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SHPL-49 is an innovative glycoside derivative that is synthesized by structural modifications of salidrosideï¼demonstrating therapeutic effects on animal models of ischemia in pre-clinical experiments. A phase I, single-center, randomized, double-blind, placebo-controlled, single and multiple dose administration study of SHPL-49 was conducted in healthy Chinese volunteers. In single-ascending-dose (SAD) study, 32 subjects randomized 6:2 to receive SHPL-49 (30â¯mg, 75â¯mg, 150â¯mg, 300â¯mg) or placebo with 30â¯minutes infusion. In multiple-ascending-dose (MAD) study, subjects were randomized 6:2 to receive SHPL-49 (75â¯mg, 150â¯mg, 300â¯mg) or placebo with 30â¯minutes infusion every 8â¯h for 7 days. Safety evaluations were conducted throughout the studies. Plasma and urine concentrations of SHPL-49 were detected and its metabolites were identified. Pharmacokinetic parameters were calculated using noncompartmental methods. SHPL-49 was generally safe and well-tolerated at single ascending doses (30-300â¯mg) and multiple ascending doses (75-300â¯mg). All adverse events were mild and resolved without any intervention. No serious adverse events were reported. In the SAD study, SHPL-49 exhibited dose-proportional plasma pharmacokinetics, with peak plasma concentration (Cmax) ranging from 673.83 to 6275.00â¯ng/mL, area under the plasma concentration-time curve (AUC0-t) ranging from 338.57 to 3732.67â¯h·ng/mL, and elimination half-life (t1/2) ranging from 0.49 to 0.67â¯h. In the MAD, the exposure was also dose-proportional and there was no significant accumulation following multiple dosing. Four metabolites were identified in urine and plasma. SHPL-49 shows a favorable pharmacokinetic, safety, and tolerability profile in healthy Chinese volunteers following a single- and multiple-ascending- dose administration in this study. For future therapeutic investigations, it is recommended to administer SHPL-49 intravenously at 8-hour intervals with a dosage range of 150-300â¯mg.
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Relação Dose-Resposta a Droga , Voluntários Saudáveis , Humanos , Masculino , Método Duplo-Cego , Adulto , Adulto Jovem , Feminino , Área Sob a Curva , Infusões Intravenosas , Glicosídeos/farmacocinética , Glicosídeos/administração & dosagem , Glucosídeos/farmacocinética , Glucosídeos/administração & dosagem , Glucosídeos/sangue , Esquema de MedicaçãoRESUMO
Background: Epidermal growth factor receptor (EGFR) T790M mutation is the standard predictive biomarker for third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment. While not all T790M-positive patients respond to third-generation EGFR-TKIs and have a good prognosis, it necessitates novel tools to supplement EGFR genotype detection for predicting efficacy and stratifying EGFR-mutant patients with various prognoses. Mixture-of-experts (MoE) is designed to disassemble a large model into many small models. Meanwhile, it is also a model ensembling method that can better capture multiple patterns of intrinsic subgroups of enrolled patients. Therefore, the combination of MoE and Cox algorithm has the potential to predict efficacy and stratify survival in non-small cell lung cancer (NSCLC) patients with EGFR mutations. Methods: We utilized the electronic medical record (EMR) and pharmacokinetic parameters of 326 T790M-mutated NSCLC patients, including 283 patients treated with Abivertinib in phase I (n=177, for training) and II (n=106, for validation) clinical trials and an additional validation cohort 2 comprising 43 patients treated with BPI-7711. Furthermore, 18 patients underwent whole-exome sequencing for biological interpretation of CoxMoE. We evaluated the predictive performance for therapeutic response using the area under the curve (AUC) and the Concordance index (C-index) for progression-free survival (PFS). Results: CoxMoE exhibited AUCs of 0.73-0.83 for predicting efficacy defined by best overall response (BoR) and achieved C-index values of 0.64-0.65 for PFS prediction in training and validating cohorts. The PFS of 198 patients with a