UNASSIGNED: Intranasal insulin (INI) is being explored as a treatment for Alzheimer\'s disease (AD). Improved memory, functional ability, and cerebrospinal fluid (CSF) AD biomarker profiles have been observed following INI administration. However, the method of intranasal delivery may significantly affect outcomes.
UNASSIGNED: To show reliable delivery of insulin to the brain using the Aptar Cartridge Pump System (CPS) intranasal delivery system.
UNASSIGNED: To visualize INI biodistribution, we developed a novel PET radiotracer, Gallium 68-radiolabeled (NOTA-conjugated) insulin, [68Ga]Ga-NOTA-insulin. We used the Aptar CPS to administer [68Ga]Ga-NOTA-insulin to anesthetized healthy adult vervet monkeys and measured brain regional activity and whole-body dosimetry following PET/CT scans.
UNASSIGNED: We observed brain penetration of [68Ga]Ga-NOTA-insulin following intranasal administration with the Aptar CPS. Radioactive uptake was seen in multiple regions, including the amygdala, putamen, hypothalamus, hippocampus, and choroid plexus. A safety profile and whole-body dosimetry were also established in a second cohort of vervets. Safety was confirmed: vitals remained stable, blood glucose levels were unchanged, and no organ was exposed to more than 2.5 mSv of radioactivity. Extrapolations from vervet organ distribution allowed for estimation of the [68Ga]Ga-NOTA-insulin absorbed dose in humans, and the maximum dose of [68Ga]Ga-NOTA-insulin that can be safely administered to humans was determined to be 185 MBq.
UNASSIGNED: The use of [68Ga]Ga-NOTA-insulin as a PET radiotracer is safe and effective for observing brain uptake in vervet monkeys. Further, the Aptar CPS successfully targets [68Ga]Ga-NOTA-insulin to the brain. The data will be essential in guiding future studies of intranasal [68Ga]Ga-NOTA-insulin administration in humans.

Parabens are alkyl esters of p-hydroxybenzoic acid that are commonly used as preservatives in personal care products such as cosmetics. Recent studies have revealed the presence of parabens in surface and tap water because of their use as disinfection products; however, little is known about their occurrence in biological samples and their bioaccumulation potential, particularly in raptor birds known as sentinels for pollutant detection. We examined the occurrence and tissue distribution of parabens, their metabolites, and halogenated byproducts in the liver, kidney, brain, and muscle of birds of prey from Texas and North Carolina (USA). Methylparaben (MeP), propylparaben (PrP), and butylparaben (BuP) were detected in more than 50% of all tissues examined, with the kidney exhibiting the highest concentration of MeP (0.65-6.84 ng/g wet wt). Para-hydroxybenzoic acid (PHBA), a primary metabolite, had the highest detection frequency (>50%) and a high accumulation range in the liver, of 4.64 to 12.55 ng/g. The chlorinated compounds chloromethylparaben and chloroethylparaben were found in over half of the tissues, of which dichloromethylparaben (2.20-3.99 ng/g) and dichloroethylparaben (1.01-5.95 ng/g) in the kidney exhibited the highest concentrations. The dibrominated derivatives dibromideethylparaben (Br2EtP) was detected in more than 50% of samples, particularly in muscle and brain. Concentrations in the range of 0.14 to 17.38 ng/g of Br2EtP were detected in the kidney. Dibromidepropylparaben (Br2PrP) was not frequently detected, but concentrations ranged from 0.09 to 21.70 ng/g in muscle. The accumulations of total amounts (sum) of parent parabens (∑P), metabolites (∑M), and halogenated byproducts (∑H) in different species were not significantly different, but their distribution in tissues differed among the species. Positive correlations were observed among MeP, PrP, BuP, and PHBA in the liver, suggesting similar origins and metabolic pathways. Environ Toxicol Chem 2024;00:1-12. © 2024 The Author(s). Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

