A Population Pharmacokinetic Analysis of L-Glutamine Exposure in Patients with Sickle Cell Disease: Evaluation of Dose and Food Effects.

BACKGROUND AND OBJECTIVE: L-Glutamine is a treatment for children and adults with sickle cell disease. A comprehensive evaluation of the pharmacokinetics of L-glutamine in sickle cell disease has not been conducted. We aimed to assess the effects of long-term dosing, multiple dose levels, and food intake on L-glutamine exposure in patients with sickle cell disease compared to normal participants. METHODS: We conducted an open-label dose-ascending trial of L-glutamine in pediatric and adult participants with sickle cell disease (N = 8) and adult healthy volunteers (N = 4), providing a total of 400 plasma L-glutamine concentrations. Each participant received three ascending oral doses (0.1 and 0.3 g/kg twice daily and 0.6 g/kg once daily) over 3 weeks. Plasma L-glutamine concentrations were quantified using ion exchange chromatography. Both a non-compartmental pharmacokinetic analysis and a population pharmacokinetic analysis were performed. RESULTS: L-glutamine had rapid absorption and elimination, and there was no significant change in the baseline (pre-dose) L-glutamine concentration throughout the study, indicating no drug accumulation. Pharmacokinetics was best described by a one-compartment model with first-order kinetics. The dose-normalized peak concentration decreased with dose escalation, indicating the capacity-limited non-linear pharmacokinetics of oral L-glutamine. A covariate analysis showed that baseline L-glutamine concentrations correlated negatively with glutamine clearance, whereas dose positively correlated with volume of distribution. Food intake did not significantly affect glutamine clearance, indicating that L-glutamine can be taken with or without food. CONCLUSIONS: We report the first pharmacokinetic study of multiple-dose, long-term oral L-glutamine therapy and the first population pharmacokinetic analysis of L-glutamine for sickle cell disease. These findings may permit optimized dosing of L-glutamine for patients with sickle cell disease to maximize treatment benefits. CLINICAL TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov (NCT04684381).

Enantiomers of 2-methylglutamate and 2-methylglutamine selectively impact mouse brain metabolism and behavior.

Imbalance of excitatory and inhibitory neurotransmission is implicated in a wide range of psychiatric and neurologic disorders. Here we tested the hypothesis that insertion of a methyl group on the stereogenic alpha carbon of L-Glu or L-Gln would impact the γ-aminobutyric acid (GABA) shunt and the glutamate-glutamine cycle. (S)-2-methylglutamate, or (S)-2MeGlu, was efficiently transported into brain and synaptosomes where it was released by membrane depolarization in a manner equivalent to endogenous L-Glu. (R)-2MeGlu was transported less efficiently into brain and synaptosomes but was not released by membrane depolarization. Each enantiomer of 2MeGlu had limited activity across a panel of over 30 glutamate and GABA receptors. While neither enantiomer of 2MeGlu was metabolized along the GABA shunt, (S)-2MeGlu was selectively converted to (S)-2-methylglutamine, or (S)-2MeGln, which was subsequently slowly hydrolyzed back to (S)-2MeGlu in brain. rac-2MeGln was also transported into brain, with similar efficiency as (S)-2MeGlu. A battery of behavioral tests in young adult wild type mice showed safety with up to single 900 mg/kg dose of (R)-2MeGlu, (S)-2MeGlu, or rac-2MeGln, suppressed locomotor activity with single ≥ 100 mg/kg dose of (R)-2MeGlu or (S)-2MeGlu. No effect on anxiety or hippocampus-dependent learning was evident. Enantiomers of 2MeGlu and 2MeGln show promise as potential pharmacologic agents and imaging probes for cells that produce or transport L-Gln.

Radiosynthesis, in vitro and preliminary in vivo evaluation of the novel glutamine derived PET tracers [18F]fluorophenylglutamine and [18F]fluorobiphenylglutamine.