low risk [median, 6.0 (range, 1.0-23.3) months in the abivertinib treated cohort; median 16.5 (range, 1.4-27.4) months in BPI-7711 treated cohort] of being non-responder increased by 43% [hazard ratio (HR), 0.56; 95% confidence interval (CI), 0.40-0.78; P=0.0013] and 50% (HR, 0; 95% CI, 0-0; P=0.01) compared to those at high-risk [median, 4.2 (range, 1.0-35) months in the abivertinib treated cohort; median, 11.0 (range, 1.4-25.1) months in BPI-7711 treated cohort]. Additionally, activated partial thromboplastin time (APTT), creatinine clearance (Ccr), monocyte, and steady-state plasma trough concentration utilited to construct model were found significantly associated with drug resistance and aggressive tumor pathways. A robust correlation was observed between APTT and Ccr with PFS (log-rank test; P<0.01) and treatment response (Wilcoxon test; P<0.05), respectively. Conclusions: CoxMoE offers a valuable approach for patient selection by forecasting therapeutic response and PFS utilizing laboratory tests and pharmacokinetic parameters in the setting of early-phase clinical trials. Simultaneously, CoxMoE could predict the efficacy of third-generation EGFR-TKI non-invasively for T790M-positive NSCLC patients, thereby complementing existing EGFR genotype detection.
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Soil degradation has become a major global problem owing to the rapid development of agriculture. The problems of soil drought and decreased soil fertility caused by soil degradation severely affect the development of the agricultural and forestry industries. In this study, we designed sodium alginate (SA)/sodium lignosulfonate (SLS) hydrogel based on the activation and crosslinking of inert Ca2+. CaCO3 and SA were mixed, and then, inert Ca2+ was activated to prepare a gel with a stable structure and a uniform interior and exterior. The crosslinking activated by inert Ca2+ enhanced the stability of the hydrogel, and the optimal swelling rate of the hydrogel reached 28.91 g/g, thereby effectively improving the water-holding capacity of the soil (77.6-108.83 g/kg). SLS was degraded into humic acid (HA) and gradually released, demonstrating a positive growth-promoting effect in plant growth experiments. The SA/SLS hydrogel can be used for soil water retention and mitigation to significantly decrease the water loss rate of soil. This study will assist in addressing soil drought and fertility loss.
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Conservação dos Recursos Hídricos , Hidrogéis , Lignina/análogos & derivados , Hidrogéis/química , Alginatos/química , Solo/química , Água/química , SódioRESUMO
The accumulation of contaminants in sediments is accelerated by human activities and poses a major threat to ecosystems and human health. In recent years, various remediation techniques have been developed for contaminated sediments. In this review, a bibliometric analysis of papers on sediment remediation indexed in the WOS database between 2009 and 2023 was conducted using VOSviewer. We describe the development of biochar and plants for sediment contaminant removal. However, the single processes of biochar remediation and phytoremediation can be impeded by (i) low efficiency, (ii) poor tolerance of plants towards pollutants, (iii) difficulty in biochar to degrade pollutants, and (iv) biochar aging causing secondary pollution. Fortunately, combination remediation, realized through the combination of biochar and plants, can overcome the shortcomings of their individual applications. Therefore, we suggest that the remediation of contaminants in sediments can be accomplished by combining biochar with macrophytes and considering multiple limiting factors. Here, we explore the challenges that co-remediation with biochar and macrophytes will face in achieving efficient and sustainable sediment remediation, including complex sediment environments, interaction mechanisms of biochar-macrophyte-microorganisms, emerging pollutants, and integrated life cycle assessments, which can provide references for combined biochar and plant remediation of sediments in the future.
