Search

Background: Spontaneous breathing during and after delayed cord clamping (DCC) stabilizes cardiopulmonary transition at birth. Caffeine stimulates breathing and decreases apnea in premature newborns. We evaluated the pharmacokinetics and physiological effects of early caffeine administration-direct injection into the umbilical vein (UV) during DCC or administered through a UV catheter (UVC) after delivery., Methods: Eighteen extremely premature lambs (125-127d, term gestation 145d) were exteriorized and instrumented. Lambs received caffeine-citrate at high (40 mg/kg) or standard-dose (20 mg/kg) via direct UV (DUV) injection during DCC, or via the UVC., Results: Mean peak plasma caffeine concentrations were lower with high-dose DUV compared to UVC (18 ± 4.3 vs. 46 ± 12 mg/L, p < 0.05). With standard-dose caffeine, mean peak plasma levels were 7.48 ± 2.6 with DUV and 28.73 ± 9.4 mg/L with UVC. The volume of distribution was higher in the DUV group compared to UVC (2.5 ± 1.0 vs. 0.69 ± 0.15 L/kg) with an estimated 39 ± 18% entering the maternal circulation. Maternal peak concentrations were 0.79 ± 0.71 and 1.43 ± 0.74 mg/L with standard and high-dose DUV, respectively., Conclusions: Caffeine injected directly into the UV during DCC is feasible but achieves lower concentrations due to high volume of distribution including maternal circulation. Further trials evaluating DUV caffeine injection should use higher caffeine doses., Impact: Respiratory stimulation with early caffeine may reduce the need for intubation in preterm infants. In the preterm lambs, caffeine injection directly into the umbilical vein during delayed cord clamping is feasible. Plasma caffeine concentrations are less than half when administered directly into the umbilical vein during delayed cord clamping compared to administration via an umbilical venous catheter following birth likely attributed to a larger volume of distribution or injection site leak. There were no significant hemodynamic alterations following caffeine injection., (© 2024. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Objective: The aim of this study is to assess the effects of administering 20 mg/kg loading dose of caffeine citrate intravenously on splanchnic oxygenation in preterm infants., Study Design: The infants with a gestational age (GA) of <34 weeks who were administered with a 20 mg/kg intravenous loading dose of caffeine citrate within 48 hours after birth were investigated prospectively. Regional splanchnic oxygen saturation (rsSO 2 ) and splanchnic fractional tissue oxygen extraction rate (sFTOE) were measured using near-infrared spectroscopy before caffeine infusion, immediately after caffeine infusion and 1, 2, 3, 4, and 6 hours (h) after dose completion; postdose values were compared with predose values., Results: A total of 41 infants with a mean GA of 29.2 ± 1.6 weeks and birth weight of 1,315 ± 257 g as well as postnatal age of 32.2 ± 10.8 hours were included in the study. rsSO 2 significantly reduced from 63.1 to 57.5% immediately after caffeine infusion, 55.1% after 1 hour, and 55.2% after 2 hours with partial recovery at 3-hour postdose. sFTOE increased correspondingly., Conclusion: Caffeine reduces splanchnic oxygenation and increases splanchnic oxygen extraction for at least 2 hours with partial recovery to predose levels at 3-hour postdose., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Gallium-68 is an ideal research and hospital-based PET radioisotope. The uptake mechanism of Gallium citrate is a combination of specific and non-specific processes, for example, vasodilatation, increased vascular permeability, plasma transferrin binding and lactoferrin and siderophores., Objective: In this study, by applying the 68 Ge/ 68 Ga generator product, a simple technique for the synthesis and quality control of 68Ga-citrate was introduced and was followed by preliminary animal studies., Methods: The synthesis of 68 Ga-citrate was performed with a cationic method using the Scintomics automated synthesis system (Scintomics GmbH GRP module 4V). Since the standard procedure for quality control (QC) was not available, the definition of chemical and radiochemical purity of 68 Ga-citrate was carried out according to the ICH Q2(R1) guideline. The standard QC tests were analysed with Scintomics 8100 radio-HPLC system equipped with a radioactivity detector. In this study, a New Zealand rabbit weighing 2520 g was used for PET/CT images., Results: 68 Ga-citrate synthesis was performed by a cationic method without using organic solvents. The labelling efficiency was found to be >98%. The HPLC method used to assess the radiochemical purity of 68 Ga -citrate was validated as rapid, accurate and reproducible enough to apply it to patients safely. The physiological distribution of 68 Ga-citrate was investigated in a healthy rabbit. The blood pool, liver, spleen, kidneys and growth plates were the most common sites of 68 Ga-citrate involvement., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

