A constrained optimum adaptive design for dose finding in early phase clinical trials.

Recently, interest has grown in the development of dose-finding methods that consider both toxicity and efficacy as endpoints. Along with responses on these, the incorporation of pharmacokinetic (PK) data can be beneficial in terms of patients' safety and can also increase the efficiency of the design for finding the best dose for the next phase. In this paper, the maximum concentration (Cmax) is used as the PK measure guiding the dose selection. The ethically attractive approach, which is based on the probability of efficacy, is used as a dose optimisation criterion. At each stage of an adaptive trial, that dose is selected for which the criterion is maximised, subject to the constraints imposed on the Cmax and the probability of toxicity. The inter-patient variability of the PK model parameters is considered, and population D-optimal sampling time points for measuring the concentration of a drug in the blood are calculated. The method is illustrated with a one-compartment PK model with first-order absorption, with the parameters being assumed to be random. The Cox model for bivariate binary responses is employed to model the dose-response outcomes. The results of a simulation study for several plausible dose-response scenarios show a significant gain in the efficiency of the design, as well as a reduction in the proportion of toxic responses.

Photobac derived from bacteriochlorophyll-a shows potential for treating brain tumor in animal models by photodynamic therapy with desired pharmacokinetics and limited toxicity in rats and dogs.

Photobac is a near infrared photosensitizer (PS) derived from naturally occurring bacteriochlorophyll- a, with a potential for treating a variety of cancer types (U87, F98 and C6 tumor cells in vitro). The main objective of the studies presented herein was to evaluate the efficacy, toxicity and pharmacokinetic profile of Photobac in animals (mice, rats and dogs) and submit these results to the United States Food and Drug Administration (US FDA) for its approval to initiate Phase I human clinical trials of glioblastoma, a deadly cancer disease with no long term cure. The photodynamic therapy (PDT) efficacy of Photobac was evaluated in mice subcutaneously implanted with U87 tumors, and in rats bearing C6 tumors implanted in brain. In both tumor types, the Photobac-PDT was quite effective. The long-term cure in rats was monitored by magnetic resonance imaging (MRI) and histopathology analysis. A detailed pharmacology, pharmacokinetics and toxicokinetic study of Photobac was investigated in both non-GLP and GLP facilities at variable doses following the US FDA parameters. Safety Pharmacology studies suggest that there is no phototoxicity, cerebral or retinal toxicity with Photobac. No metabolites of Photobac were observed following incubation in rat, dog, mini-pig and human hepatocytes. Based on current biological data, Photobac-IND received the approval for Phase-I human clinical trials to treat Glioblastoma (brain cancer), which is currently underway at our institute. Photobac has also received an orphan drug status from the US FDA, because of its potential for treating Glioblastoma as no effective treatment is currently available for this deadly disease.

[Health Benefit Evaluation for PM2.5 as Well as O3-8h Pollution Control in Chengdu, China from 2016 to 2020].

