Radiolabelled Cyclic Bisarylmercury: High Chemical and in†vivo Stability for Theranostics.

We show the synthesis of an in vivo stable mercury compound with functionality suitable for radiopharmaceuticals. The designed cyclic bisarylmercury was based on the water tolerance of organomercurials, higher bond dissociation energy of Hg-Ph to Hg-S, and the experimental evidence that acyclic structures suffer significant cleavage of one of the Hg-R bonds. The bispidine motif was chosen for its in vivo stability, chemical accessibility, and functionalization properties. Radionuclide production results in 197(m) HgCl2 (aq), so the desired mercury compound was formed via a water-tolerant organotin transmetallation. The Hg-bispidine compound showed high chemical stability in tests with an excess of sulfur-containing competitors and high in vivo stability, without any observable protein interaction by human serum assay, and good organ clearance demonstrated by biodistribution and SPECT studies in rats. In particular, no retention in the kidneys was observed, typical of unstable mercury compounds. The nat Hg analogue allowed full characterization by NMR and HRMS.

Salicylate toxicity from chronic bismuth subsalicylate use.

A 79-year-old man presented to the emergency department with a 1-week history of worsening confusion, falls and hearing impairment. An initial workup for infectious, metabolic and structural causes was unrevealing. However, further history discovered that he had been ingesting one to two bottles of Pepto-Bismol (bismuth subsalicylate) daily for gastro-oesophageal reflux symptoms. On his second day of admission, the plasma salicylate concentration was 2.08 mmol/L (reference range 1.10-2.20 mmol/L), despite no sources of salicylate in hospital. He was diagnosed with chronic salicylate toxicity and Pepto-Bismol use was discontinued. The patient was treated supportively with isotonic intravenous fluids only and plasma salicylate concentration fell to less than 0.36 mmol/L. Concurrently, all his symptoms resolved. This case highlights the potential adverse effects of over-the-counter medications. The diagnosis of chronic salicylate toxicity is challenging, specifically in the elderly and in undifferentiated presentations, as it can be missed if not suspected.

Is a timely assessment of the hematocrit necessary for cardiovascular magnetic resonance-derived extracellular volume measurements?

BACKGROUND: Cardiovascular magnetic resonance (CMR)-derived extracellular volume (ECV) requires a hematocrit (Hct) to correct contrast volume distributions in blood. However, the timely assessment of Hct can be challenging and has limited the routine clinical application of ECV. The goal of the present study was to evaluate whether ECV measurements lead to significant error if a venous Hct was unavailable on the day of CMR. METHODS: 109 patients with CMR T1 mapping and two venous Hcts (Hct0: a Hct from the day of CMR, and Hct1: a Hct from a different day) were retrospectively identified. A synthetic Hct (Hctsyn) derived from native blood T1 was also assessed. The study used two different ECV methods, (1) a conventional method in which ECV was estimated from native and postcontrast T1 maps using a region-based method, and (2) an inline method in which ECV was directly measured from inline ECV mapping. ECVs measured with Hct0, Hct1, and Hctsyn were compared for each method, and the reference ECV (ECV0) was defined using the Hct0. The error between synthetic (ECVsyn) and ECV0was analyzed for the two ECV methods. RESULTS: ECV measured using Hct1 and Hctsyn were significantly correlated with ECV0 for each method. No significant differences were observed between ECV0 and ECV measured with Hct1 (ECV1; 28.4 ± 6.6% vs. 28.3 ± 6.1%, p = 0.789) and between ECV0 and ECV calculated with Hctsyn (ECVsyn; 28.4 ± 6.6% vs. 28.2 ± 6.2%, p = 0.45) using the conventional method. Similarly, ECV0 was not significantly different from ECV1 (28.5 ± 6.7% vs. 28.5 ± 6.2, p = 0.801) and ECVsyn (28.5 ± 6.7% vs. 28.4 ± 6.0, p = 0.974) using inline method. ECVsyn values revealed relatively large discrepancies in patients with lower Hcts compared with those with higher Hcts. CONCLUSIONS: Venous Hcts measured on a different day from that of the CMR examination can still be used to measure ECV. ECVsyn can provide an alternative method to quantify ECV without needing a blood sample, but significant ECV errors occur in patients with severe anemia.