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Poluentes Ambientais , Recuperação e Remediação Ambiental , Poluentes do Solo , Humanos , Biodegradação Ambiental , Ecossistema , Estudos de Viabilidade , Carvão Vegetal , SoloRESUMO
Metal phosphides with multi-element components and amorphous structure represent a novel kind of electrocatalysts for promising activity and durability towards the oxygen evolution reaction (OER). In this work, a two-step strategy, including alloying and phosphating processes, is reported to synthesize trimetallic amorphous PdCuNiP phosphide nanoparticles for efficient OER under alkaline conditions. The synergistic effect between Pd, Cu, Ni, and P elements, as well as the amorphous structure of the obtained PdCuNiP phosphide nanoparticles, would boost the intrinsic catalytic activity of Pd nanoparticles towards a wide range of reactions. These obtained trimetallic amorphous PdCuNiP phosphide nanoparticles exhibit long-term stability, nearly a 20-fold increase in mass activity toward OER compared with the initial Pd nanoparticles, and 223 mV lower in overpotential at 10 mA cm-2. This work not only provides a reliable synthetic strategy for multi-metallic phosphide nanoparticles, but also expands the potential applications of this promising class of multi-metallic amorphous phosphides.
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In this study, to improve the soil amendment performance of film materials, composite films with the adjustable number of layers and controlled slow-release time were prepared using sodium alginate (SA), chitosan (CS) and activated charcoal (AC) as raw materials. The prepared multilayer films exhibited a wide pH response range and excellent slow-release time. The cumulative release of humic acid (HA) increased from 19.87 ± 0.98% to 66.72 ± 1.06% with increasing the pH from 4.0 to 10.0 after 700 h of slow-release. In addition, after 50 d of remediation in red soil, plantation soil, and saline soil, the NH4+-N, Olsen-P, Olsen-K, and organic matter contents in the three soils were increased by 2.91-28.62 mg/kg, 46.97-70.43 mg/kg, 55.89-77.01 mg/kg, and 12.47-22.52 g/kg, respectively, and were able to provide sustained crop growth promotion effect. This study demonstrates the promising application of multilayer film in soil remediation and agricultural production.
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Poluentes do Solo , Solo , Solo/química , Substâncias Húmicas/análise , Carvão Vegetal/química , Agricultura , Poluentes do Solo/análiseRESUMO
Formaldehyde-free epoxidized soybean oil-based resin has been prepared under acidic conditions by co-condensation of the epoxidized soybean oil and condensed tannin originating from agricultural and forestry sources as the main raw materials, whereas 1,6-hexanediamine was employed as a cross-linking agent. Fourier transform infrared spectroscopy (FTIR) and electrospray ionization (ESI) corroborated that tannin and epoxidized soybean oil underwent crosslinking under acidic conditions supported by hexamethylenediamine. A bio-based grinding wheel was fabricated by formulation of the developed resin with wood powder as source of grinding particles. The appearance, hardness, compressive strength and wear resistance of the resulting grinding wheel were studied. The results have shown that the grinding wheel possesses a smooth surface with no bubbles or cracks, and its hardness and wear resistance were greater than that of a phenolic resin-based grinding wheel. Interestingly, the grinding wheel incorporates more than 90% of its raw materials as biomass renewable materials; thus, it is generally considered non-toxic. In addition, the future feasibility of this approach to replace some petrochemical resins that are frequently used in the fabrication of grinding wheels is considered.
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The large-scale application of direct ethanol fuel cells has long been obstructed by the sluggish ethanol oxidation reaction at the anode. Current wisdom for designing and fabricating EOR electrocatalysts has been focused on crystalline materials, which result in only limited improvement in catalytic efficiency. Here, we report the amorphous PdCu (a-PdCu) nanomaterials as superior EOR electrocatalysts. The amorphization of PdCu catalysts can significantly facilitate the C-C bond cleavage, which thereby affords a C1 path faradic efficiency as high as 69.6%. Further tailoring the size and shape of a-PdCu nanocatalysts through the delicate kinetic control can result in a maximized mass activity up to 15.25 A/mgPd, outperforming most reported catalysts. Notably, accelerated durability tests indicate that both the isotropic structure and one-dimensional shape can dramatically enhance the catalytic durability of the catalysts. This work provides valuable guidance for the rational design and fabrication of amorphous noble metal-based electrocatalysts for fuel cells.