Both particulate matter with aerodynamics of less than 2.5 (PM2.5) and ozone are the two main air pollutants in China, which seriously endanger human health. To estimate the adverse impacts of PM2.5 and ozone on human health during the implementation of air pollution prevention and control actions in Chengdu, both the generalized additive model and the nonlinear distribution lag model of epidemiology were adopted to explore the exposure-response relationship coefficients ß of daily ozone 8h maximum concentration average (O3-8h), as well as that of PM2.5 on disease deaths in Chengdu from 2014 to 2016. On this basis, the environmental risk model and environmental value assessment model were both adopted to evaluate the health effects and health benefits in Chengdu from 2016 to 2020, respectively, with the assumption that PM2.5 and O3-8h concentration were reduced to specified air pollution control limits (35 µg·m-3 and 70 µg·m-3, respectively). The results showed 1 the annual concentration of PM2.5 presented gradually decreasing trends in Chengdu from 2016 to 2020. Specifically, ρ(PM2.5) from 63 µg·m-3 in 2016 decreased to 40.92 µg·m-3 in 2020. The average annual decline rate was approximately 9.8%. In contrast, the annual concentration of O3-8h from 155 µg·m-3 in 2016 increased to 169 µg·m-3 in 2020, and the increasing rate was approximately 2.4%. 2 Both PM2.5 and O3-8h had lag effects on three types of disease deaths. Under the maximum lag effect, the corresponding exposure-response relationship coefficients ß of PM2.5were 0.0003600, 0.0005001, and 0.0009237 for all-cause, cardiovascular, and respiratory premature deaths, respectively, whereas the corresponding ß of O3-8h were 0.0003103, 0.0006726, and 0.0007002, respectively. 3 If ρ(PM2.5) was reduced to the national secondary standard limit (35 µg·m-3), the corresponding number of health beneficiaries and economic benefits declined yearly. Specifically, the health beneficiary number of all-cause, cardiovascular, and respiratory disease deaths were reduced from 1128, 416, and 328 in 2016 to 229, 96, and 54 in 2020, respectively. There were a total number of 3314 avoidable premature deaths for all-cause diseases during the five years, resulting in a total health economic benefit of 7.66 billion yuan. 4 If we assume that ρ(O3-8h) was reduced to the concentration limit specified by the World Health Organization (70 µg·m-3), the corresponding number of health beneficiaries and economic benefits were increasing yearly. Specifically, the health beneficiaries' numbers of all-cause, cardiovascular, and respiratory disease deaths rose from 1919, 779, and 606 in 2016 to 2429, 1157, and 635 in 2020, respectively. The annual average growth rates of avoidable all-cause and cardiovascular mortality were 6.85% and 10.72%, respectively, which was higher than the annual average rise rate of ρ(O3-8h). There were 10790 total avoidable deaths from all-cause diseases during the five years, resulting in a total health economic benefit of 26.62 billion yuan. These findings indicate that PM2.5 pollution in Chengdu had been well controlled, whereas O3 pollution had become more severe and had become another key air pollutant threatening human health. Therefore, the synchronous control of PM2.5 and ozone should be implemented in the future.

Genetic Polymorphisms Associated with Vincristine Pharmacokinetics and Vincristine-Induced Peripheral Neuropathy in Pediatric Oncology Patients.

Vincristine (VCR) is an important component of curative chemotherapy for many childhood cancers. Its main side effect is VCR-induced peripheral neuropathy (VIPN), a dose limiting toxicity. Some children are more susceptible to VIPN, which is at least partially dependent on genetic factors and pharmacokinetics (PK). In this study, we identify and replicate genetic variants associated with VCR PK and VIPN. Patient samples from a randomized clinical trial studying the effect of administration duration of VCR on VIPN in 90 patients were used. PK sampling was conducted on between one and five occasions at multiple time points. A linear two-compartment model with first-order elimination was used, and targeted next-generation DNA sequencing was performed. Genotype-trait associations were analyzed using mixed-effect models or logistic regression analysis for repeated measures, or Poisson regression analysis in which the highest VIPN score per patient was included. Nine single-nucleotide polymorphisms (SNPs) in seven genes (NDRG1, GARS, FIG4, FGD4, SEPTIN9, CEP72, and ETAA1) were associated with VIPN. Furthermore, three SNPs in three genes (MTNR1B, RAB7A and SNU13) were associated with PK of VCR. In conclusion, PK of VCR and VIPN are influenced by SNPs; upfront identification of those that lead to an altered susceptibility to VIPN or VCR exposure could help individualize VCR treatment.

Chiral mesoporous silica nano-screws as an efficient biomimetic oral drug delivery platform through multiple topological mechanisms.