Effects of acute oral lead exposure on the levels of essential elements of mice: a metallomics and dose-dependent study.

BACKGROUND AND OBJECTIVES: Lead (Pb) has been reported to disturb the metabolism of essential elements, such as calcium (Ca), magnesium (Mg), iron (Fe) and zinc (Zn) in vivo. This study focused on the relationship between various dose of Pb and the essential elements. METHODS: 50 healthy male C57BL/6 mice underwent oral administration of 0.2 mL lead acetate trihydrate solution (0, 20, 100, 500, and 1000 mg Pb/day/kg body weight) for 3 days. The concentrations of Pb and four essential elements (Ca, Zn, Fe and Mg) in the blood, kidney, liver, bone and brain were quantified with inductively coupled plasma mass spectrometry. RESULTS: Various doses of Pb led to significant increases in the contents of Ca, Fe and Zn in the liver, and decreased contents of Mg and Fe in the blood in a dose-dependent pattern. The Pb dose of 20 mg/kg reduced the concentration of bone Ca, which did not continue to show an obvious decline with continued increases in the oral Pb dose. Pb also caused alterations in the Mg distribution pattern, and decreased the correlation of Mg, Ca and Zn in the brain, both findings were dose-dependent. In addition to the changes in metallomics, the related oxidative stress was exacerbated, but no significant changes were detected in hepatic and renal histopathological lesions after a short period of Pb exposure. CONCLUSIONS: This study contributes to a thorough analysis of the Pb-poisoning mechanism, and indicates that the concentrations of essential elements could be used as sensitive toxicological indicators of Pb exposure.

The interaction of lead exposure and CCM3 defect plays an important role in regulating angiogenesis through eNOS/NO pathway.

In this study, we aimed to explore the role of nitric oxide (NO) in regulating angiogenesis in cerebral cavernous malformations 3 gene (CCM3)-deficient mice exposed to lead during vascular development; further, we aimed to identify and study the potential mechanism involved as well. Angiogenesis was detected by whole mount immunofluorescent staining of retinal vessels in WT and CCM3+/- mice. Brain microvascular endothelial cells (BMECs) isolated from WT and CCM3+/- mice, primary HUVECs, and immortalized HUVECs (imHUVECs) (CCM3+/+ and CCM3-/-) were used and treated with lead acetate (PbAc). RT-PCR and Western blotting were used to detect the mRNA and protein expression of iNOS, eNOS, and VEGF genes. The results showed that both lead exposure and CCM3 gene deficiency adversely affected endothelial cell function, causing abnormal angiogenesis and vascular remodeling. The mRNA expression of eNOS and iNOS was significantly different in WT and CCM3+/- BMECs (0.04 ± 0.001 vs. 0.016 ± 0.002; 0.26 ± 0.002 vs. 0.306 ± 0.002, respectively), and the expression of eNOS and iNOS in imHUVECs (CCM3+/+ and CCM3-/-) also increased after PbAc exposure. In conclusion, CCM3 gene-deficient mice were more susceptible to abnormal vascular development after low-level lead exposure, probably due to the release of NO.

A comparison of multifunctional donors of carbon monoxide: Their anticoagulant, antioxidant, anti-aggregatory and cytotoxicity activities in an in vitro model.