What Is Known and Objectives: Caffeine citrate is a commonly used methylxanthine for pharmacologic treatment of apnea of prematurity. The aim of this study was to develop and verify a population pharmacokinetic (PPK) model, which can provide a reference for individualized caffeine citrate treatment of apnea in Chinese premature infants., Methods: A total of 88 serum concentration measurements from 46 preterm patients (median gestational age 29 weeks) were retrospectively collected and the relevant clinical data of patients were recorded. The PPK analysis was performed by non-linear mixed-effect modelling method using NONMEM. Allometric scaling was applied in the PPK analysis, and the final model was evaluated by graphic and statistical methods, including goodness-of-fit plots, normalized prediction distribution errors plots and bootstrap procedures., Results: A one-compartment model with first-order elimination was successfully fitted to the data. The typical scaled values for the parameters clearance and volume of distribution (V) were 0.268 L/h and 109 L per 70 kg, respectively. The weight at the time of blood collection (CW) and post-natal age were identified as important predictors for pharmacokinetic parameters of caffeine. The evaluation process showed good stability and predictability of the final PPK model., What Is New and Conclusion: This is a complete PPK study of caffeine citrate in Chinese premature infants with apnea, which complements caffeine pharmacokinetic data of the premature from China. A final PPK model was developed which may serve as a beneficial tool for the use of caffeine citrate in the treatment of apnea in Chinese preterm infants., (© 2020 John Wiley & Sons Ltd.)

The plasma elimination half-life of caffeine in the newborn is approximately 100 h. Caffeine is rapidly absorbed with complete bioavailability following oral dosing. Switching between parenteral and oral administration requires no dose adjustments. Caffeine has wide interindividual pharmacodynamic variability and a wide therapeutic index in preterm newborns. Thresholds of measurable efficacy on respiratory drive have been documented at plasma levels around 2 mg/L. At these low levels, caffeine competitively inhibits adenosine receptors (A1 and A2A). The toxicity threshold is ill-defined and possibly as high as 60 mg/L which can be lethal in adults. High doses of caffeine may produce better control of apnea. However, at high systemic drug concentrations, the pharmacodynamic actions of caffeine become more complex and worrisome. They include inhibition of GABA receptors and cholinergic receptors in addition to adenosine receptor inhibition, intracellular calcium mobilization and actions on adrenergic, dopaminergic and phosphodiesterase systems. The role of pharmacogenomic factors as determinants of neonatal pharmacologic response and clinical effects remains to be explored., (© 2020 Published by Elsevier Ltd.)

Garcinia cambogia is one of the most commonly used anti-obesity dietary supplements, and hydroxycitric acid (HCA) is a major constituent in the commercial preparations of Garcinia. High doses of HCA are often consumed without much awareness of its pharmacokinetic and toxicokinetic parameters, and therefore, a complete understanding of its effects is lacking. The first step in understanding these parameters is the availability of a reliable bioanalytical method. Here, we present the first report on a UPLC-MS/MS method for analysis of HCA in rat plasma after a simplified and cost-effective protein precipitation. Chromatographic separation of the analytes in the supernatant was achieved using hydrophilic interaction liquid chromatography, where mass parameters were optimized and a rapid 5-min quantitative assay was developed. The method was highly sensitive, accurate, precise and linear in the concentration range of 10.5-5000 ng/mL (validated according to the United States Food and Drug Administration guidelines). Further, the method was successfully used to describe the pharmacokinetic profile of HCA in rat plasma after the administration of pure HCA and commercial Garcinia preparations., (© 2020 John Wiley & Sons, Ltd.)

Caffeine is widely used in preterm neonates suffering from apnea of prematurity (AOP), and it has become one of the most frequently prescribed medications in neonatal intensive care units. Goal of this study is to investigate how caffeine citrate treatment affects sleep-wake behavior in preterm neonates. The observational study consists of 64 preterm neonates during their first 5 days of life with gestational age (GA) <32 weeks or very low birthweight of < 1500 g. A total of 52 patients treated with caffeine citrate and 12 patients without caffeine citrate were included. Sleep-wake behavior was scored in three stages: active sleep, quiet sleep, and wakefulness. Individual caffeine concentration of every neonate was simulated with a pharmacokinetic model. In neonates with GA ≥ 28 weeks, wakefulness increased and active sleep decreased with increasing caffeine concentrations, whereas quiet sleep remained unchanged. In neonates with GA < 28 weeks, no clear caffeine effects on sleep-wake behavior could be demonstrated. Caffeine increases fraction of wakefulness, alertness, and most probably also arousability at cost of active but not quiet sleep in preterm neonates. As such, caffeine should therefore not affect time for physical and cerebral regeneration during sleep in preterm neonates., (© 2020 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.)