INTRODUCTION: Glucose has been deemed the driving force of tumor growth for decades. However, research has shown that several tumors metabolically shift towards glutaminolysis. The development of radiolabeled glutamine derivatives could be a useful molecular imaging tool for visualizing these tumors. We elaborated on the glutamine-derived PET tracers by developing two novel probes, namely [18F]fluorophenylglutamine and [18F]fluorobiphenylglutamine. MATERIALS AND METHODS: Both tracers were labelled with fluorine-18 using our recently reported ruthenium-based direct aromatic fluorination method. Their affinity was evaluated with a [3H]glutamine inhibition experiment in a human PC-3 and a rat F98 cell line. The imaging potential of [18F]fluorophenylglutamine and [18F]fluorobiphenylglutamine was tested using a mouse PC-3 and a rat F98 tumor model. RESULTS: The radiosynthesis of both tracers was successful with overall non-decay corrected yields of 18.46 ± 4.18% (n = 10) ([18F]fluorophenylglutamine) and 8.05 ± 3.25% (n = 5) ([18F]fluorobiphenylglutamine). In vitro inhibition experiments showed a moderate and low affinity of fluorophenylglutamine and fluorobiphenylglutamine, respectively, towards the human ASCT-2 transporter. Both compounds had a low affinity towards the rat ASCT-2 transporter. These results were endorsed by the in vivo experiments with low uptake of both tracers in the F98 rat xenograft, low uptake of [18F]FBPG in the mice PC-3 xenograft and a moderate uptake of [18F]FPG in the PC-3 tumors. CONCLUSION: We investigated the imaging potential of two novel PET radiotracers [18F]FPG and [18F]FBPG. [18F]FPG is the first example of a glutamine radiotracer derivatized with a phenyl group which enables the exploration of further derivatization of the phenyl group to increase the affinity and imaging qualities. We hypothesize that increasing the affinity of [18F]FPG by optimizing the substituents of the arene ring can result in a high-quality glutamine-based PET radiotracer. Advances in Knowledge and Implications for patient care: We hereby report novel glutamine-based PET-tracers. These tracers are tagged on the arene group with fluorine-18, hereby preventing in vivo defluorination, which can occur with alkyl labelled tracers (e.g. (2S,4R)4-[18F]fluoroglutamine). [18F]FPG shows clear tumor uptake in vivo, has no in vivo defluorination and has a straightforward production. We believe this tracer is a good starting point for the development of a high-quality tracer which is useful for the clinical visualization of the glutamine transport.

(2S, 4R)-4-[18F]Fluoroglutamine for In vivo PET Imaging of Glioma Xenografts in Mice: an Evaluation of Multiple Pharmacokinetic Models.

PURPOSE: The glutamine analogue (2S, 4R)-4-[18F]fluoroglutamine ([18F]FGln) was investigated to further characterize its pharmacokinetics and acquire in vivo positron emission tomography (PET) images of separate orthotopic and subcutaneous glioma xenografts in mice. PROCEDURES: [18F]FGln was synthesized at a high radiochemical purity as analyzed by high-performance liquid chromatography. An orthotopic model was created by injecting luciferase-expressing patient-derived BT3 glioma cells into the right hemisphere of BALB/cOlaHsd-Foxn1nu mouse brains (tumor growth monitored via in vivo bioluminescence), the subcutaneous model by injecting rat BT4C glioma cells into the flank and neck regions of Foxn1nu/nu mice. Dynamic PET images were acquired after injecting 10-12 MBq of the tracer into mouse tail veins. Animals were sacrificed 63 min after tracer injection, and ex vivo biodistributions were measured. Tumors and whole brains (with tumors) were cryosectioned, autoradiographed, and stained with hematoxylin-eosin. All images were analyzed with CARIMAS software. Blood sampling of 6 Foxn1nu/nu and 6 C57BL/6J mice was performed after 9-14 MBq of tracer was injected at time points between 5 and 60 min then assayed for erythrocyte uptake, plasma protein binding, and plasma parent-fraction of radioactivity to correct PET image-derived whole-blood radioactivity and apply the data to multiple pharmacokinetic models. RESULTS: Orthotopic human glioma xenografts displayed PET image tumor-to-healthy brain region ratio of 3.6 and 4.8 while subcutaneously xenografted BT4C gliomas displayed (n = 12) a tumor-to-muscle (flank) ratio of 1.9 ± 0.7 (range 1.3-3.4). Using PET image-derived blood radioactivity corrected by population-based stability analyses, tumor uptake pharmacokinetics fit Logan and Yokoi modeling for reversible uptake. CONCLUSIONS: The results reinforce that [18F]FGln has preferential uptake in glioma tissue versus that of corresponding healthy tissue and fits well with reversible uptake models.

Pharmacokinetic Assessment of 18F-(2S,4R)-4-Fluoroglutamine in Patients with Cancer.

18F-(2S,4R)-4-fluoroglutamine (18F-FGln) is an investigational PET radiotracer for imaging tumor glutamine flux and metabolism. The aim of this study was to investigate its pharmacokinetic properties in patients with cancer. Methods: Fifty lesions from 41 patients (21 men and 20 women, aged 54 ± 14 y) were analyzed. Thirty-minute dynamic PET scans were performed concurrently with a rapid intravenous bolus injection of 232 ± 82 MBq of 18F-FGln, followed by 2 static PET scans at 97 ± 14 and 190 ± 12 min after injection. Five patients also underwent a second 18F-FGln study 4-13 wk after initiation of therapy with glutaminase, dual TORC1/2, or programmed death-1 inhibitors. Blood samples were collected to determine plasma and metabolite fractions and to scale the image-derived input function. Regions of interest were manually drawn to calculate SUVs. Pharmacokinetic modeling with both reversible and irreversible 1- and 2-tissue-compartment models was performed to calculate the kinetic rate constants K1, k2, k3, and k4 The analysis was repeated with truncated 30-min dynamic datasets. Results: Intratumor 18F-FGln uptake patterns demonstrated substantial heterogeneity in different lesion types. In most lesions, the reversible 2-tissue-compartment model was chosen as the most appropriate according to the Akaike information criterion. K1, a surrogate biomarker for 18F-FGln intracellular transport, was the kinetic rate constant that was most correlated both with SUV at 30 min (Spearman ρ = 0.71) and with SUV at 190 min (ρ = 0.51). Only K1 was reproducible from truncated 30-min datasets (intraclass correlation coefficient, 0.96). k3, a surrogate biomarker for glutaminolysis rate, was relatively low in about 50% of lesions. Treatment with glutaminase inhibitor CB-839 substantially reduced the glutaminolysis rates as measured by k3Conclusion:18F-FGln dynamic PET is a sensitive tool for studying glutamine transport and metabolism in human malignancies. Analysis of dynamic data facilitates better understanding of 18F-FGln pharmacokinetics and may be necessary for response assessment to targeted therapies that impact intracellular glutamine pool size and tumor glutaminolysis rates.