The study examines the effect of two water-soluble carbon monoxide (CO) donors, CORM-3 and CORM-A1, on selected parameters of oxidative stress and hemostasis in human plasma and blood platelets in vitro. It also compares their activity with that of the lipid-soluble CORM-2. The oxidation of amino acid residues in plasma proteins was evaluated by measuring the amounts of thiol and carbonyl groups. Plasma lipid peroxidation was measured as thiobarbituric acid reactive substance (TBARS) concentration. In addition, three haemostatic parameters of plasma were studied, viz. activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT), and one haemostatic parameter of platelets (platelet aggregation). Treatment with CORM-3 and CORM-A1 (all concentrations from 0.1 to 100 µM) decreased thiol group oxidation induced by H2O2/Fe. Incubation with CORM-3 and CORM-A1 also influenced plasma coagulation activity, e.g. CORM-3 and CORM-A1 significantly prolonged TT at the two highest tested concentrations (50 and 100 µM). Only CORM-2 at the highest tested concentration (100 µM) and CORM-3 (50 and 100 µM) reduced platelet aggregation induced by ADP. None of the tested CORMs caused platelet damage. The treatment of various diseases associated with oxidative stress, including cardiovascular diseases, may be enhanced by the administration of CO donors CORM-2 and CORM-3, these being modulators of oxidative stress and hemostasis.

In Vivo Instability of 177Lu-DOTATATE During Peptide Receptor Radionuclide Therapy.

Peptide receptor radiotherapy using 177Lu-labeled somatostatin ligand analogs is a well-established treatment for neuroendocrine tumors, with 177Lu-DOTATATE having acquired marketing authorization in Europe and the United States. The investigation of the pharmacokinetics of these radiopharmaceuticals in vivo in humans is crucial for personalized treatment management and understanding of treatment effects. Such an investigation requires input data on the in vivo stability of the radiopharmaceuticals in blood and plasma. The work presented here is devoted to the investigation of the in vivo stability of 177Lu-DOTATATE in humans affected by neuroendocrine tumors. Methods: Blood samples of 6 patients undergoing 177Lu-DOTATATE were taken at 0.5, 4, 24, and 96 h after injection. Analysis of metabolic stability was performed using high-performance liquid chromatography. Results: A fast metabolism of the radiopharmaceutical was observed, with the fraction of intact 177Lu-DOTATATE in plasma decreasing rapidly to 23% ± 5% (mean ± SD) at 24 h and 1.7% ±0. 9% at 96 h after injection. Conclusion: The in vivo stability of 177Lu-DOTATATE is much lower than previously assumed, with the major part of radioactivity in plasma consisting of 177Lu-labeled metabolites already at 24 h after injection.

Comparison of zinc acetate hydrate and polaprezinc for zinc deficiency in patients on maintenance hemodialysis: A single-center, open-label, prospective randomized study.

The efficacy and safety of zinc acetate hydrate (ZAH) for zinc supplementation in patients on maintenance hemodialysis (MHD) remains unknown. In this prospective, single-center, open-label, parallel-group trial for MHD patients with serum zinc level <70 µg/dL, we compared ZAH (zinc; 50 mg/day) and polaprezinc (PPZ; zinc; 34 mg/day) beyond 6-month administration in a 1:1 randomization manner. The ZAH and PPZ groups had 44 and 47 patients, respectively. At 3 months, the change rate of serum zinc levels in the ZAH group was significantly higher than that in the PPZ group. Three months after the study, serum copper levels significantly decreased in the ZAH group, but not in the PPZ group. No significant differences were noted in anemia management in either group. ZAH was superior to PPZ in increasing serum zinc levels. Clinicians should note the stronger decline in serum copper levels when using ZAH for MHD patients.

Bismuth Concentrations in Patients Treated in Real-Life Practice with a Bismuth Subcitrate-Metronidazole-Tetracycline Preparation: The SAPHARY Study.