The aim of this work is to determine the effect of chronic immobilization stress on kinetics and dosimetry of 67 Ga in a mouse model. A control group (CG) and a stress group (SG), each with 15 mice, were included in the study, and the latter group was subjected to a chronic immobilization stress model 2 h daily for 14 consecutive days. At day 13, 67 Ga-citrate was administered intraperitoneally (11.24 ± 0.44 MBq) to each mouse. Then, sets of three mice were obtained sequentially at 24, 36, 48, 60 and 72 h, in which the radionuclide activity was measured with an activity counter. The 67 Ga biokinetic data showed a fast blood clearance in the SG, with a mean residence time of 0.06 h. The calculated mean radiation absorbed doses were: liver (2.45 × 10 -03 Gy), heart (3.17 × 10 -04 Gy) and kidney (1.88 × 10 -04 Gy) in the SG. The results show that stress reduced weight gain by approximately 13% and also increased adrenal gland weight by 26%. On the other hand, chronic stress accelerates 67 Ga clearance after 24 h compared to normal conditions. It is concluded that murine organisms under chronic immobilization stress have higher gallium-67 clearance rates, decreasing the cumulated activity and absorbed dose in all organs.

Double tracer studies in healthy human volunteers with stable isotopes of cerium citrate were performed with the aim of investigating the gastro-intestinal absorption of cerium (Ce), its plasma clearance and urinary excretion. In the present work, results of the clearance of Ce in blood plasma are shown after simultaneous intravenous and oral administration of a Ce tracer. Inductively coupled plasma mass spectrometry was used to determine the tracer concentrations in plasma. The results show that about 80% of the injected Ce citrate cleared from the plasma within the 5 mins post-administration. The data obtained are compared to a revised biokinetic model of Ce, which was initially developed by the International Commission on Radiological Protection (ICRP). The measured plasma clearance of Ce citrate was mostly consistent with that predicted by the ICRP biokinetic model. Furthermore, in an effort to quantify the uncertainty of the model prediction, the laboratory animal data on which the ICRP biokinetic Ce model is based, was analyzed. The measured plasma clearance and its uncertainty was also compared to the plasma clearance uncertainty predicted by the model. It was found that the measured plasma clearance during the first 15 min after administration is in a good agreement with the modelled plasma clearance. In general, the measured clearance falls inside the 95% confidence interval predicted by the biokinetic model.

Physicochemical properties of actinides highly influence internal intake and biodistribution. An a priori knowledge of the dissolution properties of compounds involved in accidental exposure would be of great help in early dose assessment. However, this information is rarely available, leading to difficulties in interpreting excretion data from contaminated victims. We developed an in vitro acellular assay to predict in vivo bioavailability of actinides and improve medical handling of the victims. Various actinides of different physicochemical properties were used to validate the reliability of the assay to mimic in vivo behavior of the contaminants. Our assay was designed as a dynamic muticompartmental system in which an agarose gel represents the retention compartment of actinides and a dynamic phase the transfer compartment. Relevant physiological conditions were obtained by introducing various components both in the static and dynamic phases. The proposed model may provide a good prediction of in vivo behavior and could be used as a first assessment to predict the fraction of actinides that could be potentially transferred from retention compartments, as well as the fraction available to chelating drugs., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The plant Gastrodia elata is a type of the orchid plant Gastrodia elata Bl. which contains glycosides, phenols, polysaccharides, sterols, and organic acids and a variety of active ingredients are proved to have certain pharmacological activities. To understand the process in the body of Gastridua elata, we used HPLC to study pharmacokinetics and tissue distributions of adenosine, 4-hydroxybenzyl alcohol and Parishin C in rats. The results showed that the three ingredients could be detected in plasma and different organizations at various time points. There was no significant difference in systemic clearance at three ingredients and it may be show that the three ingredients distributed (0.475±0.025, 0.518±0.033, 0.699±0.051) quickly and eliminated (5.37±0.87, 4.54±0.69, 5.34±0.82) slowly in plasma. There was the highest content of adenosine in spleen, followed by liver and lung. The highest content of 4-hydroxybenzylacohol in liver, and was higher in spleen. Parishin C was highest in heart, followed by liver and spleen. It is obvious that the contents of three ingredients are all higher in liver. The trends of the three ingredients' contents in G. rhizome extract were consistent with the contents in the plasma after intravenous administration.