PD-L1 is expressed in many tumors but rarely in normal tissues, therefore, it can be a target of PET imaging. In this work, we developed new peptide-based PET probes [18F]AlF-PAI-PDL1p and [68Ga]Ga-PAI-PDL1p with yields of 20-25 % and 40-55 %, respectively. [18F]AlF-PAI-PDL1p and [68Ga]Ga-PAI-PDL1p were synthesized within 30 min with high molar activities. [18F]AlF-PAI-PDL1p and [68Ga]Ga-PAI-PDL1p showed good stability in vivo and in vitro. In vitro cell studies showed [18F]AlF-PAI-PDL1p and [68Ga]Ga-PAI-PDL1p target PD-L1 specifically, with high uptake of 61.52 ± 4.39 and 19.29 ± 2.17 %ID/1 million cells in B16F10 cells at 60 min, respectively. Biodistribution results showed that both [18F]AlF-PAI-PDL1p and [68Ga]Ga-PAI-PDL1p had lower liver accumulation. In vivo PET imaging results showed that [18F]AlF-PAI-PDL1p had a high tumor uptake of 4.23 ± 0.81 %ID/g at 2 h and increased uptake of 6.60 ± 1.01 %ID/g at 12 h. [68Ga]Ga-PAI-PDL1p also showed high tumor uptake of 2.30 ± 0.20 %ID/g at 2 h and slightly increased uptake of 3.80 ± 0.26 %ID/g at 6 h. In conclusion, [18F]AlF-PAI-PDL1p and [68Ga]Ga-PAI-PDL1 seemed to be potential tracers for PET imaging of PD-L1 expression.

An open-label, single-center, phase I study was conducted to determine the absolute bioavailability and absorption, distribution, metabolism, and excretion of capivasertib-a potent, selective AKT serine/threonine kinase inhibitor-in healthy males. In part 1, six participants received a single oral dose of capivasertib (400 mg; tablets) followed by a [14C]-radiolabeled intravenous microdose of capivasertib (100 μg). After a 14-day washout, five of the participants proceeded to part 2 and received a single oral dose of [14C]capivasertib (400 mg; solution). In part 1, median time of maximum observed concentration for capivasertib was 1.7 hours, geometric mean terminal elimination half-life was 12.9 hours, and absolute bioavailability was estimated at 28.6% (90% confidence interval, 23.9 to 34.2). In part 2, a high proportion of the administered radioactivity was recovered over the 168-hour sampling period [mean recovery: 95.1% (feces, 50.4%; urine, 44.7%)]. Unchanged capivasertib in urine accounted for 7.4% of the total dose and 21.1% of the systemically available drug. Geometric mean renal clearance was 8.3 L/h, suggesting active tubular secretion. Twelve metabolites were identified in plasma. M11 (AZ14102143)-the glucuronide conjugate of capivasertib, inactive as an AKT serine/threonine kinase inhibitor-was the most abundant, accounting for a mean 78.4% of the plasma drug-related area under the curve. Of 22 metabolites identified in excreta, M11 was the most abundant (mean 28.2% of administered dose), indicating direct glucuronidation as one of the major routes of metabolism. No new safety concerns were identified. SIGNIFICANCE STATEMENT: This study provides characterization of the pharmacokinetics of capivasertib-a potent, selective AKT serine/threonine kinase (AKT) inhibitor-including absolute bioavailability, mass balance, and metabolic fate in humans; the findings are being used to inform further clinical development. Absolute bioavailability was estimated at 28.6%, and mean recovery of the administered dose in excreta over 168 hours was 95.1%. M11 (AZ14102143)-the glucuronide conjugate, inactive as an AKT inhibitor-was the most abundant identified metabolite in plasma and excreta.

暂无摘要。

Antibiotic-associated diarrhea (AAD) is a common side effect of antibiotic therapy, characterized by intestinal inflammation which reduces the quality of life of patients. Xianglian Pill (XLP) has long been used to treat abdominal pain, diarrhea, bacillary dysentery and enteritis. Studies found that XLP has curative effect on AAD; however, the chemical constituents and mechanism of XLP have not been fully elucidated because of the lack of in vitro and in vivo studies. In this study, ultra-high performance liquid chromatography mass spectrometry method (UPLC-Q-Exactive-Orbitrap-HRMS) was used to examine the components of the XLP. Then, the binding between active compounds and the key targets was studied using network pharmacology and molecular docking. A comparative tissue distribution study was established for the simultaneous determination of the 10 active components in healthy and AAD mouse models. Forty-six components were characterized from XLP. According to the network pharmacology degree value, a prediction was made that encompassed 42 components and 14 core targets, which were intricately involved in crucial biological pathways, such as the AGE-RAGE signaling, cellular senescence, and MAPK signaling. Tissue distribution analysis showed that the 10 components were widely distributed in the heart, liver, spleen, lungs, kidneys, small intestine, and large intestine of mice, with varying concentrations in healthy and AAD mice. Molecular docking analysis also indicated that the active compounds in the tissue distribution could bind tightly to key targets of network pharmacological studies. This study provides a reference for further investigations of the relationships between the chemical components and pharmacological activities of XLP.