INTRODUCTION: A fixed-dose association of bismuth subcitrate, metronidazole and tetracycline (BMT) (Pylera®, Allergan, NJ, USA) was made available in France in 2013 for the eradication of Helicobacter pylori. Due to a historical issue of bismuth encephalopathy, the French Health Authorities requested a study of blood and plasma bismuth concentrations with BMT in daily practice. AIMS: The aim of the study was to measure eventual bismuth accumulation and neurological toxicity in patients prescribed BMT. METHODS: Patients initiating BMT for H. pylori between March 2014 and December 2015 were included. A blood sample was taken before first BMT intake and 24 h after the last intake, for assay of bismuth. A concentration > 50 µg/L was considered abnormal. Neurological complaints were assessed at inclusion, at the end of the 10-day treatment course, and 28 days later. RESULTS: 202 patients were included, of whom 190 took at least one dose of BMT, and 167 provided both required blood samples. Mean blood bismuth concentrations after the BMT course were 16.9 µg/L (95% confidence interval 15.6-18.3). Concentrations were > 50 µg/L (56.0 µg/L and 50.9 µg/L) in two elderly patients, one of whom presented mild, transient memory impairment during treatment. Non-serious neurological symptoms occurred in 20% of all patients and treatment failure was documented in 5% of patients. CONCLUSIONS: In this study measuring blood bismuth concentrations in real-life practice, in < 1% of patients the BMT course resulted in blood bismuth concentrations > 50 µg/L. No serious neurological adverse events were observed. STUDY REGISTRATION: EU-PAS register EUPAS3142 at www.encepp.eu ; ENCePP study seal.

Evaluation of the Interaction of Amino Acid Infusion on 177Lu-Dotatate Pharmacokinetics in Patients with Gastroenteropancreatic Neuroendocrine Tumors.

BACKGROUND AND OBJECTIVE: 177Lu-Dotatate is a radio-labeled analog of somatostatin used in the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. In order to prevent nephrotoxic effects of 177Lu-Dotatate a co-infusion of amino acids (AA) is administered, resulting in a decrease in tubular renal reabsorption of 177Lu-Dotatate. This study aimed to quantify the impact of AA co-infusion on the pharmacokinetics of 177Lu-Dotatate in cancer patients and to evaluate its relationship with toxicity during the first treatment cycle (C1). METHODS: 7.4 GBq of 177Lu-Dotatate was administered to 42 patients over a 30-min intravenous infusion. Infusion of AA started 2 h before and continued for 6 h after the infusion of 177Lu-Dotatate. Radioactivity-time data (n = 346) were analyzed using NONMEM® (version 7.2.0). RESULTS: 177Lu-Dotatate pharmacokinetics was best described by a three-compartment model with first-order elimination. AA co-infusion had a significant effect ('fixed effect') on 177Lu-Dotatate pharmacokinetics, with a mean value of 1.5-fold (95% confidence interval 1.03-1.97) increase in the elimination rate constant (k10) from 0.204 to 0.306 h-1, but this AA co-infusion effect was associated with a large inter-individual variability (IIV) of 104%. The individual k10 values increased during concomitant AA infusion by a factor ranging from 1.01 to 21.3 for 27 patients, whereas the opposite effect was observed in 15 patients (range 0.36-0.99) of whom seven had a k10 value lower than 0.85. This variability in AA effect contributed to the variability in 177Lu-Dotatate plasma exposure (area under the concentration-time curve from time zero to Day 15 for C1 [AUCDay15]) that correlated with lymphopenia observed at Day 15 (p = 0.004). CONCLUSIONS: A substantial effect of AA co-infusion on 177Lu-Dotatate pharmacokinetics was shown but was associated with high IIV, contributing to IIV in hematological toxicity.

Control of metabolic predisposition to cardiovascular complications of chronic kidney disease by effervescent calcium magnesium citrate: a feasibility study.