The current study was designed to develop and optimize lazaroid loaded nano-structured lipid carriers (LAZ-NLCs) using design of experiment approach for enhancing lazaroid brain exposure. Response surface plots were used to determine the effects of independent variables (amount of PEGylating agent and liquid lipid) on dependent variables (particle size, zeta potential and encapsulation efficiency), while numerical optimization was used for optimizing LAZ-NLCs composition. The optimal LAZ-NLCs were spherical in shape with measured size of 172.3 ± 3.54 nm, surface charge of -4.54 ± 0.87 mV and encapsulation efficiency of 85.01 ± 2.60%. The optimal LAZ-NLCs were also evaluated for hemolytic potential, storage stability and solid-state properties. The plasma pharmacokinetics along with brain and hepatic distributions of control lazaroid citrate solution and optimal LAZ-NLCs formulation were evaluated in Sprague-Dawley rats after the single bolus intravenous administration. The optimized LAZ-NLCs and the control lazaroid citrate solution had similar plasma pharmacokinetic profiles; however, differential organ bio-distributions were observed. The lazaroid exposure in brain was enhanced by two times with a decreased liver exposure by half for the NLCs group compared to the solution group., (Copyright © 2018 Elsevier B.V. All rights reserved.)

As with any new molecular imaging modality, accurate characterization of abnormalities on Ga-PSMA PET/CT imaging can be accomplished only if one is aware of the normal distribution pattern, physiological variants, and potential sources of false imaging findings. Altered biodistribution can have a significant impact on scan interpretation. Presented here is a rare case in which radiopharmaceutical radiolysis occurred causing excessive free Ga-citrate showing as an increased vascular activity. As Ga-PSMA PET/CT imaging is a relatively new imaging technique, it is important to be aware of such a potential technical pitfall in clinical practice in order to prevent scan misinterpretation.

Objective: To identify dosing strategies that will assure stable caffeine concentrations in preterm neonates despite changing caffeine clearance during the first 8 weeks of life., Methods: A 3-step simulation approach was used to compute caffeine doses that would achieve stable caffeine concentrations in the first 8 weeks after birth: (1) a mathematical weight change model was developed based on published weight distribution data; (2) a pharmacokinetic model was developed based on published models that accounts for individual body weight, postnatal, and gestational age on caffeine clearance and volume of distribution; and (3) caffeine concentrations were simulated for different dosing regimens., Results: A standard dosing regimen of caffeine citrate (using a 20 mg/kg loading dose and 5 mg/kg/day maintenance dose) is associated with a maximal trough caffeine concentration of 15 mg/L after 1 week of treatment. However, trough concentrations subsequently exhibit a clinically relevant decrease because of increasing clearance. Model-based simulations indicate that an adjusted maintenance dose of 6 mg/kg/day in the second week, 7 mg/kg/day in the third to fourth week and 8 mg/kg/day in the fifth to eighth week assures stable caffeine concentrations with a target trough concentration of 15 mg/L., Conclusions: To assure stable caffeine concentrations during the first 8 weeks of life, the caffeine citrate maintenance dose needs to be increased by 1 mg/kg every 1-2 weeks. These simple adjustments are expected to maintain exposure to stable caffeine concentrations throughout this important developmental period and might enhance both the short- and long-term beneficial effects of caffeine treatment., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Evaluate whether saliva could be a useful alternative to serum for routine therapeutic drug monitoring of caffeine in preterm infants using the enzyme multiplied immunoassay technique (EMIT) assay., Methods: We conducted a prospective study including preterm infants (less than 34 weeks' amenorrhea) admitted to the intensive care and neonatal medicine department. All infants received 5, 10, 15, 20 and 25mg/kg/day of citrate caffeine intravenously from the first to the fifth day of birth, respectively. For each patient, two concomitant blood and saliva samples corresponding to the trough concentrations were collected 24hours after each caffeine dose. The caffeine concentrations were determined using the EMIT ® 2000 caffeine assay., Results: Thirteen preterm infants were included. The saliva and the serum caffeine concentration increased proportionally to the administered dose. Saliva and serum kinetics were comparable and the saliva caffeine concentrations were correlated to the serum ones (r 2 =0.76)., Conclusion: Saliva caffeine monitoring by EMIT is a valid, useful and safe alternative to serum in preterm infants., (Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Nanocarriers have the potential to improve the therapeutic index of currently available drugs by improving their efficacy and achieving therapeutic steady-state levels over an extended period. The association of maghemite-rhodium citrate (MRC) nanoparticles (NPs) has the potential to increase specificity of the cytotoxic action. However, the interaction of these NPs with cells, their uptake mechanism, and subcellular localization need to be elucidated. This work evaluates the uptake mechanism of MRC NPs in metastatic and nonmetastatic breast cancer-cell models, comparing them to a nontumor cell line. MRC NPs uptake in breast cancer cells was more effective than in normal cells, with regard to both the amount of internalized material and the achievement of more strategic intracellular distribution. Moreover, this process occurred through a clathrin-dependent endocytosis pathway with different basal expression levels of this protein in the cell lines tested., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Abnormalities in zinc homeostasis are indicated in many human diseases, including Alzheimer disease (AD). 63 Zn-zinc citrate was developed as a positron emission tomography (PET) imaging probe of zinc transport and used in a first-in-human study in 6 healthy elderly individuals and 6 patients with clinically confirmed AD. Dynamic PET imaging of the brain was performed for 30 minutes following intravenous administration of 63 Zn-zinc citrate (∼330 MBq). Subsequently, body PET images were acquired. Urine and venous blood were analyzed to give information on urinary excretion and pharmacokinetics. Regional cerebral 63 Zn clearances were compared with 11 C-Pittsburgh Compound B ( 11 C-PiB) and 18 F-fluorodeoxyglucose ( 18 F-FDG) imaging data. 63 Zn-zinc citrate was well tolerated in human participants with no adverse events monitored. Tissues of highest uptake were liver, pancreas, and kidney, with moderate uptake being seen in intestines, prostate (in males), thyroid, spleen, stomach, pituitary, and salivary glands. Moderate brain uptake was observed, and regional dependencies were observed in 63 Zn clearance kinetics in relationship with regions of high amyloid-β plaque burden ( 11 C-PiB) and 18 F-FDG hypometabolism. In conclusion, zinc transport was successfully imaged in human participants using the PET probe 63 Zn-zinc citrate. Primary sites of uptake in the digestive system accent the role of zinc in gastrointestinal function. Preliminary information on zinc kinetics in patients with AD evidenced regional differences in clearance rates in correspondence with regional amyloid-β pathology, warranting further imaging studies of zinc homeostasis in patients with AD., (© The Author(s) 2016.)