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Layered double hydroxides (LDHs) often require the use of carbon materials to improve their stability, conductivity, and specific surface area to accommodate new directions in the development of high-performance energy storage materials. Herein, 2D nickel cobalt layered double hydroxide (NCLDH) nanosheets are regulated to form 3D flower-like spheres by fungus bran-derived carbon dots (CDs) via an in situ growth method. The prepared sample (CDs/NCLDH) shows abundant accessible active sites and favorable electrical conductivity, which is aided by strong interactions between CDs and NCLDH. The optimized CDs/NCLDH exhibits significantly enhanced electrochemical performances, including ultrahigh specific capacitance (2100F g-1 at 1 A g-1) and a great rate capability, which are two times higher than those of the NCLDH electrode. Additionally, the asymmetric supercapacitor device assembled with the CDs/NCLDH positive electrode and the fungus bran-derived activated carbon (FBC) negative electrode achieves a superior energy density of 52.5 Wh kg-1 at an ultrahigh powder density of 750 W kg-1. With their simple synthesis method and excellent electrochemical performance, the role of the CDs provides new insights for the development of LDHs with improved performance.
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Hidróxidos , Níquel , Biomassa , Cobalto/química , Eletrodos , Hidróxidos/química , Níquel/químicaRESUMO
Calcium-dependent, neuronal adenylyl cyclase subtype 1 (AC1) is critical for cortical potentiation and chronic pain. NB001 is a first-in-class drug acting as a selective inhibitor against AC1. The present study delineated the pharmacokinetic (PK) properties of human-used NB001 (hNB001) formulated as immediate-release tablet. This first-in-human (FIH) study was designed as randomized, double-blind, placebo-controlled trial. hNB001 showed placebo-like safety and good tolerability in healthy volunteers. A linear dose-exposure relationship was demonstrated at doses between 20 mg and 400 mg. The relatively small systemic exposure of hNB001 in human showed low bioavailability of this compound through oral administration, which can be improved through future dosage research. Food intake had minimal impact on the absorption of hNB001 tablet. Animal experiments further confirmed that hNB001 had strong analgesic effect in animal models of neuropathic pain. In brain slice prepared from the anterior cingulate cortex (ACC), bath application of hNB001 blocked the induction of long-term potentiation (LTP). These results from both rodents and human strongly suggest that hNB001 can be safely used for the future treatment of different types of chronic pain in human patients.
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Trifosfato de Adenosina , Inibidores de Adenilil Ciclases , Adenilil Ciclases , Dor Crônica , Neuralgia , Trifosfato de Adenosina/administração & dosagem , Trifosfato de Adenosina/efeitos adversos , Trifosfato de Adenosina/análogos & derivados , Inibidores de Adenilil Ciclases/administração & dosagem , Inibidores de Adenilil Ciclases/efeitos adversos , Adenilil Ciclases/metabolismo , Dor Crônica/tratamento farmacológico , Dor Crônica/enzimologia , Giro do Cíngulo/metabolismo , Humanos , Neuralgia/tratamento farmacológico , Neuralgia/enzimologiaRESUMO
To find a cocatalyst that can replace noble metals, fungal carbon dot (CD) modified molybdenum disulfide (MoS2) cocatalyst system was designed. The composites were prepared by hydrothermal and calcination methods with different ratios of CDs, MoS2 and nitrogen-rich carbon nitride (p-C3N5). p-C3N5 has excellent electronic properties, and MoS2 modified by CDs (D-MoS2) can significantly enhance the photocatalytic performance of p-C3N5 by improving the photogenerated electron migration efficiency. The experiments showed that the developed CDs/MoS2/C3N5 composites exhibited excellent performance in both photocatalytic hydrogen (H2) evolution and methylene blue (MB) degradation, with CMSCN5 (D-MoS2 with 5% mass fraction) showing the best photocatalytic activity. The corresponding H2 evolution rate of CMSCN5 was 444 µmol g-1h-1 and 1.45 times higher than that of unmodified p-C3N5, by 120 min, the removal rate of MB was up to 93.51%. The 5 cycle tests showed that CMSCN5 had great stability. The high charge mobility and high density of H2 evolution active sites of MoS2 nanosheets, together with the electron storage and transfer properties of CDs can obviously improve electron migration and reduce the photogenerated carrier recombination on the p-C3N5 surface. The design and preparation of such composites offer broad prospects for the development of photocatalytic systems with noble metal-free cocatalysts.