AIMS: Cardiovascular (CV) complications are common in chronic kidney disease (CKD). Numerous metabolic disturbances including hyperphosphatemia, high circulating calciprotein particles (CPP), hyperparathyroidism, metabolic acidosis, and magnesium deficiency are associated with, and likely pathogenic for CV complications in CKD. The goal of this feasibility study was to determine whether effervescent calcium magnesium citrate (EffCaMgCit) ameliorates the aforementioned pathogenic intermediates. METHODS: Nine patients with Stage 3 and nine patients with Stage 5D CKD underwent a randomized crossover study, where they took EffCaMgCit three times daily for 7 days in one phase, and a conventional phosphorus binder calcium acetate (CaAc) three times daily for 7 days in the other phase. Two-hour postprandial blood samples were obtained on the day before and on the 7th day of treatment. RESULTS: In Stage 5D CKD, EffCaMgCit significantly increased T50 (half time for conversion of primary to secondary CPP) from baseline by 63% (P = 0.013), coincident with statistically non-significant declines in serum phosphorus by 25% and in saturation of octacalcium phosphate by 35%; CaAc did not change T50. In Stage 3 CKD, neither EffCaMgCit nor CaAc altered T50. With EffCaMgCit, a significant increase in plasma citrate was accompanied by statistically non-significant increase in serum Mg and phosphate. CaAc was without effect in any of these parameters in Stage 3 CKD. In both Stages 3 and 5D, both drugs significantly reduced serum parathyroid hormone. Only EffCaMgCit significantly increased serum bicarbonate by 3 mM (P = 0.015) in Stage 5D. CONCLUSIONS: In Stage 5D, EffCaMgCit inhibited formation of CPP, suppressed PTH, and conferred magnesium and alkali loads. These effects were unique, since they were not observed with CaAc. In Stage 3 CKD, neither of the regimens have any effect. These metabolic changes suggest that EffCaMgCit might be useful in protecting against cardiovascular complications of CKD by ameliorating pathobiologic intermediates.

Complementarity of molecular and elemental mass spectrometric imaging of Gadovist™ in mouse tissues.

Drug biodistribution analyses can be considered a key issue in pharmaceutical discovery and development. Here, mass spectrometric imaging can be employed as a powerful tool to investigate distributions of drug compounds in biologically and medically relevant tissue sections. Both matrix-assisted laser desorption ionization-mass spectrometric imaging as molecular method and laser ablation inductively coupled plasma-mass spectrometric imaging as elemental detection method were applied to determine drug distributions in tissue thin sections. Several mouse organs including the heart, kidney, liver, and brain were analyzed with regard to distribution of Gadovist™, a gadolinium-based contrast agent already approved for clinical investigation. This work demonstrated the successful detection and localization of Gadovist™ in several organs. Furthermore, the results gave evidence that gadolinium-based contrast agents in general can be well analyzed by mass spectrometric imaging methods. In conclusion, the combined application of molecular and elemental mass spectrometry could complement each other and thus confirm analytical results or provide additional information.

The effect of lead (Pb) exposure and iron (Fe) deficiency on intestinal lactobacilli, E. coli and yeast: A study in experimental rats.

OBJECTIVE: The current study investigated the additive effect of oral lead (Pb) exposure and dietary iron (Fe) deficiency on intestinal lactobacilli, E. coli, and yeast in SD rats. METHODS: Weanling rats were fed on control diet (CD) or iron deficient diet (ID) for 4 weeks, followed by oral Pb exposure for another 4 weeks. Lead exposure was withdrawn for 2 weeks, and then resumed after 2 weeks. Blood samples were collected to determine haemoglobin (Hb), serum iron, blood Pb and δ-Aminolevulenic acid dehydratase (ALAD) activity. Fecal samples were collected to enumerate the lactobacilli, E. coli and yeast population on selective agar media and determine Pb levels. RESULTS: Hb and serum Fe levels decreased significantly in iron deficient rats. Pb exposed rats had a significant increase in blood Pb levels and decreased ALAD activity. The lactobacilli population was significantly decreased (p<0.05) in ID rats compared to the CD group. Further, a significant decrease in the lactobacilli population was observed in Pb exposed rats irrespective of the dietary regimen. Upon withdrawal of Pb exposure, lactobacilli increased significantly in both the CD+Pb and ID+Pb groups, whereas re-exposure to Pb decreased lactobacilli population. The E. coli and yeast populations were inconsistent among both the ID and Pb exposed rats compared to controls. Fecal Pb levels increased significantly in Pb exposed rats irrespective of diet. CONCLUSION: An additive effect of dietary Fe deficiency and oral Pb exposure resulted in greater reductions in the intestinal lactobacilli population compared to either treatment alone. In addition, transient withdrawal of Pb exposure led to improved lactobacilli population irrespective of Fe status.

Pharmacokinetic of meglumine antimoniate encapsulated in phosphatidylserine-liposomes in mice model: A candidate formulation for visceral leishmaniasis.