To study the pharmacokinetics of deoxypodophyllotoxin and its metabolites in non-small cell lung cancer (NSCLC) bearing mice.Using the established LC-MS/MS method for simultaneous determination of deoxypodophyllotoxin and its three main metabolites (M1, M2 and M7) in biological samples, the concentrations of deoxypodophyllotoxin and its metabolites in plasma, tumour and major tissues of tumour-bearing mice were investigated after 6.25 and 25 mg/kg intravenous administration of deoxypodophyllotoxin.The exposure results of drug concentration showed that after intravenous injection of 6.25 and 25 mg/kg of DPT into tumour-bearing mice, the AUC ratio of DPT in tumour tissue to DPT in plasma was 4.23 and 3.80, respectively. While, the AUC ratio of metabolite M2 in tumour tissue to M2 in plasma was 0.82 and 0.76, respectively.Deoxypodophyllotoxin had higher affinity with tumour tissues than plasma, while its metabolite M2 had less affinity with tumour tissues than deoxypodophyllotoxin, but the exposure level of M2 in plasma was higher than that of deoxypodophyllotoxin. Deoxypodophyllotoxin was widely distributed in tumour-bearing mice. After intravenous injection of 25 mg/kg deoxypodophyllotoxin, the concentration of deoxypodophyllotoxin in other tissues except liver and muscle was relatively high, especially in lung, fat and reproductive organs.

The aim of the work is to study the nature of the distribution of 2-A-4.6-DNP in the organisms of warm-blooded animals with intragastric administration of a toxicant. The study was carried out using the methods of TLC, UV-Visible spectroscopy, and GC-MS using derivatives of 2-A-4.6-DNP. Male Wistar rats at the age of 4 months were considered as a model of the body of a warm-blooded animal. An oily suspension of 2-A-4.6-DNF was administered intragastrically in an amount of three times the LD50. Extraction of the target substance from the biomaterial was carried out by double infusion (30 minutes each) with a mixture of acetone-acetonitrile (1:1), the amount of the mixture exceeded the weight of the biomaterial by 2 times. Extractions were purified by TLC method using «Sorbfil» plates and acetone-chloroform (7: 3) mobile phase. Preliminary identification was carried out at the same time using a standard substance. Confirmatory identification was carried out by the absorption of dimethylformamide eluates in «SF-2000», as well as by the retention time and mass spectra of the major compound of the corresponding chromatographic peaks after GC-MS analysis. The quantitative content was determined spectrophotometrically, in DMF, by optical density at the analytical wavelength (490 nm). 2-Amino-4.6-dinitrophenol was found unchanged in the blood and in all the studied hollow and parenchymal organs of poisoned rats. The largest amount of 2-amino-4.6-dinitrophenol (mg/100 g) was found in the stomach walls (199.39±25.43) and stomach contents (143.14±22.63), a significant amount of the substance was found in the heart (33.49±3.66), skeletal muscles (30.70±2.64), as well as in the spleen (24.30±1.96).
UNASSIGNED: Изучение характера распределения 2-А-4,6-ДНФ в организмах теплокровных животных при внутрижелудочном введении токсиканта.
UNASSIGNED: Исследование проводили с применением методов тонкослойной хроматографии (ТСХ), электронной спектрофотометрии, а также газовой хроматографии-масс-спектрометрии (ГХ-МС) после дериватизации исследуемого вещества. В качестве модели организма теплокровного животного рассматривали мужских особей крыс породы Wistar в возрасте 4 мес. Масляную суспензию (в подсолнечном масле) 2-А-4,6-ДНФ вводили внутрижелудочным путем в количестве трехкратной LD50. Извлечение целевого вещества из биоматериала выполняли путем двукратного (по 30 мин) настаивания со смесью ацетон-ацетонитрил (1:1), количество смеси превышало массу биоматериала в 2 раза. Очистку извлечений осуществляли методом ТСХ, использовали пластины Sorbfil и подвижную фаза ацетон-хлороформ (7:3). Одновременно с очисткой проводили предварительную идентификацию с использованием вещества-стандарта. Подтверждающую идентификацию выполняли по поглощению диметилформамидных элюатов в СФ-2000, а также по времени удерживания и масс-спектрам major-соединения соответствующих хроматографических пиков после исследования методом ГХ-МС. Количественное содержание определяли спектрофотометрически, в среде диметилформамида, по оптической плотности при аналитической длине волны (490 нм).
UNASSIGNED: 2-амино-4,6-динитрофенол обнаруживался в неизменном виде в крови и во всех исследованных полых и паренхиматозных органах отравленных крыс. Наибольшее количество 2-амино-4,6-динитрофенола (мг/100 г) обнаружено в стенках желудка (199,39±25,43) и содержимом желудка (143,14±22,63), значительное количество вещества найдено в сердце (33,49±3,66), скелетных мышцах (30,70±2,64), а также в селезенке (24,30±1,96).