Efficacy of enteral glutamine supplementation in patients with severe and predicted severe acute pancreatitis- A randomized controlled trial.

BACKGROUND: In severe acute pancreatitis (AP), intravenous glutamine has been shown to reduce the rate of complications, hospital stay, and mortality. In the present randomized trial, we aimed to evaluate the effect of enteral glutamine supplementation on clinical outcomes, gut permeability, systemic inflammation, oxidative stress, and plasma glutamine levels in patients with severe and predicted severe AP. METHODS: Patients with AP admitted within 72 h of onset of symptoms were included. The primary outcome measure was development of infected pancreatic and peri-pancreatic necrosis and in-hospital mortality. High-sensitivity C-reactive protein (HS-CRP) and interleukin-6 (IL-6) were evaluated as markers of inflammation; plasma thiobarbituric acid reactive substances (TBARS) and activities of serum superoxide dismutase and glutathione peroxidase were determined to evaluate oxidative stress; serum polyethylene glycol (PEG) was tested for intestinal permeability; subjective global assessment (SGA) was used for nutritional assessment, and an improvement in organ function was measured by the Modified Marshall score. Intention-to-treat analysis was used. A p-value of < 0.05 was considered statistically significant. RESULTS: After power calculation, we enrolled 18 patients in the glutamine and 22 in the control arm. There was no significant improvement in the development of infected necrosis and in-hospital mortality between the groups. Improvement in Modified Marshall score was observed in a higher proportion of patients receiving glutamine (15 [83.3%] vs. 12 [54.5%]; p = 0.05). Plasma glutamine levels improved more in glutamine-treated group (432.72 ± 307.83 vs. 618.06 ± 543.29 µM/L; p = 0.004), while it was lower in controls (576.90 ± 477.97 vs. 528.20 ± 410.45 µM/L; p = 0.003). PEG level was lower after glutamine supplementation (39.91 ± 11.97 vs. 32.30 ± 7.39 ng/mL; p = 0.02). Statistically significant reduction in IL-6 concentration was observed in the glutamine group at the end of treatment (87.44 ± 7.1 vs. 63.42 ± 33.7 µM/L; p = 0.02). CONCLUSIONS: Despite absence of improvement in infected necrosis and in-hospital mortality, enteral glutamine supplementation showed improvement in gut permeability, oxidative stress, and a trend towards improvement in organ function as depicted by improvement in the Modified Marshall score. TRIAL REGISTRATION: NCT01503320.

Nutrients, immune system, and exercise: Where will it take us?

The immune system plays a key role in controlling infections, repairing injuries, and restoring homeostasis. Immune cells are bioenergetically expensive during activation, which requires a tightly regulated control of the metabolic pathways, which is mostly regulated by two cellular energy sensors: Adenosine monophosphate-activated protein kinase and mammalian target of rapamycin. The activation and inhibition of this pathways can change cell subtype differentiation. Exercise intensity and duration and nutrient availability (especially glucose and glutamine) tightly regulate immune cell differentiation and function through Adenosine monophosphate-activated protein kinase and mammalian target of rapamycin signaling. Herein, we discuss the innate and adaptive immune-cell metabolism and how they can be affected by exercise and nutrients.

A cell-based test system for the assessment of pharmacokinetics of NOD1 and NOD2 receptor agonists.

Agonists of nucleotide oligomerization domain (NOD) 1 and NOD2 receptors represent a promising class of immunostimulants and immunological adjuvants. Here, we describe a cell-based test system to assess their pharmacokinetics. In this system, NOD1 and NOD2 agonist concentrations in sera are determined using a reporter cell line, 293Luc, which contains an NF-κB-inducible luciferase reporter construct and naturally expresses NOD1 and NOD2. The 293Luc cells dose-dependently respond to different NOD1 and NOD2 agonists in the nanomolar to low-micromolar concentration range. To verify that the NF-κB-inducing activity of serum samples is due to the administered agonist and not to secondarily induced endogenous molecules, a 293Luc-derived NOD1/NOD2 double-knockout clone is used. Within-run and between-run precisions of the system are <15% and <20%, respectively. Applicability of the novel assay is illustrated by studying pharmacokinetics of two specific NOD2 agonists (N­acetyl­d­glucosaminyl­N­acetyl­d­muramyl­l­alanyl­d­isoglutamine and N­glycolyl­d­muramyl­l­alanyl­d­isoglutamine) and a specific NOD1 agonist (N­acetyl­d­glucosaminyl­N­acetyl­d­sorbitolamine­d­lactoyl­l­alanyl­d­isoglutamyl­meso­diaminopimelic acid). In summary, the test system described here can potentially be used to assess pharmacokinetics of NOD1 and NOD2 agonists in different animal species.