Inhibition of the sodium-coupled citrate transporter (NaCT or SLC13A5) has been proposed as a new therapeutic approach for prevention and treatment of metabolic diseases. In a previous report, we discovered dicarboxylate 1a (PF-06649298) which inhibits the transport of citrate in in vitro and in vivo settings via a specific interaction with NaCT. Herein, we report the optimization of this series leading to 4a (PF-06761281), a more potent inhibitor with suitable in vivo pharmacokinetic profile for assessment of in vivo pharmacodynamics. Compound 4a was used to demonstrate dose-dependent inhibition of radioactive [(14)C]citrate uptake in liver and kidney in vivo, resulting in modest reductions in plasma glucose concentrations.

Objective: Centhaquin citrate is a novel agent being developed for use in the treatment of haemorrhagic shock. It has decreased mortality in rat, rabbit and pig models of hypovolaemic shock compared to hypertonic saline and lactated Ringer's resuscitation. The pharmacokinetics of centhaquin citrate have not been described to date., Methods: Sixteen male Sprague Dawley rats were given an intravenous bolus of 0.45 mg/kg centhaquin citrate. Rats were divided into two groups; plasma concentrations were measured at five time points for each group within 24 h after administration. Competing compartmental pharmacokinetic models were assessed. The nonparametric adaptive grid function within the Pmetrics package for R was used for parameter estimation. Predicted concentrations were calculated using population median and individual Bayesian posterior parameters., Key Findings: A two-compartment model of centhaquin citrate best fit the data. Median (IQR) values for elimination coefficient (Ke), volume of distribution (V) and intercompartmental transfer rates (Kcp, Kpc) were 8.8 (5.2-12.8) h(-1), 6.4 (2.8-10.4) l, 11.9 (4.6-15.0) h(-1) and 3.7 (2.3-9.1) h(-1), respectively., Conclusion: This is the first report of the pharmacokinetic parameters of centhaquin citrate in a rat model. Centhaquin citrate was found to have a short half-life with a large volume of distribution., (© 2015 Royal Pharmaceutical Society.)