In the microscale, bacteria with helical body shapes have been reported to yield advantages in many bio-processes. In the human society, there are also wisdoms in knowing how to recognize and make use of helical shapes with multi-functionality. Herein, we designed atypical chiral mesoporous silica nano-screws (CMSWs) with ideal topological structures (e.g., small section area, relative rough surface, screw-like body with three-dimension chirality) and demonstrated that CMSWs displayed enhanced bio-adhesion, mucus-penetration and cellular uptake (contributed by the macropinocytosis and caveolae-mediated endocytosis pathways) abilities compared to the chiral mesoporous silica nanospheres (CMSSs) and chiral mesoporous silica nanorods (CMSRs), achieving extended retention duration in the gastrointestinal (GI) tract and superior adsorption in the blood circulation (up to 2.61- and 5.65-times in AUC). After doxorubicin (DOX) loading into CMSs, DOX@CMSWs exhibited controlled drug release manners with pH responsiveness in vitro. Orally administered DOX@CMSWs could efficiently overcome the intestinal epithelium barrier (IEB), and resulted in satisfactory oral bioavailability of DOX (up to 348%). CMSWs were also proved to exhibit good biocompatibility and unique biodegradability. These findings displayed superior ability of CMSWs in crossing IEB through multiple topological mechanisms and would provide useful information on the rational design of nano-drug delivery systems.

Women have higher levels of CoQ10 than men when supplemented with a single dose of CoQ10 with monoglycerides omega-3 or rice oil and followed for 48 h: a crossover randomised triple blind controlled study.

Coenzyme Q10 (CoQ10), a lipid involved in ATP synthesis, exhibits very limited oral absorption, and its endogenous production decreases with ageing and with the occurrence of oxidative stress. Our group previously showed that monoglycerides omega-3 (MAG-OM3) increase OM3 plasma concentrations. Since CoQ10 is liposoluble, we hypothesised that its 48 h pharmacokinetics is higher when provided with MAG-OM3 compared to CoQ10 alone (in powder form) or added to rice oil (a neutral triacylglycerol oil). A randomised triple-blind crossover study was performed with fifteen men and fifteen women consuming the three supplements providing 200 mg of CoQ10 in a random order. Blood samples were collected before (t = 0) and 1, 3, 5, 6, 7, 8, 10, 11, 24 and 48 h after the supplement intake. Plasma total CoQ10 concentrations were analysed on ultrahigh-performance liquid chromatography coupled to a tandem mass spectrometer (UPLC-MS/MS). Participants were 26⋅1 ± 4⋅8 years old. When CoQ10 was provided with rice or MAG-OM3 oils, the 48 h area under the curve (AUC 0-48 h) was approximately two times higher compared to when provided without an oil. The delta max concentration (ΔCmax) of plasma CoQ10 was, respectively, 2 (MAG-OM3) and 2⋅5 (rice oil) times higher compared to CoQ10 alone. There was a significant sex by treatment interaction (P = 0⋅0250) for the AUC 0-6 h supporting that in postprandial, men and women do not respond the same way to the different supplement. Women had a higher CoQ10 concentration 48 h after the single-dose intake compared to men. We conclude that CoQ10 supplements must be provided with lipids, and their kinetics is different between men and women.

[Effects of Interaction between PM2.5 and O 3 8-h max on Mortality of Cardiovascular Diseases in Chengdu].