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Carbono , Molibdênio , Catálise , Dissulfetos , Elétrons , Nitrilas , NitrogênioRESUMO
A novel N-rich sugarcane-like photocatalyst CdS/C3N5 (CCN) was prepared by a thermal polymerization method and tested for generating H2 and realizing antiphotocorrosive performance. The best photocatalytic H2 evolution is obtained for a CdS to C3N5 mass ratio of 1:1 (CCN3), which is nearly 33 and 3 times higher than that of pure C3N5 and CdS, respectively. CCN3 can be used to effectively reduce CdS photocorrosion and increase stability because of its N-rich performance and sugarcane-like structure, which can affect electron transport and enhance the internal binding force, respectively. CCN3 can maintain a high H2 evolution ability after 5 cycles, while still maintaining the original sugarcane-like shape, which has an anti-photocorrosive ability.
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Hidrogênio , Nitrogênio , Biomimética , Compostos de Cádmio , Catálise , Luz , SulfetosRESUMO
In this work, pH-responsive gel spheres for controlled release of humic acid (CSGCHs) were prepared by an integrated instillation technology using a composite material of sodium alginate (SA) and charcoal activated carbon (CAC) as a carrier, and their slow-release performance, pH-responsive performance, and soil amendment performance were investigated. The results showed that the prepared CSGCH was uniform in size with obvious base responsiveness. Soil remediation experiments revealed that CSGCH could play a good role in the remediation of different types of soils. After 50 days of remediation, the content of nutrients and organic matter in the soil increased significantly and the pH and salt content of saline soils decreased by 15.2 and 29.8%, respectively. The plant experiment showed that CSGCH could effectively promote the growth of crops. Therefore, the prepared soil conditioner has a great potential value for improving soil conditions and promoting crop growth in agricultural applications.
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Carvão Vegetal , Poluentes do Solo , Alginatos , Biomassa , Preparações de Ação Retardada , Substâncias Húmicas , Concentração de Íons de Hidrogênio , Solo , Poluentes do Solo/análise , TecnologiaRESUMO
Platinum (Pt) has found wide use as an electrocatalyst for sustainable energy conversion systems1-3. The activity of Pt is controlled by its electronic structure (typically, the d-band centre), which depends sensitively on lattice strain4,5. This dependence can be exploited for catalyst design4,6-8, and the use of core-shell structures and elastic substrates has resulted in strain-engineered Pt catalysts with drastically improved electrocatalytic performances7,9-13. However, it is challenging to map in detail the strain-activity correlations in Pt-catalysed conversions, which can involve a number of distinct processes, and to identify the optimal strain modification for specific reactions. Here we show that when ultrathin Pt shells are deposited on palladium-based nanocubes, expansion and shrinkage of the nanocubes through phosphorization and dephosphorization induces strain in the Pt(100) lattice that can be adjusted from -5.1 per cent to 5.9 per cent. We use this strain control to tune the electrocatalytic activity of the Pt shells over a wide range, finding that the strain-activity correlation for the methanol oxidation reaction and hydrogen evolution reaction follows an M-shaped curve and a volcano-shaped curve, respectively. We anticipate that our approach can be used to screen out lattice strain that will optimize the performance of Pt catalysts-and potentially other metal catalysts-for a wide range of reactions.