Nanoparticles based on poly(lactic-co-glycolic acid) (PLGA) with various surface chemistry are widely used in biomedicine for theranostic applications. The nature of the external coating of nanoparticles has a significant influence on their efficiency as drug carriers or visualization agents. However, information about the mechanisms of nanoparticle accumulation in tumors and the influence of their surface properties on biodistribution is scarce due to the lack of systematic evaluation. Here we investigate the effect of different polymer coatings of the surface on in vitro and in vivo properties of PLGA nanoparticles. Namely, cell binding efficiency, cytotoxicity, efficiency of fluorescent bioimaging, and tumor accumulation were tested. The highest binding efficiency in vitro and cytotoxicity were observed for positively charged polymers. Interestingly, in vivo fluorescent visualization of tumor-bearing mice and quantitative measurements of biodistribution of magnetite-loaded nanoparticles indicated different dependences of accumulation in tumors on the coating of PLGA nanoparticles. This means that nanoparticle surface properties can simultaneously enhance imaging efficiency and decrease quantitative accumulation in tumors. The obtained data demonstrate the complexity of the dependence of nanoparticles\' effectiveness for theranostic applications on surface features. We believe that this study will contribute to the rational design of nanoparticles for effective cancer diagnostics and therapy.

BACKGROUND: PET/CT imaging with Zirconium-89 labeled [89Zr]Zr-DFO-girentuximab, which targets tumor antigen CAIX, may aid in the differentiation and characterization of clear cell renal cell carcinomas (RCC) and other renal and extrarenal lesions, and has been studied in European and American cohorts. We report results from a phase I study that evaluated the safety profile, biodistribution, and dosimetry of [89Zr]Zr-DFO-girentuximab in Japanese patients with suspected RCC.
METHODS: Eligible adult patients received 37 MBq (± 10%; 10 mg mass dose) of intravenous [89Zr]Zr-DFO-girentuximab. Safety and tolerability profile was assessed based on adverse events, concomitant medications, physical examination, vital signs, hematology, serum chemistry, urinalysis, human anti-chimeric antibody measurement, and 12-lead electrocardiograms at predefined intervals. Biodistribution and normal organ and tumor dosimetry were evaluated with PET/CT images acquired at 0.5, 4, 24, 72 h and Day 5 ± 2 d after administration.
RESULTS: [89Zr]Zr-DFO-girentuximab was administered in six patients as per protocol. No treatment-emergent adverse events were reported. Dosimetry analysis showed that radioactivity was widely distributed in the body, and that the absorbed dose in healthy organs was highest in the liver (mean ± standard deviation) (1.365 ± 0.245 mGy/MBq), kidney (1.126 ± 0.190 mGy/MBq), heart wall (1.096 ± 0.232 mGy/MBq), and spleen (1.072 ± 0.466 mGy/MBq). The mean effective dose, adjusted by the radioactive dose administered, was 0.470 mSv/MBq. The radiation dose was highly accumulated in the targeted tumor, while any abnormal accumulation in other organs was not reported.
CONCLUSIONS: This study demonstrates that [89Zr]Zr-DFO-girentuximab administered to Japanese patients with suspected RCC has a favorable safety profile and is well tolerated and has a similar dosimetry profile to previously studied populations.