PET Imaging of 18F-(2 S,4 R)4-Fluoroglutamine Accumulation in Breast Cancer: From Xenografts to Patients.

Sustaining the growth of tumor cells requires extra energy and metabolic building blocks. In addition to consuming glucose, glutamine may play the role as an alternative source of nutrient for growth and survival. We aim to characterize a glutamine analog, 18F-(2 S,4 R)4-fluoroglutamine (18F-(2 S,4 R)4-FGln), as an imaging agent for interrogating the role of glutamine from the in vitro study of tumor cells to clinical manifestation in breast cancer patients. Purity was measured by radio-high-performance liquid chromatography (radio-HPLC), and the stability after production was evaluated in phosphate buffer saline (PBS), saline, and mouse and human serum buffers. The presence of Myc expression in MCF-7 and U87 cells was conducted using qPCR. In vitro cell uptake of 18F-(2 S,4 R)4-FGln in MCF-7 and U87 cells was directly compared with 18F-fluorodeoxyglucose (18F-FDG). In vivo biodistribution and micro-PET imaging of 18F-(2 S,4 R)4-FGln in MCF-7 bearing BALB/c nude mice were performed. PET/CT imaging of 18F-(2 S,4 R)4-FGln was compared with 18F-FDG in the same group of breast cancer patients ( n = 10). We successfully synthesized 18F-(2 S,4 R)4-FGln with a high radiochemical purity (>98%), and the radiochemical purity was unchanged in PBS and saline buffers during a 2 h incubation. In vitro cell uptake studies of 18F-(2 S,4 R)4-FGln displayed a rapid and higher uptake in MCF-7 and U87 cells as compared with 18F-FDG. Biodistribution and micro-PET images showed excellent tumor accumulation of 18F-(2 S,4 R)4-FGln in the MCF-7-implanted mice tumor model. In a preliminary clinical study, 18F-(2 S,4 R)4-FGln/PET detected more lesions in breast cancer patients than 18F-FDG/PET (90% vs 80%). Additionally, in one patient with breast lobular carcinoma, there was a lesion mean standardized uptake value (SUVmean) and maximum standardized uptake value (SUVmax) for 18F-(2 S,4 R)4-FGln higher than those obtained by 18F-FDG, as determined by PET imaging. 18F-(2 S,4 R)4-FGln may be a useful glutamine-targeting metabolic probe for noninvasive imaging of breast cancer.

Preclinical study of an 18F-labeled glutamine derivative for cancer imaging.

INTRODUCTION: The emerging evidence that demonstrated the extra-demand of glutamine for cancer surviving strongly called for the development of PET tracer for imaging glutamine uptake in cancer. In this work, [18F]Gln-BF3 as a natural glutamine derivative was synthesized to explore its potential application of imaging glutamine uptake for cancer diagnosis. METHODS: [18F]Gln-BF3 was prepared by deprotection of purified precursor trityl-Gln-BF3 (amide bond protected with triphenylmethyl group) using TFA and radiolabeled using 18F-19F isotope exchange protocol. PET imaging and biodistribution studies were conducted in Balb/c mice bearing 4T1 xenograft. RESULTS: Gln-BF3 was identified with HRMS ([M-H]- = 169.0765). [18F]Gln-BF3 was radiolabeled in high radiochemical yield (RCY > 25%) and characterized with Radio-HPLC-MS. Preliminary PET imaging showed the radioactivity was fast cleared from muscle tissue and excreted mainly via the renal pathway. PET study demonstrated that uptake of [18F]Gln-BF3 in 4T1 xenografts was significant. The biodistribution results of [18F]Gln-BF3 in mice bearing 4T1 xenograft indicate a tumor-to-muscle ratio of 2.58 ±â€¯0.64 (n = 4) and a 6.29 ±â€¯0.42%ID/g (n = 4) uptake in tumor at 45 min post injection. CONCLUSION: [18F]Gln-BF3 was radiolabeled in a "kit-like" manner and showed notable and tumor-selective uptake in tumor-bearing animal models, suggesting that this new strategy of radiolabeling amino acid provided a promising solution for the future development of glutamine-derived PET tracers.