OBJECTIVE: To explore the health risks of the interactive effects between PM2.5 and ozone on cardiovascular mortality in Chengdu. METHODS: Daily data on the mortality of cardiovascular diseases, including data for both men and women, during 2014-2016 were collected. The meteorological data, the daily average of particulate matter with aerodynamic diameter less than 2.5 micrometers (PM2.5), and the daily ozone 8 h maximum concentration (O 3 8-h max) in Chengdu of the same period were also collected. Generalized Additive Models (GAMs) were adopted to explore the respective adverse health effects of PM2.5 and O 3 8-h max and the synergistic effects between PM2.5 and O 3 8-h max on the mortality of cardiovascular diseases in the city. RESULTS: The highest health risks of PM2.5 and O 3 8-h max for mortality of cardiovascular diseases were found to be the strongest for the cumulative effect of the lag of one day (lag01). For every 10 µg/m 3 increment in the mass concentration of PM2.5 (lag01), the associated increase in risks for total, male, and female cardiovascular mortalities was 0.35%, 0.26% and 0.38%, respectively. For every 10 µg/m 3 increment in the mass concentration of O 3 8-h max (lag01), the associated increase in risks for total, male, and female cardiovascular mortalities was 0.66%, 0.43%, and 1.05%, respectively. The total, male, and female cardiovascular mortalities all reached their maximum values when high concentration of PM2.5 coexisted with high concentrations of O 3 8-h max. CONCLUSION: There was a synergistic amplification effect between high concentrations of PM2.5 and high concentrations of O 3 8-h max on cardiovascular mortality.

Pharmaceutical strategies to extend pulmonary exposure of inhaled medicines.

Pulmonary administration route has been extensively exploited for the treatment of local lung diseases such as asthma, chronic obstructive pulmonary diseases and respiratory infections, and systemic diseases such as diabetes. Most inhaled medicines could be cleared rapidly from the lungs and their therapeutic effects are transit. The inhaled medicines with extended pulmonary exposure may not only improve the patient compliance by reducing the frequency of drug administration, but also enhance the clinical benefits to the patients with improved therapeutic outcomes. This article systematically reviews the physical and chemical strategies to extend the pulmonary exposure of the inhaled medicines. It starts with an introduction of various physiological and pathophysiological barriers for designing inhaled medicines with extended lung exposure, which is followed by recent advances in various strategies to overcome these barriers. Finally, the applications of the inhaled medicines with extended lung exposure for the treatment of various diseases and the safety concerns associated to various strategies to extend the pulmonary exposure of the inhaled medicines are summarized.

Adamantinomatous craniopharyngioma associated with a compromised blood-brain barrier: patient series.

BACKGROUND: Adamantinomatous craniopharyngioma (ACP) is a highly morbid adult and pediatric brain tumor derived from epithelial remnants of the craniopharyngeal canal (Rathke's pouch), which gives rise to the anterior pituitary gland. Standard therapy includes maximal safe resection with or without radiation therapy. Systemic antitumor therapy remains elusive. Immune-related paracrine signaling involving the interleukin-6 receptor (IL-6R) may contribute to ACP pathogenesis. Tocilizumab, a recombinant humanized monoclonal antibody against IL-6R, is approved by the US Food and Drug Administration but does not cross an intact blood-brain barrier. OBSERVATIONS: In a phase 0 trial design, a single dose of tocilizumab was delivered intravenously before clinically indicated surgical intervention in 3 children with ACP. The presence of tocilizumab was assayed in plasma, tumor tissue, tumor cyst fluid, and cerebrospinal fluid (n = 1) using a novel enzyme-linked immunosorbent assay. Tocilizumab reached ACP tumor tissue and/or cyst fluid after one systemic dose in every patient. LESSONS: This finding helps explain extant data that indicate tocilizumab may contribute to ACP therapy. It further indicates that ACP does not reside behind an intact blood-brain barrier, dramatically broadening the range of potential antitumor therapies against this tumor. This has substantial implications for the design of future clinical trials for novel therapies against ACP in both children and adults.

Design, synthesis and pharmacological evaluation of 4-(3-chloro-4-(3-cyclopropylthioureido)-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (WXFL-152): a novel triple angiokinase inhibitor for cancer therapy.