Ethnopharmacological Relevance: Gastrodia elata Blume, a traditional Chinese herb, was widely used against convulsant, vertigo, paralysis, epilepsy, tetanus, asthma and immune dysfunctions. Gastrodin is one of the major bioactive components of G. elata and it is known for its anticonvulsive, anti-inflammatory, antiepileptic and neuroprotective effects., Materials and Methods: An ultra high performance liquid chromatography-fluorescence detection (UHPLC-FLD) method was developed to determine gastrodin in rat plasma. Gastrodin and Thiamphenicol (internal standard, IS) were extracted from rat plasma by immediately protein precipitation. The pharmacokinetics of gastrodin in rats by following differently administered types was studies: intragastric administration of gastrodin (100mg/kg), parishin (116 mg/kg, with the same mole of gastrodin moiety) and G. elata extract (2.3g/kg, with the same mole of gastrodin moiety). Non-compartmental pharmacokinetic profiles were constructed using the software of WinNonlin (Phoenix, version 6.3), and the pharmacokinetic parameters were compared using unpaired Student's t-test., Results: The results showed that the pharmacokinetic parameters, including Cmax, Tmax, AUC0-∞, t1/2, MRT, Vd, CL, were quite different among the three types of gastrodin administration. The administration of parishin and G. elata extract, which either could convert to gastrodin in vivo or contained free gastrodin and abundant gastrodin conjugates, gave rise to higher elimination half-life (t1/2) and mean residence time (MRT) values for gastrodin compared to free gastrodin administered., Conclusion: The comparison of the pharmacokinetics of gastrodin among three different administered types of gastrodin in rats suggested that administration of parishin or G. elata extract in clinic may result in a longer duration time of action than that of the administration of free gastrodin. The results may provide some guidance for the clinical applications of parishin and G. elata., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The aim of the present study was to evaluate the effect of silver nanoparticles (AgNPs) on Enchytraeus crypticus, applying a combined toxicokinetics and toxicodynamics approach to understand the relationship between survival and the development of internal Ag concentrations in the animals over time. Toxicity tests were conducted in medium composed of well-defined aqueous solutions added to inert quartz sand to avoid the complexity of soil conditions. Citrate-coated AgNPs (AgNP-Cit) and polyvinylpyrrolidone-coated AgNPs (AgNP-PVP) were tested and compared with silver nitrate (AgNO3), which was used as a positive control for Ag ion effects. The median lethal concentration (LC50) values based on Ag concentrations in the solution phase of the test medium decreased over time and reached steady state after 7 d, with AgNO3 and AgNP-PVP being more toxic than AgNP-Cit. Slow dissolution may explain the low uptake kinetics and lower toxicity of AgNP-Cit compared with the other 2 Ag forms. The LC50 values based on internal Ag concentrations in the animals were almost stable over time, highlighting the importance of integrating toxicokinetics and toxicodynamics and relating survival with internal Ag concentrations. Neither survival-based elimination rates nor internal LC50s in the organisms showed any significant evidence of nano-specific effects for both AgNPs, although they suggested some uptake of particulate Ag for AgNP-Cit. The authors conclude that the toxicity of both types of AgNP probably is mainly attributable to the release of Ag ions., (© 2015 SETAC.)

Multiple myeloma (MM) is a plasma cell neoplasm with skeletal destruction which could also spread to extramedullary regions. Common diagnostic imaging modalities include skeletal radiography, computed tomography (CT), magnetic resonance imaging (MRI). Recently, PET/CT is proposed as an ideal tomographic tool for diagnosis and follow-up, but impending factors includes high cost, limited availability of cameras and radiotracers. Bone scan and gallium scan are usually considered of limited clinical value. Herein, we present a 66-year-old Taiwanese man with MM, who was hospitalized to our hospital for bone pain control. Bone and gallium scintigraphies were obtained for bone pain and infection workup. However, unexpected features of discordant osseous uptake with high gallium-to-bone uptake ratio and extramedullary gallium uptake were noted which both indicated poor prognosis of MM. The patient then passed away due to rapid disease progression. In conclusion, although gallium and bone scintigraphies are considered less sensitive for MM, combined use may be a good alternative for 18F-FDG PET/CT in evaluation of disease extent and prognosis, especially in high-risk patients or with suspicion of disease progression.

Heparin, despite its significant side-effects, is the most commonly used anticoagulant for continuous renal replacement therapy in critical care setting. In recent years, citrate has gained much popularity by improving continuous renal replacement therapy circuit survival and decreasing blood transfusion requirements. However, its complex metabolic consequences warrant modification in the design of the citrate-based continuous renal replacement therapy protocol. With thorough understanding of the therapeutic mechanism of citrate, a simple and practicable protocol can be devised. Citrate-based continuous renal replacement therapy can be safely and widely used in the clinical setting with appropriate clinical staff training.

Background: (68)Ga-triacetylfusarinine C (TAFC) and (68)Ga-ferrioxamine E (FOXE) show great potential to be used as highly sensitive and selective tracers for Aspergillus infection imaging. Here we report on a comparison of the ex vivo biodistribution and small animal imaging of (68)Ga-TAFC and (68)Ga-FOXE versus (68)Ga-colloid and (68)Ga-citrate as unspecific control in mice., Methods: The radiochemical purity of tested (68)Ga labelled tracers was determined by RP-HPLC or ITLC-SG. Ex vivo biodistribution was studied in normal DBA/2 mice 30 min and 90 min p.i. Static and dynamic imaging were performed using µPET/CT., Results: (68)Ga-TAFC and (68)Ga-FOXE showed rapid renal excretion and low blood values even 90 min p.i. (68)Ga-TAFC showed almost no retention in other organs while (68)Ga-FOXE displayed some uptake in gastrointestinal tract. (68)Ga-colloid and (68)Ga-citrate revealed significantly different ex vivo biodistribution. (68)Ga-colloid showed pronounced radioactivity retention in the liver, while (68)Ga-citrate displayed high blood values and significant retention of radioactivity in highly perfused organs., Conclusions: From the results, both (68)Ga-TAFC and (68)Ga-FOXE have excellent and significantly different in vivo behaviour compared to (68)Ga-colloid and (68)Ga-citrate. (68)Ga-TAFC in particular confirmed its great potential use as a specific tracer for Aspergillus infection imaging.