Prevention of oral mucositis secondary to antineoplastic treatments in head and neck cancer by supplementation with oral glutamine / Prevención de la mucositis oral secundaria a los tratamientos antineoplásicos en el cáncer de cabeza y cuello mediante suplemento con glutamina oral

Objectives: to evaluate the efficacy of glutamine in the prevention of the incidence of oral mucositis secondary to cancer therapies in patients with head and neck cancer (HNC). Secondary objectives were to know the incidence of odynophagia, interruptions of treatment and the requirements of analgesia and nasogastric tube. Material and methods: prospective cohort study of patients with squamous cell carcinoma of HNC treated with radiotherapy ± concomitant chemotherapy. We compared 131 patients receiving glutamine orally at a dose of 10 g/8 hours with 131 patients who did not receive it. Results: patients not taking glutamine had a hazard ratio 1.78 times higher of mucositis (95% CI [1.01-3.16], p = 0.047). Regarding odynophagia, patients not taking glutamine had a hazard ratio 2.87 times higher (95% CI [1.62-5.18], p = 0.0003). The 19.8% of patients who did not take glutamine discontinued treatment versus 6.9% of patients who took (p = 0.002). Regarding support requirements, 87.8% of patients without glutamine required analgesia versus 77.9% of patients with glutamine (p = 0.03) and nasogastric tube was indicated in 9.9% and 3.1% respectively (p = 0.02). Conclusion: oral glutamine in patients receiving cancer treatments for HNC prevents the incidence of oral mucositis and odynophagia, and decreases treatment interruptions and the use of analgesia and nasogastric tube

Objetivos: evaluar la eficacia de la glutamina en la prevención de la incidencia de mucositis secundaria a las terapias oncológicas en pacientes con carcinoma de cabeza y cuello. Los objetivos secundarios fueron conocer la incidencia de odinofagia e interrupciones de los tratamientos y los requerimientos de analgesia y sonda nasogástrica. Material y métodos: estudio prospectivo de cohortes de pacientes con carcinoma epidermoide de cabeza y cuello tratados con radioterapia ± quimioterapia concomitante. Se compararon 131 pacientes que recibieron glutamina oral a una dosis de 10 g/8 horas con 131 pacientes que no la recibieron. Resultados: los pacientes que no tomaron glutamina tuvieron una hazard ratio 1,78 veces mayor de mucositis (IC 95% [1,01-3,16], p = 0,047). Respecto a la odinofagia, los pacientes que no tomaron glutamina tuvieron una hazard ratio 2,87 veces mayor (IC 95% [1,62-5,18], p = 0,0003]. El 19,8% de los pacientes que no tomaron glutamina interrumpieron el tratamiento versus 6,9% de los pacientes que la tomaron (p = 0,002). En cuanto a los tratamientos de soporte, el 87,8% de los pacientes sin glutamina requirieron analgesia versus 77,9% de los pacientes con glutamina (p = 0,03) y la sonda nasogástrica fue indicada en un 9,9% y 3,1% respectivamente (p = 0,02). Conclusión: la glutamina oral en pacientes que reciben tratamiento por carcinoma de cabeza y cuello, previene la incidencia de mucositis oral y odinofagia y disminuye las interrupciones de tratamientos y el uso de analgesia y sonda nasogástrica

Alanine and glycine conjugates of (2S,4R)-4-[18F]fluoroglutamine for tumor imaging.

INTRODUCTION: Glutamine is an essential source of energy, metabolic substrates, and building block for supporting tumor proliferation. Previously, (2S,4R)-4-[18F]fluoroglutamine (4F-Gln) was reported as a glutamine-related metabolic imaging agent. To improve the in vivo kinetics of this radiotracer, two new dipeptides, [18F]Gly-(2S,4R)4-fluoroglutamine (Gly-4F-Gln) and [18F]Ala-(2S,4R)4-fluoroglutamine (Ala-4F-Gln) were investigated. METHODS: Radiolabeling was performed via 2-steps 18F-fluorination. Cell uptake studies of Gly-4F-Gln and Ala-4F-Gln were investigated in 9 L cell lines. In vitro and in vivo metabolism studies were carried out in Fisher 344 rats. Biodistribution and microPET imaging studies were performed in 9 L tumor-bearing rats. RESULTS: In vitro incubation of these [18F]dipeptides in rat and human blood showed a rapid conversion to (2S,4R)-4-[18F]fluoroglutamine (t1/2 = 2.3 and 0.2 min for [18F]Gly-4F-Gln and [18F]Ala-4F-Gln, respectively for human blood). Biodistribution and PET imaging in Fisher 344 rats bearing 9 L tumor xenografts showed that these dipeptides rapidly localized in the tumors, comparable to that of (2S,4R)-4-[18F]fluoroglutamine (4F-Gln). CONCLUSIONS: The results support that these dipeptides, [18F]Gly-4F-Gln and [18F]Ala-4F-Gln, are prodrugs, which hydrolyze in the blood after an iv injection. They appear to be selectively taken up and trapped by tumor tissue in vivo. The dipeptide, [18F]Ala-4F-Gln, may be suitable as a PET tracer for imaging glutaminolysis in tumors.