Angiokinases, such as vascular endothelial-, fibroblast- and platelet-derived growth factor receptors (VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinase inhibitor has achieved great success in recent years. In this study, we presented the design, synthesis, target identification, molecular mechanism, pharmacodynamics (PD) and pharmacokinetics (PK) research of a novel triple-angiokinase inhibitor WXFL-152. WXFL-152, identified from a series of 4-oxyquinoline derivatives based on a structure-activity relationship study, inhibited the proliferation of vascular endothelial cells (ECs) and pericytes by blocking the angiokinase signals VEGF/VEGFR2, FGF/FGFRs and PDGF/PDGFRß simultaneously in vitro. Significant anticancer effects of WXFL-152 were confirmed in multiple preclinical tumor xenograft models, including a patient-derived tumor xenograft (PDX) model. Pharmacokinetic studies of WXFL-152 demonstrated high favourable bioavailability with single-dose and continuous multi-dose by oral administration in rats and beagles. In conclusion, WXFL-152, which is currently in phase Ib clinical trials, is a novel and effective triple-angiokinase inhibitor with clear PD and PK in tumor therapy.

Predictors of Systemic Exposure to Topical Crisaborole: A Nonlinear Regression Analysis.

Crisaborole ointment, 2%, is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild to moderate atopic dermatitis. Results from 2 randomized, double-blind, vehicle-controlled phase 3 studies showed that twice-daily crisaborole in children and adults with mild to moderate atopic dermatitis was efficacious and well tolerated. Initial pharmacokinetics (PK) studies of crisaborole indicated absorption with measurable systemic levels of crisaborole. The current analysis was conducted to correlate steady-state systemic exposure parameters with ointment dose and identify covariates impacting PK parameters in healthy participants and patients with atopic dermatitis or psoriasis. A nonlinear regression analysis was conducted using ointment dose and noncompartmental PK parameters at steady state (area under the curve [AUCss ] and maximum concentration [Cmax,ss ]). PK data were available from 244 participants across 6 clinical studies (AUCss , N = 239; Cmax,ss , N = 241). Disease condition had the greatest impact on slope in both models, corresponding to 2.5-fold higher AUCss and Cmax,ss values at a given ointment dose in patients with atopic dermatitis or psoriasis relative to healthy participants. Disease severity, race/ethnicity, and sex had marginal effects on AUCss and Cmax,ss . Systemic exposures were similar across age groups ≥2 years of age when the same percentage of body surface area (%BSA) was treated. Predictive performance plots for AUCss and Cmax,ss for different age groups demonstrated that the models adequately describe the observed data. Model predictions indicated that systemic exposure to crisaborole in pediatric patients (2-17 years) is unlikely to exceed systemic exposure in adults (≥18 years), even at the highest possible ointment dose corresponding to a %BSA of 90.

Gender effect on the pharmacokinetics of thymoquinone: Preclinical investigation and in silico modeling in male and female rats.

Thymoquinone is the most biologically active constituent of Nigella sativa (black seed). A monoterpene compound chemically known as 2-methyl-5-isopropyl-1, 4-quinone. In this study, the gender-dependent pharmacokinetic behavior of thymoquinone in rats was investigated. Thymoquinone was administered orally (20 mg/kg) and intravenously (5 mg/kg) to male and female rats and blood samples were collected at specific time points. Plasma concentration-time curves were plotted and pharmacokinetic parameters were determined using the non-compartmental analysis. In addition, simulations of steady state concentrations of thymoquinone in male and female rats were performed using GastroPlus PK software. After oral administration, the maximum plasma concentration (Cmax) of thymoquinone was 4.52 ±â€¯0.092 µg/ml in male rats and 5.22 ±â€¯0.154 µg/ml in female rats (p = 0.002). Similarly, after intravenous administration, the Cmax was 8.36 ±â€¯0.132 µg/ml in males and 9.51 ±â€¯0.158 µg/ml in females (p = 0.550). The area under the plasma concentration-time curve (AUC)0-∞ following oral dosing was 47.38 ±â€¯0.821 µg/ml·h in females and 43.63 ±â€¯0.953 µg/ml·h in males (p = 0.014). Pharmacokinetics and plasma concentration vs. time profiles for multiple oral doses of thymoquinone in rats were predicted using a simulation model to compare the simulation results with the experimental plasma pharmacokinetic data. The differences observed in thymoquinone pharmacokinetics between male and female rats after a single dose were not evident for the simulated steady-state parameters. The findings suggest that the gender difference does not seem to play a significant role in thymoquinone disposition at steady state.