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Noble metal-based nanomaterials with amorphous structures are promising candidates for developing efficient electrocatalysts. However, their synthesis remains a significant challenge, especially under mild conditions. In this paper, we report a general strategy for preparing amorphous PdM nanowires (a-PdM NWs, M = Fe, Co, Ni, and Cu) at low temperatures by exploiting glassy non-noble metal (M) nuclei generated by special ligand adsorption as the amorphization dictator. When evaluated as electrocatalysts toward formic acid oxidation, a-PdCu NWs can deliver the mass and specific activities as high as 2.93 A/mgPd and 5.33 mA/cm2, respectively; these are the highest values for PdCu-based catalysts reported thus far, far surpassing the crystalline-dominant counterparts and commercial Pd/C. Theoretical calculations suggest that the outstanding catalytic performance of a-PdCu NWs arises from the amorphization-induced high surface reactivity, which can efficiently activate the chemically stable C-H bond and thereby significantly facilitate the dissociation of HCOOH.
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As an excellent electrocatalyst, platinum (Pt) is often deposited as a thin layer on a nanoscale substrate to achieve high utilization efficiency. However, the practical application of the as-designed catalysts has been substantially restricted by the poor durability arising from the leaching of cores. Herein, by employing amorphous palladium phosphide (a-Pd-P) as substrates, we develop a class of leaching-free, ultrastable core-shell Pt catalysts with well-controlled shell thicknesses and surface structures for fuel cell electrocatalysis. When a submonolayer of Pt is deposited on the 6 nm nanocubes, the resulting Pd@a-Pd-P@PtSML core-shell catalyst can deliver a mass activity as high as 4.08 A/mgPt and 1.37 A/mgPd+Pt toward the oxygen reduction reaction at 0.9 V vs the reversible hydrogen electrode and undergoes 50â¯000 potential cycles with only â¼9% activity loss and negligible structural deformation. As elucidated by the DFT calculations, the superior durability of the catalysts originates from the high corrosion resistance of the disordered a-Pd-P substrates and the strong interfacial Pt-P interactions between the Pt shell and amorphous Pd-P layer.
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Titanium dioxide (TiO2) was prepared from four natural wood spices that served as templates. The wood templates were impregnated by a titanium dioxide precursor and then underwent high-temperature calcination to obtain TiO2 with a wood-like hierarchical porous structure. The microstructure of TiO2 based on the wood template was characterized by scanning electron microscopy, X-ray diffraction and nitrogen adsorption-desorption tests. The formaldehyde adsorption and degradation properties of TiO2 based on a wood template are discussed. The results showed that TiO2 based on a wood template could effectively replicate the micro- and mesoscopic pore structure of wood, and the pore size distribution in the TiO2 ranged from 1 to 100 nm. The TiO2 that was prepared based on a wood template showed a certain adsorption effect on formaldehyde under visible light, and the photocatalytic degradation of a formaldehyde solution was achieved when irritated by ultraviolet light. In addition, the properties of the TiO2 prepared by different tree species was also different. The TiO2 prepared by larch and Chinese fir exhibited a large specific surface area, pore volume, and high degradation efficiency of formaldehyde solution. After 280 min of irradiation with an ultraviolet light source, the degradation rates of the formaldehyde solution were 19.91% and 18.85%.
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In studying indoor air quality, the concentration of volatile organic compounds (VOCs) emitted from wood-based panels and products is considered a main influencing factor. VOCs with low concentrations, even below the detection limit, can also have negative effects. Herein, VOCs emitted from particleboards and laminated boards were collected and analysed by GC-MS, and key odorous VOCs were identified using the odor activity value. Compared with laminated boards, particleboards showed higher concentration of total volatile organic compound (TVOC). Halogenated compounds, esters, and aromatic hydrocarbons were main contributors to total VOC emissions, which could relate to the addition of additives used during panel manufacturing. Eleven VOCs were identified that listed as hazardous air pollutants in the US Clean Air Act. Aldehydes were the major contributor to the OAV; most aldehydes have unpleasant odors, such as fatty acids, which contribute to the smell of surrounding air. Octanal was the dominant odorant in the aldehyde compounds.