Unlabelled: Imaging of inflammation early after myocardial infarction (MI) is a promising approach to the guidance of novel molecular interventions that support endogenous healing processes. (18)F-FDG PET has been used, but may be complicated by physiological myocyte uptake. We evaluated the potential of two alternative imaging targets: lactoferrin binding by (68)Ga-citrate and somatostatin receptor binding by (68)Ga-DOTATATE., Methods: C57Bl/6 mice underwent permanent coronary artery ligation. Serial PET imaging was performed 3 - 7 days after MI using (68)Ga-citrate, (68)Ga-DOTATATE, or (18)F-FDG with ketamine/xylazine suppression of myocyte glucose uptake. Myocardial perfusion was evaluated by (13)N-ammonia PET and cardiac geometry by contrast-enhanced ECG-gated CT., Results: Mice exhibited a perfusion defect of 30 - 40% (of the total left ventricle) with apical anterolateral wall akinesia and thinning on day 7 after MI. (18)F-FDG with ketamine/xylazine suppression demonstrated distinct uptake in the infarct region, as well as in the border zone and remote myocardium. The myocardial standardized uptake value in MI mice was significantly higher than in healthy mice under ketamine/xylazine anaesthesia (1.9 ± 0.4 vs. 1.0 ± 0.1). (68)Ga images exhibited high blood pool activity with no specific myocardial uptake up to 90 min after injection (tissue-to-blood contrast 0.9). (68)Ga-DOTATATE was rapidly cleared from the blood, but myocardial SUV was very low (0.10 ± 0.03)., Conclusion: Neither (68)Ga nor (68)Ga-DOTATATE is a useful alternative to (18)F-FDG for PET imaging of myocardial inflammation after MI in mice. Among the three tested approaches, (18)F-FDG with ketamine/xylazine suppression of cardiomyocyte uptake remains the most practical imaging marker of post-infarct inflammation.

Hemorrhagic complications have been reported in up to 30% of critically ill patients with AKI undergoing RRT with systemic anticoagulation. Because bleeding is associated with significantly increased mortality risk, strategies aimed at reducing hemorrhagic complications while maintaining extracorporeal circulation should be implemented. Among the alternatives to systemic anticoagulation, regional citrate anticoagulation has been shown to prolong circuit life while reducing the incidence of hemorrhagic complications and lowering transfusion needs. For these reasons, the recently published Kidney Disease Improving Global Outcomes Clinical Practice Guidelines for Acute Kidney Injury have recommended regional citrate anticoagulation as the preferred anticoagulation modality for continuous RRT in critically ill patients in whom it is not contraindicated. However, the use of regional citrate anticoagulation is still limited because of concerns related to the risk of metabolic complications, the complexity of the proposed protocols, and the need for customized solutions. The introduction of simplified anticoagulation protocols based on citrate and the development of dialysis monitors with integrated infusion systems and dedicated software could lead to the wider use of regional citrate anticoagulation in upcoming years., (Copyright © 2014 by the American Society of Nephrology.)

A rapid, sensitive and reliable UHPLC-ESI-MS/MS method was developed for simultaneous determination of gastrodin and parishin in rat plasma. The LLOQ of the two analytes were 1.00×10(-1) and 8.30×10(-5)μg/mL, respectively. The intra-day and inter-day precision were all less than 10% of the relative standard deviation (RSD), whilst the accuracy were all within ±15% of the relative error (RE). The proposed method was successfully applied for pharmacokinetics study on the two analytes in rats after oral administration of Gastrodiae rhizoma (GR) extract and powder at low, medium and high dosages. Blood samples were collected from the suborbital vein at predetermined time points and were precipitated using methanol. Chromatographic separations were carried out on a Kinetex XB-C18 column (2.1mm×150mm, 1.7μm) with a gradient mobile phase of acetonitrile-water with 0.1% formic acid as a modifier. The pharmacokinetic parameters of the two analytes in rats were obtained and the relative bioavailability of gastrodin and parishin in two formulations were calculated. The results indicated that higher bioavailability was obtained when low dosage of GR powder was used, whereas, higher bioavailability values were obtained when medium and high dosages of GR extract were used., (Copyright © 2014. Published by Elsevier B.V.)