Impact of chemical modification of sulfamidase on distribution to brain interstitial fluid and to CSF after an intravenous administration in awake, freely-moving rats.

Mucopolysaccharidosis III A (MPS IIIA) is an autosomal recessive lysosomal storage disorder caused by deficiency of the enzyme sulfamidase. The disorder results in accumulation of heparan sulfate, lysosomal enlargement and cellular and organ dysfunction. Patients exhibit progressive neurodegeneration and behavioral problems and no treatment is currently available. Enzyme replacement therapy is explored as potential treatment strategy for MPS IIIA patients and to modify the disease, sulfamidase must reach the brain. The glycans of recombinant human sulfamidase (rhSulfamidase) can be chemically modified to generate CM-rhSulfamidase. The chemical modification reduced the affinity to the cation-independent mannose-6-phosphate receptor with the aim a prolonged higher concentration in circulation and thus at the blood brain barrier. The pharmacokinetic properties in serum and the distribution to brain and to cerebrospinal fluid (CSF) of chemically modified recombinant human sulfamidase (CM-rhSulfamidase) were studied and compared to those of rhSulfamidase, after a single intravenous (i.v.) 30 mg/kg dose in awake, freely-moving male Sprague Dawley rats. Distribution to brain was studied by microdialysis of the interstitial fluid in prefrontal cortex and by repeated intra-individual CSF sampling from the cisterna magna. Push-pull microdialysis facilitated sampling of brain interstitial fluid to determine large molecule concentrations in awake, freely-moving male Sprague Dawley rats. Together with repeated serum and CSF sampling, push-pull microdialysis facilitated determination of CM-rhSulfamidase and rhSulfamidase kinetics after i.v. administration by non-compartments analysis and by a population modelling approach. Chemical modification increased the area under the concentration versus time in serum, CSF and brain interstitial fluid at least 7-fold. The results and the outcome of a population modelling approach of the concentration versus time data indicated that both compounds pass the BBB with an equilibrium established fairly rapid after administration. We suggest that prolonged high serum concentrations facilitated high brain interstitial fluid concentrations, which could be favorable to reach various target cells in the brain.

Design, synthesis, and biological evaluation of novel tetrahydroprotoberberine derivatives (THPBs) as proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators for the treatment of hyperlipidemia.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) modulators may attenuate PCSK9-induced low-density lipoprotein receptor (LDLR) degradation in lysosome and promote the clearance of circulating low-density lipoprotein cholesterol (LDL-C). A novel series of tetrahydroprotoberberine derivatives (THPBs) were designed, synthesized, and evaluated as PCSK9 modulators for the treatment of hyperlipidemia. Among them, eight compounds exhibited excellent activities in downregulating hepatic PCSK9 expression better than berberine in HepG2 cells. In addition, five compounds 15, 18, 22, (R)-22, and (S)-22 showed better performance in the low-density lipoprotein, labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanine perchlorate (DiI-LDL) uptake assay, compared with berberine at the same concentration. Compound 22, selected for in vivo evaluation, demonstrated significant reductions of total cholesterol (TC) and LDL-C in hyperlipidemic hamsters with a good pharmacokinetic profile. Further exploring of the lipid-lowering mechanism showed that compound 22 promoted hepatic LDLR expression in a dose-dependent manner in HepG2 cells. Additional results of human ether-à-go-go related gene (hERG) inhibition assay indicated the potential druggability for compound 22, which is a promising lead compound for the development of PCSK9 modulator for the treatment of hyperlipidemia.

Development of marine water quality criteria for inorganic mercury in China based on the retrievable toxicity data and a comparison with relevant criteria or guidelines.