In Vivo PET Assay of Tumor Glutamine Flux and Metabolism: In-Human Trial of 18F-(2S,4R)-4-Fluoroglutamine.

Purpose To assess the clinical safety, pharmacokinetics, and tumor imaging characteristics of fluorine 18-(2S,4R)-4-fluoroglutamine (FGln), a glutamine analog radiologic imaging agent. Materials and Methods This study was approved by the institutional review board and conducted under a U.S. Food and Drug Administration-approved Investigational New Drug application in accordance with the Helsinki Declaration and the Health Insurance Portability and Accountability Act. All patients provided written informed consent. Between January 2013 and October 2016, 25 adult patients with cancer received an intravenous bolus of FGln tracer (mean, 244 MBq ± 118, <100 µg) followed by positron emission tomography (PET) and blood radioassays. Patient data were summarized with descriptive statistics. FGln biodistribution and plasma amino acid levels in nonfasting patients (n = 13) were compared with those from patients who fasted at least 8 hours before injection (n = 12) by using nonparametric one-way analysis of variance with Bonferroni correction. Tumor FGln avidity versus fluorodeoxyglucose (FDG) avidity in patients with paired PET scans (n = 15) was evaluated with the Fisher exact test. P < .05 was considered indicative of a statistically significant difference. Results FGln PET depicted tumors of different cancer types (breast, pancreas, renal, neuroendocrine, lung, colon, lymphoma, bile duct, or glioma) in 17 of the 25 patients, predominantly clinically aggressive tumors with genetic mutations implicated in abnormal glutamine metabolism. Acute fasting had no significant effect on FGln biodistribution and plasma amino acid levels. FGln-avid tumors were uniformly FDG-avid but not vice versa (P = .07). Patients experienced no adverse effects. Conclusion Preliminary human FGln PET trial results provide clinical validation of abnormal glutamine metabolism as a potential tumor biomarker for targeted radiotracer imaging in several different cancer types. © RSNA, 2018 Online supplemental material is available for this article. Clinical trial registration no. NCT01697930.

Efeitos da ingestão de semente de linhaça e seu possivel efeito hipocolesterolêmico / Effects of linseed intake and its possible hypocholesterolemic effects

Introdução: O colesterol é essencial para a vida. Em excesso no sangue, deposita-se nas paredes das artérias promovendo seu estreitamento ou obstrução. Objetivos: O objetivo foi verificar o possível efeito hipocolesterolêmico da semente de linhaça. Materiais e Métodos: Utilizaram-se 30 ratos Wistar fêmeas divididos em três grupos: Controle, Hipercolesterolêmico, e Linhaça. Os parâmetros avaliados foram: ingestão hídrica; ingestão de ração; peso corporal; gordura peritoneal e níveis de colesterol; Resultados e Discussão: O grupo controle apresentou maior ingestão hídrica (57,46 ± 0,13mL) e ração (30,68 ± 1,96g) quando comparados ao hipercolesterolêmico e linhaça; Para peso corporal total, somente o controle não sofreu alteração; Em relação ao acúmulo de gordura peritoneal, o grupo hipercolesterolêmico se sobressaiu (17,06 ± 3,99g) em comparação ao linhaça e ao controle; para os níveis de colesterol sérico, o grupo controle obteve (1,14 ± 0,14g), sendo observado portanto no grupo linhaça (1,66 ± 0,16g), uma maior aproximação para o resultado do grupo controle do que do hipercolesterolêmico (2,20 ± 6,32g), resultado que nos leva a reconhecer que a linhaça surtiu efeito benéfico sobre o colesterol. Conclusão: Os resultados obtidos demonstram benefícios na utilização da semente para redução dos níveis de gordura peritoneal, peso total e colesterol

Introduction: Cholesterol is essential for life, when in excess in blood, is deposited on the artery walls promoting its narrowing or obstruction. Objectives: The objective was to verify the possible hypocholesterolemic effect of linseed. Methods: We used 30 female Wistar rats divided into three groups: control, hypercholesterolemic, and linseed. The evaluated parameters were: water intake, feed intake, body weight, peritoneal fat, and cholesterol levels; Results and Discussion: The results were: the control group had a higher fluid intake (57.46 ± 0.13ml) and feed (30.68 ± 1.96g) when compared to hypercholesterolemic and linseed; for total body weight, only the control group did not change; in relation to the accumulation of peritoneal fat, the hypercholesterolemic group stood out (17.06 ± 3.99g) compared to linseed and control; for serum cholesterol levels, the control group obtained (1.14 ± 0.14g), thus being observed in linseed group (1.66 ± 0.16g), closer to the result of the control group than the hypercholesterolemic (2.20 ± 6.32g), a result that leads us to recognize that linseed has had a beneficial effect on cholesterol.Conclusion: The results obtained demonstrate benefits in the use of the seed to reduce levels of peritoneal fat, total weight and cholesterol

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18F-GP1, a Novel PET Tracer Designed for High-Sensitivity, Low-Background Detection of Thrombi.