Visceral leishmaniasis (VL) is a fatal parasitic disease caused by the protozoan Leishmania spp. Meglumine antimoniate (MA) is the main treatment and has demonstrated a promising efficacy in a VL-model when encapsulated into negatively charged liposomes. Considering the current concept for the evaluation of pharmacokinetic parameters at early phases of drug discovery, we developed a formulation of MA-encapsulated into phosphatidylserine liposomes (MA-LP) and analyzed the in vitro antileishmanial activity, physicochemical properties, and pharmacokinetic profile in a mice model. The liposomal formulation had an internal mean diameter of 114 nm and a high stability in plasma. MA-LP was 23-fold more in vitro effective against Leishmania infantum-infected macrophages than the free drug, with a selectivity index higher than 220. The pharmacokinetic studies demonstrated that the liposomes increased the uptake of the drug by the liver and spleen and promoted sustained levels. MA-LP was first eliminated through renal excretion, followed by biliary excretion. In the blood, MA-LP followed a biexponential open model. This work emphasizes the importance of liposomes as potential drug delivery systems for visceral leishmaniasis.

UHPLC-MS and MALDI-MS study of aluminum phthalocyanine chloride and development of a bioanalytical method for its quantification in nanoemulsions and biological matrices.

Metal phthalocyanines are promising components in photodynamic therapy. Aluminum phthalocyanine chloride (AlClPc) has been used to treat oral cancer in mice, human carious tissue, lung cancer cells and other conditions. To overcome the high hydrophobicity of AlClPc, phthalocyanine is often encapsulated in nanoformulations. Despite increased usage, little is known about the pharmacokinetics and biodistribution of AlClPc. The aim of this study was the development and validation of a UHPLC-MS method for the determination of AlClPc in solution after extraction from nanoformulations and biological matrices such as plasma and tissue. The described method has been assayed as to selectivity, linearity, limits of detection and quantification, precision and recovery. The present study is the first to describe the behavior of AlClPc in biological matrices with mass spectrometry as well as the first to describe the chromatographic behavior of AlClPc contaminants. Molecular mass analysis identified dechlorination of AlClPc by both LC/MS and MALDI-MS and an adduct formation in LC/MS. The parameters observed indicated that the method has applicability and robustness for use in biodistribution studies.

Differences in gadolinium retention after repeated injections of macrocyclic MR contrast agents to rats.

PURPOSE: To compare the levels of gadolinium in the blood, cerebrum, cerebellum, liver, femur, kidneys, and skin after multiple exposure of rats to the macrocyclic gadolinium-based contrast agents (GBCAs) gadoterate, gadobutrol, and gadoteridol. MATERIALS AND METHODS: Fifty male Wistar Han rats were randomized to three exposure groups (n = 15 per group) and one control group (n = 5). Animals in the exposure groups received a total of 20 GBCA administrations (four administrations per week for 5 consecutive weeks) at a dose of 0.6 mmol/kg bodyweight. After a 28-day recovery period animals were sacrificed and the blood and tissues harvested for determination of gadolinium (Gd) levels. Gd determination was performed by inductively coupled plasma mass spectrometry (ICP-MS). RESULTS: After 28 days' recovery no Gd was found in the blood, liver, or skin of any animal in any group. Significantly lower levels of Gd were noted with gadoteridol compared to gadoterate and gadobutrol in the cerebellum (0.150 ± 0.022 vs. 0.292 ± 0.057 and 0.287 ± 0.056 nmol/g, respectively; P < 0.001), cerebrum (0.116 ± 0.036 vs. 0.250 ± 0.032 and 0.263 ± 0.045 nmol/g, respectively; P < 0.001), and kidneys (25 ± 13 vs. 139 ± 88 [P < 0.01] and 204 ± 109 [P < 0.001], respectively). Higher levels of Gd were noted in the femur (7.48 ± 1.37 vs. 5.69 ± 1.75 and 8.60 ± 2.04 nmol/g, respectively) with significantly less Gd determined for gadoterate than for gadobutrol (P < 0.001) and gadoteridol (P < 0.05). CONCLUSION: Differences exist between macrocyclic agents in terms of their propensity to accumulate in tissues. The observed differences in Gd concentration point to differences in GBCA washout rates in this setting and in this experimental model, with gadoteridol being the GBCA that is most efficiently removed from both cerebral and renal tissues. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2018;47:746-752.

