disadvantages of intracorporal laparoscopic knot tying are decreased sensation of the tension applied to the tissues and the knot; and difficulty in knotting because of technical requirements and limited space. The most common extracorporal knots: Duncan, Roeder, modified 4-S Roeder, Tayside, Yanni and GEA knots. Extracorporally tied knots are obviously much easier to tie than intracorporal one;, but they can cause tissue trauma from pulling long lengths of suture through the needle tract, excessive tension on the tissue while pushing the knot into position, and loss of focus on the operative field during knotting. One kind of knot-pusher would not fit for all and we suggest to use different knot-pushers for different suture materials. In robotic assisted suturing the operative time decreased, the stability has increased and the skills can be developed in simulation labs.

Niosomes decorated with dual ligands targeting brain endothelial transporters increase cargo penetration across the blood-brain barrier.

Nanoparticles targeting transporters of the blood-brain barrier (BBB) are promising candidates to increase the brain penetration of biopharmacons. Solute carriers (SLC) are expressed at high levels in brain endothelial cells and show a specific pattern at the BBB. The aim of our study was to test glutathione and ligands of SLC transporters as single or dual BBB targeting molecules for nanovesicles. High mRNA expression levels for hexose and neutral amino acid transporting SLCs were found in isolated rat brain microvessels and our rat primary cell based co-culture BBB model. Niosomes were derivatized with glutathione and SLC ligands glucopyranose and alanine. Serum albumin complexed with Evans blue (67 kDa), which has a very low BBB penetration, was selected as a cargo. The presence of targeting ligands on niosomes, especially dual labeling, increased the uptake of the cargo molecule in cultured brain endothelial cells. This cellular uptake was temperature dependent and could be decreased with a metabolic inhibitor and endocytosis blockers filipin and cytochalasin D. Making the negative surface charge of brain endothelial cells more positive with a cationic lipid or digesting the glycocalyx with neuraminidase elevated the uptake of the cargo after treatment with targeted nanocarriers. Treatment with niosomes increased plasma membrane fluidity, suggesting the fusion of nanovesicles with endothelial cell membranes. Targeting ligands elevated the permeability of the cargo across the BBB in the culture model and in mice, and dual-ligand decoration of niosomes was more effective than single ligand labeling. Our data indicate that dual labeling with ligands of multiple SLC transporters can potentially be exploited for BBB targeting of nanoparticles.

["Fast track" colorectal surgery]. / "Fast track" vastagbélsebészet.

Many factors have effect on the enhanced recovery after colon surgery. Not only the technical skill but the perioperative events needed to be optimized by the pre- and postoperative issues. Articles were obtained with search for keywords in Medline electronic database and evidences have been ranked according to the recommendation of the Oxford Evidence-Based Medicine Centre. Multicentric, randomised studies have proved that preoperative bowel emptying could not decrease the number of anastomotic insufficiency and wound infection rate; the use of abdominal drains is not necessary in every case; the proper, early oral intake is safe and well tolerated in colo-rectal surgery, and with laparoscopic surgery the same results can be achieved as with open ones. The evidences found even are not used completely. The advantage of laparoscopic surgery can be improved with fast track methods. To use correctly the affecting factors it is essential to know the current literature.

[Liberation of active substance from pharmaceutical suspensions I. Effect of surfactants on the active substance dissolving]. / Hatóanyag liberációja gyógyszeres szuszpenziókból I. Felületaktív anyagok hatása a hatóanyag kioldódására.

Liberation of active agent from suspensions containing sulfadimidine was investigated. There are three physico-chemical steps of the process: (i) dissolving active agent in the vehicle of suspension, (ii) partitioning dissolved molecules between the membrane and the suspension, and (iii) diffusion of active substance through membrane into the acceptor phase. The vehicle of suspensions contained surface active agents in 0.01 to 1.00 mass % concentration range. The liberation of active substance was examined with Hanson vertical diffusion cell. A multiplicative function, a square root one and an exponential equation were fitted at the analysis of results. It was established that the square root function and the exponential one fitted well to the measuring points. Relationships were found between the concentration and HLB values of surfactants and the rate constant of liberation. There is a characteristic correlation between the constants of Higuchi's equation and modified Weibull one, too.

From the Cover: In Vitro and In Vivo Blood-Brain Barrier Penetration Studies with the Novel Cyanide Antidote Candidate Dimethyl Trisulfide in Mice.

Recent in vitro and in vivo studies highlight the strong potential of dimethyl trisulfide (DMTS) as an antidote for cyanide (CN) intoxication. Due to its high oxygen demand, the brain is one of the main target organs of CN. The blood-brain barrier (BBB) regulates the uptake of molecules into the brain. In the literature, there is no data about the ability of DMTS to penetrate the BBB. Therefore, our aim was to test the in vitro BBB penetration of DMTS and its in vivo pharmacokinetics in blood and brain. The in vitro BBB penetration of DMTS was measured by using a parallel artificial membrane permeability assay (BBB-PAMPA), and a triple BBB co-culture model. The pharmacokinetics was investigated in a mouse model by following the DMTS concentration in blood and brain at regular time intervals following intramuscular administration. DMTS showed high penetrability in both in vitro systems (apparent permeability coefficients: BBB-PAMPA 11.8 × 10-6 cm/s; cell culture 158 × 10-6 cm/s) without causing cell toxicity and leaving the cellular barrier intact. DMTS immediately absorbed into the blood after the intramuscular injection (5 min), and rapidly penetrated the brain of mice (10 min). In addition to the observed passive diffusion in the in vitro studies, the contribution of facilitated and/or active transport to the measured high permeability of DMTS in the pharmacokinetic studies can be hypothesized. Earlier investigations demonstrating the antidotal efficacy of DMTS against CN together with the present results highlight the promise of DMTS as a brain-protective CN antidote.