Thromboembolic diseases such as myocardial infarction, stroke, transient ischemic attacks, and pulmonary embolism are major causes of morbidity and mortality worldwide. Glycoprotein IIb/IIIa (GPIIb/IIIa) is the key receptor involved in platelet aggregation and is a validated target for therapeutic approaches and diagnostic imaging. The aim of this study was to develop and characterize a specific small-molecule tracer for PET imaging that binds with high affinity to GPIIb/IIIa receptors and has suitable pharmacokinetic properties to overcome limitations of previous approaches. Methods: Binding of 18F-GP1 to GPIIb/IIIa receptors was investigated in competition binding assays and autoradiography using a fresh cardiac thrombus from an explanted human heart. The clot-to-blood ratio for 18F-GP1 was investigated by an in vitro blood flow model. Biodistribution and thrombus detection was investigated in cynomolgus monkeys after insertion of a roughened catheter into either the vena cava or the aorta. Results:18F-GP1 is an 18F-labeled small molecule for PET imaging of thrombi. The half maximal inhibitory concentration of 18F-GP1 to GPIIb/IIIa was 20 nM. 18F-GP1 bound to thrombi with a mean clot-to-blood ratio of 95. Binding was specific and can be displaced by excess nonradioactive derivative. Binding was not affected by anticoagulants such as aspirin or heparin. 18F-GP1 showed rapid blood clearance and a low background after intravenous injection in cynomolgus monkeys. Small arterial, venous thrombi, thrombotic depositions on damaged endothelial surface, and small cerebral emboli were detected in vivo by PET imaging. Conclusions:18F-GP1 binds specifically with high affinity to the GPIIb/IIIa receptor involved in platelet aggregation. Because of its favorable preclinical characteristics, 18F-GP1 is currently being investigated in a human clinical study.

Residual gastric volume evaluation with ultrasonography after ingestion of carbohydrate- or carbohydrate plus glutamine-enriched beverages: a randomized, crossover clinical trial with healthy volunteers / Avaliação do volume residual gástrico em voluntários saudáveis usando a ultrassonografia, após ingestão de solução líquida enriquecida com carboidrato e glutamina. Estudo clínico, randomizado, duplo cego e cruzado

ABSTRACT BACKGROUND Abbreviation of preoperative fasting to 2 hours with maltodextrin (CHO)-enriched beverage is a safe procedure and may enhance postoperative recovery. Addition of glutamine (GLN) to CHO beverages may include potential benefits to the metabolism. However, by adding a nitrogenous source to CHO beverages, gastric emptying may be delayed and increase the risk of bronchoaspiration during anesthesia. OBJECTIVE In this study of safety, we aimed at investigating the residual gastric volume (RGV) 2 hours after the intake of either CHO beverage alone or CHO beverage combined with GLN. METHODS We performed a randomized, crossover clinical trial. We assessed RGV by means of abdominal ultrasonography (US) in 20 healthy volunteers (10 males and 10 females) after an overnight fast of 8 hours. Then, they were randomized to receive 600 mL (400 mL immediately after US followed by another 200 mL 2 hours afterwards) of either CHO (12.5% maltodextrin) or CHO-GLN (12.5% maltodextrin plus 15 g GLN). Two sequential US evaluations were done at 120 and 180 minutes after ingestion of the second dose. The interval of time between ingestion of the two types of beverages was 2 weeks. RESULTS The mean (SD) RGV observed after 8 hours fasting (13.56±13.25 mL) did not statistically differ (P>0.05) from the RGV observed after ingesting CHO beverage at both 120 (16.32±11.78 mL) and 180 minutes (14.60±10.39 mL). The RGV obtained at 120 (15.63±18.83 mL) and 180 (13.65±10.27 mL) minutes after CHO-GLN beverage also was not significantly different from the fasting condition. CONCLUSION The RGV at 120 and 180 minutes after ingestion of CHO beverage combined with GLN is similar to that observed after an overnight fast.

RESUMO CONTEXTO A abreviação do jejum pré-operatório com solução enriquecida com maltodextrina é segura, recomendada por sociedades de anestesiologia e acelera a recuperação pós-operatória. A associação de glutamina à maltodextrina resultaria em benefícios metabólicos, porém, esta associação pode alterar o volume do resíduo gástrico e consequentemente risco de broncoaspiração. OBJETIVO Avaliaremos, usando a ultrassonografia, o volume residual gástrico em jejum de 8 horas e após 120 e 180 minutos da ingestão de solução de maltodextrina isolada ou associada a 15 g de glutamina. MÉTODOS Estudo clínico, randomizado, duplo cego e cruzado. Vinte voluntários saudáveis, sendo 10 do sexo masculino e 10 do sexo feminino, foram submetidos a seguinte sequência de avaliação, independente da solução usada. Os voluntários foram avaliados em jejum de 8 horas, 120 e 180 minutos após a ingestão da solução de maltodextrina 12,5% e 120 e 180 após a ingestão da solução de maltodextrina 12,5% mais 15 g de glutamina. RESULTADOS Não houve diferença estatisticamente significativa entre os volumes obtidos após jejum de 8 horas (13,56 mL) e os obtidos após 120 (16,32 mL) e 180 minutos (14,60 mL) da ingestão da solução de maltodextrina 12,5% (P>0,05). Para a solução enriquecida com glutamina, os volumes obtidos após 120 minutos (15,63 mL) e 180 minutos (13,65 mL) também não demostraram diferença estatisticamente significativa quando comparados ao jejum (P>0,05). CONCLUSÃO O volume residual gástrico após 120 e 180 minutos da ingestão das soluções de maltodextrina a 12,5% isolada ou associada a 15 g de glutamina é semelhante ao observado em jejum.