Blood clearance and occupational exposure for 177Lu-DOTATATE compared to 177Lu-PSMA radionuclide therapy.

The main target of this work is to examine blood clearance and external exposure for 177Lu-DOTATATE compared with new emerging 177Lu-PSMA therapy. Blood clearance and radiation exposure of 31 patients treated with 5.5 ± 1.1 GBq 177Lu-DOTATATE were compared to those of 23 patients treated with 7.4 GBq 177Lu-PSMA. Dose rates were measured at several distances and time points up to 120 h after treatment. Blood samples were collected conjunctively after infusion. Caregiver's cumulative dose was measured by means of an OSL (optically stimulated luminescence) dosimeter for 4-5 days and medical staff's dose was also estimated using electronic personal dosimeters. Finger dose was determined via ring TLD (Thermoluminescence Dosimeter) for radiopharmacists and nurses. Dose rates due to 177Lu-DOTATATE at a distance of 1 m, 4 h and 6 h after infusion, were 3.0 ± 2.8 and 2 ± 1.9 µSv/(h GBq), respectively, while those due to 177Lu-PSMA were 3.1 ± 0.8 and 2.2 ± 0.9 µSv/(h GBq). Total effective dose of 17 caregivers was 100-200 µSv for 177Lu-DOTATATE therapy. Mean effective doses to nurses and radiopharmacists were 5 and 4 µSv per patient, respectively, while those for physicists and physicians were 2 µSv per patient. For 177Lu-DOTATATE, effective half-life in blood and early elimination phase were 0.31 ± 0.13 and 4.5 ± 1 h, while they were found as 0.4 ± 0.1 and 5 ± 1 h, respectively, for 177Lu-PSMA. The first micturition time following 177Lu-DOTATATE infusion was noted after 36 ± 14 min, while the second and third voiding times were after 74 ± 9 and 128 ± 41 min, respectively. It is concluded that blood clearance and radiation exposure for 177Lu-DOTATATE are very similar to those for 177Lu-PSMA, and both treatment modalities are reasonably reliable for outpatient treatment, since the mean dose rate [2.1 µSv/(h GBq)] decreased below the dose rate that allows release of the patient from the hospital (20 µSv/h) after 6 h at 1 m distance.

Lead Transiently Promotes Granulocyte-Macrophage Progenitor Differentiation and Subsequently Suppresses Common Myeloid Progenitor Differentiation.

Lead (Pb) is a toxic heavy metal affecting human health; it is known to be harmful to various organs or systems, yet the mechanisms by which Pb influences immune cell development remain to be defined. In this study, we show that Pb exposure (1250 ppm via drinking water) selectively impacted the development of myeloid cells (myelopoiesis). After Pb treatment of adult C57BL/6 mice, the numbers of granulocyte-macrophage progenitors (GMP) were consistently reduced, whereas the numbers of myeloid cells were increased at week (wk) 1 and decreased at wk8 after initiating the Pb exposure. Functional assays indicate that Pb accelerated GMP differentiation in a reactive oxygen species-dependent manner after treatment for 1 week and inhibited common myeloid progenitor differentiation by upregulating interferon regulatory factor 8 (IRF8) expression after treatment for 8 weeks. Consistent with the distinct Pb influences on myeloid cells observed at wk1 and wk8, Pb caused an inflammatory environment in vivo at wk8, but not at wk1. Furthermore, like the observations in mice during the Pb exposure, bloods from humans occupationally exposed to Pb had their numbers of monocytes, neutrophils and GMP negatively associated with the Pb concentration, whereas IRF8 expression in common myeloid progenitor, but not GMP, was positively correlated with the Pb concentration. These data suggest an occupationally relevant level of Pb exposure preferentially influences myelopoiesis involving reactive oxygen species and IRF8, which may contribute to the current understanding of the hematopoietic toxicology of Pb.