The development of marine water quality criteria (WQC) in China has been insufficient because data on the toxicity of pollutants for marine organisms based on the species sensitivity distribution (SSD) method are lacking. The Chinese aquatic environmental quality standards, including those for seawater, were derived from the developed countries. Therefore, establishing Chinese marine WQC is crucial for identifying the sensitivity of marine species in China and will improve their protection from threats. Mercury (Hg) is one of the primary pollutants commonly exceeding Chinese seawater quality standards. Several countries have developed their marine WQC for inorganic Hg in the past decades, but no study has been conducted in China. In this study, 45 acute toxicity and 14 chronic toxicity data of inorganic Hg on the marine species which inhabit in China were obtained mainly from the ECOTOX database, the CNKI, and the Google Scholar. The acute and chronic hazardous concentrations for 5% of the species (HC5) were calculated based on the best-fit distribution model Sweibull. The criteria for maximum and continuous concentrations of 1.30 and 0.66 µg/L, respectively, for inorganic Hg to protect marine organisms in China were derived by halving the HC5 values. The criteria were comparable to those of the United States, Australia, and the European Union countries, indicating the general applicability of WQCs developed based on the classical SSD method using different species groups. This study may provide valuable information for assessing marine ecological risk in China.

Influence of chitosan coating on the oral bioavailability of gold nanoparticles in rats.

Gold nanoparticles are one of the most extensively investigated metallic nanoparticles for several applications. It is less toxic than other metallic nanolattices. The exceptional electrical and thermal conductivity of gold make it possible to be administered as non-invasive radiofrequency irradiation therapy that produces sufficient heat to kill tumor cells. Nanoparticles are generally administered intravenously instead of orally due to negligible oral absorption and cellular uptake. This study evaluated the oral bioavailability of gold nanoparticles coated with chitosan (C-AuNPs), a natural mucoadhesive polymer. We employed traditional method of evaluating bioavailability that involve estimation of maximum concentrations and area under the curve of 3 nm chitosan coated gold nanoparticles (C-AuNPs) in the rat plasma following intravenous and oral administrations (0.8 mg and 8 mg/kg body weight respectively). The oral bioavailability of C-AuNPs was found to be 2.46% (approximately 25 folds higher than polyethylene glycol (PEG) coated gold nanoparticles, reported earlier). These findings suggest that chitosan coating could be better than PEG coating for the enhancement of oral bioavailability of nanoparticles.

Pharmacokinetic data of synthetic cathinones in female Sprague-Dawley rats.

The synthetic cathinones methylone, butylone, and pentylone differ from each other through the one carbon lengthening of the α-alkyl chain: methylone (-CH3), butylone (-CH2CH3), and pentylone (-CH2CH2CH3) while 3,4-methylenedioxymethamphetamine (MDMA) differs from methylone by a single oxygen atom. Studies with MDMA, suggests that there may be male and female pharmacokinetic and pharmacodynamic differences. In the present study, we present the plasma pharmacokinetic data relative to a 20 mg/kg, subcutaneous doses of methylone, butylone and pentylone in female Sprague-Dawley rats. Briefly, plasma samples were collected via a jugular vein cannula, purified, and analyzed using a HPLC system. While we have previously reported on the consistent relationship between structure and pharmacokinetics of these synthetic cathinones in male, Sprague-Dawley rats (Grecco and Sprague, 2016), this data set suggests that there is no consistent relationship of chemical structure and pharmacokinetics of methylone, butylone and pentylone in female Sprague-Dawley rats. The findings from the present study further emphasize the need for the inclusion of female subjects in the pharmacokinetic studies of synthetic cathinones as it is very possible male-female differences may exist in rodent models.

Dose-proportional pharmacokinetic properties of GLA5PR GLARS-NF1 controlled-release pregabalin in healthy Korean volunteers: a randomized, open, single-dose, parallel study.