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Poluentes Atmosféricos , Monitoramento Ambiental , Compostos Orgânicos Voláteis , Madeira , Poluição do Ar em Ambientes Fechados , OdorantesRESUMO
PURPOSE: SPT-07A is an intravenous injection of (+)-2-borneol being developed for the treatment of acute ischemic stroke. This study aimed to investigate the pharmacokinetics, pharmacodynamics, safety, tolerability, and mass balance of SPT-07A after sequentially administered single and multiple infusions of SPT-07A at 10 mg, 20 mg, or 40 mg. METHODS: This phase I, double-blind, randomized, placebo-controlled, dose-escalation study was conducted in 36 Chinese healthy volunteers. Each cohort enrolled 12 eligible subjects, who were 9:3 randomized to receive SPT-07A or matching placebo during the two study occasions, that is, an initial single-dose occasion followed by a 7-day multiple-dose occasion with a dosing interval of 12 h. Pharmacokinetic, pharmacodynamic assessments regarding effects on the central nervous system (CNS) were performed pre-dose and several times post-dose. Safety and tolerability were evaluated throughout the study for each cohort. RESULTS: Following single intravenous (i.v.) administration of 10 mg to 40 mg SPT-07A, the plasma SPT-07A concentration reached its peak by the end of infusion. Thereafter, the plasma concentration declined in a multiphase exponential manner with an average terminal elimination half-life of 3.85 to 8.93 h. The exposure parameters of SPT-07A increased dose proportionally. Steady state of SPT-07A was reached after 12-hourly i.v. administrations for 4 days with minimal accumulations. No significant difference of change-from-baseline was observed in the pharmacodynamic measurements between each of the three SPT-07A-treated groups and the placebo group. A total of 41 adverse events (AEs) were reported in 77.8% subjects at 10 mg (7/9), 20 mg (7/9), and 40 mg (7/9), respectively. The AE incidence in placebo group was also 77.8% (7/9). All AEs were mild or moderate in severity and self-limited. SPT-07A was mainly excreted in human urine in glucuronic acid conjugate forms. The total urine recovery rate approximated 84.69% of the administered dose. CONCLUSIONS: SPT-07A was safe and well tolerated after single and multiple intravenous administrations of SPT-07A in the range of 10 mg to 40 mg. SPT-07A presented linear pharmacokinetics in human. Based on plasma exposure, the doses of 10-40 mg twice daily resulted in exposure levels comparable with those obtained at doses demonstrating potential efficacy on AIS animal models and were thus recommended as therapeutic exploratory doses in the phase II clinical trial.
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Canfanos/farmacologia , Canfanos/farmacocinética , Acidente Vascular Cerebral/tratamento farmacológico , Adulto , Canfanos/efeitos adversos , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Infusões IntravenosasRESUMO
Abivertinib represents a highly selective irreversible epidermal growth factor receptor tyrosine kinase inhibitor. Two major metabolites of abivertinib, M7 and MII-6, were detected in human plasma, which are recommended to be monitored for safety reasons in clinical trial. A high-throughput quantification method utilizing liquid chromatography-tandem mass spectrometry was designed and verified to quantify abivertinib's primary metabolites in human plasma. Solid-phase extraction was used to process the plasma, and then the analytes underwent a gradient elution separation in an Aquity UPLC BEH C18 column (1.7 µm, 2.1 × 50 mm) with mobile phase A (10 mm ammonium acetate containing 0.1% formic acid) and mobile phase B (methanol-acetonitrile, 2:8, v/v, with 0.1% formic acid). Ion transitions of M7 (m/z 490.2 â 405.1) and MII-6 (m/z 476.2 â 391.1) were monitored under multiple reaction monitoring mode and electrospray ionization in positive ion mode. This simultaneous determination method was found to have acceptable precision, accuracy and linearity in the 0.5-500 ng/mL range for M7 and the 0.5-500 ng/mL range for MII-6, accompanied by a mild matrix effect but high recovery. Further stability assessments indicated that both analytes remained stable throughout the entire experimental process from harvesting whole blood to plasma extraction and analysis.