Residual gastric volume evaluation with ultrasonography after ingestion of carbohydrate- or carbohydrate plus glutamine-enriched beverages: a randomized, crossover clinical trial with healthy volunteers.

BACKGROUND: - Abbreviation of preoperative fasting to 2 hours with maltodextrin (CHO)-enriched beverage is a safe procedure and may enhance postoperative recovery. Addition of glutamine (GLN) to CHO beverages may include potential benefits to the metabolism. However, by adding a nitrogenous source to CHO beverages, gastric emptying may be delayed and increase the risk of bronchoaspiration during anesthesia. OBJECTIVE: - In this study of safety, we aimed at investigating the residual gastric volume (RGV) 2 hours after the intake of either CHO beverage alone or CHO beverage combined with GLN. METHODS: - We performed a randomized, crossover clinical trial. We assessed RGV by means of abdominal ultrasonography (US) in 20 healthy volunteers (10 males and 10 females) after an overnight fast of 8 hours. Then, they were randomized to receive 600 mL (400 mL immediately after US followed by another 200 mL 2 hours afterwards) of either CHO (12.5% maltodextrin) or CHO-GLN (12.5% maltodextrin plus 15 g GLN). Two sequential US evaluations were done at 120 and 180 minutes after ingestion of the second dose. The interval of time between ingestion of the two types of beverages was 2 weeks. RESULTS: - The mean (SD) RGV observed after 8 hours fasting (13.56±13.25 mL) did not statistically differ (P>0.05) from the RGV observed after ingesting CHO beverage at both 120 (16.32±11.78 mL) and 180 minutes (14.60±10.39 mL). The RGV obtained at 120 (15.63±18.83 mL) and 180 (13.65±10.27 mL) minutes after CHO-GLN beverage also was not significantly different from the fasting condition. CONCLUSION: - The RGV at 120 and 180 minutes after ingestion of CHO beverage combined with GLN is similar to that observed after an overnight fast.

May glutamine addiction drive the delivery of antitumor cisplatin-based Pt(IV) prodrugs?

A small series of Pt(IV) prodrugs containing Gln-like (Gln=glutamine) axial ligands has been designed with the aim to take advantage of the increased demand of Gln showed by some cancer cells (glutamine addiction). In complex 4 the Gln, linked through the α-carboxylic group is recognized by the Gln transporters, in particular by the solute carrier transporter SLC1A5. All compounds showed cellular accumulation, as well as antiproliferative activity, related to their lipophilicity, as already demonstrated for the majority of Pt(IV) prodrugs, that enter cells mainly by passive diffusion. On the contrary, when the Gln concentration in cell medium is near or lower to the physiological value, complex 4 acts as a Trojan horse: it enters SLC1A5-overexpressing cells, where, upon reduction, it releases the active metabolite cisplatin and the Gln-containing ligand, thus preventing any possible extrusion by the L-type amino acid transporter LAT1. This selective mechanism could decrease off-target accumulation of 4 and, consequently, Pt-associated side-effects.

Radiosynthesis and preliminary biological evaluation of N-(2-[18F]fluoropropionyl)-L-glutamine as a PET tracer for tumor imaging.

In this study, radiosynthesis and biological evaluation of a new [18F]labeled glutamine analogue, N-(2-[18F]fluoropropionyl)-L-glutamine ([18F]FPGLN) for tumor PET imaging are performed. [18F]FPGLN was synthesized via a two-step reaction sequence from 4-nitrophenyl-2-[18F]fluoropropionate ([18F]NFP) with a decay-corrected yield of 30 ± 5% (n=10) and a specific activity of 48 ± 10 GBq/µmol after 125 ± 5 min of radiosynthesis. The biodistribution of [18F]FPGLN was determined in normal Kunming mice and high uptake of [18F]FPGLN was observed within the kidneys and quickly excreted through the urinary bladder. In vitro cell experiments showed that [18F]FPGLN was primarily transported by Na+-dependent system XAG- and was not incorporated into proteins. [18F]FPGLN displayed better stability in vitro than that in vivo. PET/CT studies revealed that intense accumulation of [18F]FPGLN were shown in human SPC-A-1 lung adenocarcinoma and PC-3 prostate cancer xenografts. The results support that [18F]FPGLN seems to be a possible PET tracer for tumor imaging.