PURPOSE: The aim of this study was to evaluate the dose-proportional pharmacokinetic characteristics of pregabalin following the administration of GLA5PR GLARS-NF1 tablets (150, 300, 450, and 600 mg) in the fed state. SUBJECTS AND METHODS: An open-label, randomized, single-dose, parallel study was conducted in 40 eligible subjects who were randomly assigned to receive a single 150, 300, 450, or 600 mg dose of GLA5PR GLARS-NF1. Serial blood samples were collected before and after dosing for 36 hours, and plasma concentrations were determined using liquid chromatography-tandem mass spectrometry. Safety profiles were evaluated throughout the study (trial registration number: NCT02327000). RESULTS: Thirty-seven subjects completed the studies. The area under the plasma concentration-time curve up to the last measurable concentration of pregabalin exhibited dose proportionality following administration of GLA5PR GLARS-NF1 tablets from 150 to 600 mg while its maximum plasma concentration showed dose proportionality at a dose range of 150-450 mg. The safety evaluations showed no clinically significant finding after administration of GLA5PR GLARS-NF1 tablets (150, 300, 450, and 600 mg) in the fed state. CONCLUSIONS: The dose-proportional properties of GLA5PR GLARS-NF1 150-450 mg tablets were determined.

Water quality criteria derivation and ecological risk assessment for triphenyltin in China.

Triphenyltin (TPT) is one of the most toxic chemicals artificially discharged into aquatic environment with human activities. Due to its intensive use in antifouling paints and adverse effects on non-target species, TPT has aroused wide concern in both saltwater and freshwater environment. Nevertheless, the water quality criteria (WQC) are not available in China, which impedes the risk assessment for this emerging pollutant. This study aims to establish the WQC of TPT for both freshwater and saltwater ecosystems. With the derived WQC, a four-level tiered ecological risk assessment (ERA) approach was employed to assess the ecological risks of this emerging pollutant in Chinese waters. Through the species sensitivity distribution (SSD) methodology, the freshwater criterion maximum concentration (CMC) and criterion continuous concentration (CCC) were derived as 396 ng Sn L-1 and 5.60 ng Sn L-1, respectively, whereas the saltwater CMC and CCC were 66.5 ng Sn L-1 and 4.11 ng Sn L-1, respectively. The ecological risk assessment for TPT demonstrated that the acute risk was negligible whereas the chronic risk was significant with HQ (Hazard Quotient) values of up to 5.669 and 57.1% of coastal waters in China facing clear risk. TPT contamination in coastal environment, therefore, warrants further concern.

Time is spine: a review of translational advances in spinal cord injury.

Acute traumatic spinal cord injury (SCI) is a devastating event with far-reaching physical, emotional, and economic consequences for patients, families, and society at large. Timely delivery of specialized care has reduced mortality; however, long-term neurological recovery continues to be limited. In recent years, a number of exciting neuroprotective and regenerative strategies have emerged and have come under active investigation in clinical trials, and several more are coming down the translational pipeline. Among ongoing trials are RISCIS (riluzole), INSPIRE (Neuro-Spinal Scaffold), MASC (minocycline), and SPRING (VX-210). Microstructural MRI techniques have improved our ability to image the injured spinal cord at high resolution. This innovation, combined with serum and cerebrospinal fluid (CSF) analysis, holds the promise of providing a quantitative biomarker readout of spinal cord neural tissue injury, which may improve prognostication and facilitate stratification of patients for enrollment into clinical trials. Given evidence of the effectiveness of early surgical decompression and growing recognition of the concept that "time is spine," infrastructural changes at a systems level are being implemented in many regions around the world to provide a streamlined process for transfer of patients with acute SCI to a specialized unit. With the continued aging of the population, central cord syndrome is soon expected to become the most common form of acute traumatic SCI; characterization of the pathophysiology, natural history, and optimal treatment of these injuries is hence a key public health priority. Collaborative international efforts have led to the development of clinical practice guidelines for traumatic SCI based on robust evaluation of current evidence. The current article provides an in-depth review of progress in SCI, covering the above areas.