Understanding the interaction of nanoparticles with biological fluid is important for predicting the behavior and toxicity of nanoparticles in living systems. The earthworm Eisenia andrei was exposed to citrate-coated silver nanoparticles (cAgNPs), and the interaction of cAgNPs with earthworm coelomic fluid (ECF), the cytotoxicity of cAgNPs in earthworm coelomocytes was assessed. The neutral red retention assay showed a reduction in lysosomal stability after exposure. The toxicity of silver ions dissolved from cAgNPs in the soil medium was not significant. The aggregation and dissolution of cAgNPs increased in ECF, which contains various electrolytes that alter the properties of nanoparticles, and their subsequent toxicity. Microscopic and dissolution studies demonstrated that the aggregation of cAgNPs rapidly increased, and readily dissolved in ECF. The bioavailability of cAgNPs to earthworms induced lysosomal cytotoxicity. This is the first report to test the interaction and lysosomal cytotoxicity of nanoparticles in earthworm biofluids., (Copyright © 2014 John Wiley & Sons, Ltd.)

Unlabelled: 2-[(18)F]fluoro-2-deoxy-D-glucose ((18)FDG) is a glucose surrogate commonly used in clinical or animal imaging but rarely in plant imaging to trace glucose metabolism. Recently, (18)FDG has been employed in plant imaging for studying photoassimilate translocation and glycoside biosynthesis. There is growing evidence that (18)FDG could be used as a tracer in plant imaging studies to trace sugar dynamics. However, to confirm this hypothesis, it was necessary to show that the observed (18)FDG distribution in an intact plant is an outcome of the chemical nature of the introduced radiotracer and not of the plant vascular architecture or radiotracer introduction method., Methods: In the present work, we fed (18)FDG and [(68)Ga]gallium-citrate ((68)Ga-citrate) solution through mature Arabidopsis thaliana leaf and monitored subsequent radioactivity distribution using positron autoradiography. The possible route of radioactivity translocation was elucidated through stem-girdling experiments. We also employed a bi-functional positron emission tomography/computed tomography (PET/CT) modality to capture (18)FDG radiotracer dynamics in one of the plants in order to assess applicability of PET/CT for 4-D imaging in an intact plant., Results: Autoradiography results showed that [(18)F] radioactivity accumulated mostly in roots and young growing parts such as the shoot apex, which are known to act as sinks for photoassimilate. [(18)F] radioactivity translocation, in this case, occurred mainly via phloem. PET/CT results corroborated with autoradiography. [(68)Ga] radioactivity, on the other hand, was mainly translocated to neighboring leaves and its translocation occurred via both xylem and phloem., Conclusion: The radioactivity distribution pattern and translocation route observed after (18)FDG feeding is markedly different from that of (68)Ga-citrate. [(18)F] radioactivity distribution pattern in an intact plant is found similar to the typical distribution pattern of photoassimilates. Despite its limitations in quantification and resolution, PET/CT could be a useful tool to elucidate in vivo dynamics of [(18)F] radioactivity in intact plants., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Humans face the risk of exposure to silver nanoparticles (AgNPs) due to their extensive application in consumer products. AgNPs can interact with many substances in the human body due to their chemically unstable nature and high activity properties, which might result in unknown hazards and even some serious diseases for humans. As the basic constituent element of human bodies, amino acids (AAs) differ in concentration and variety in different cells and tissues. Thus, understanding the transformation of citrate-coated AgNPs in the presence of AAs is crucial for determining their fate and toxicity in the human body. Our study focused on the transformation of the morphology, dissolution behavior and reaction product of AgNPs in different AA-containing systems and then evaluated the effect of these transformations on the cytotoxicity of AgNPs. The obtained results indicated that the addition of glycine with the lowest Ag(+) binding energy had little effect on the transformations and toxicity of AgNPs. While in the presence of histidine with higher Ag(+) binding energy, the Ag(+) release and particle size of AgNPs obviously increased. These transformations resulted in a decrease in the cytotoxicity of AgNPs due to the formation of Ag-His complex and the growth of AgNPs. Furthermore, l-cysteine with the highest Ag(+) binding energy could easily interact with AgNPs, transforming them completely to form [Ag(Cys)n](+) and Ag2S precipitates, which induced the largest decrease in AgNP toxicity. In summary, our results may provide useful information to understand the fate, transformation, and toxicity of citrate-coated AgNPs in the human body., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: Abnormalities of zinc homeostasis are indicated in many human diseases. A noninvasive imaging method for monitoring zinc in the body would be useful to understand zinc dynamics in health and disease. To provide a PET imaging agent for zinc, we have investigated production of (63)Zn (half-life, 38.5 min) via the (63)Cu(p,n)(63)Zn reaction using isotopically enriched solutions of (63)Cu-copper nitrate. A solution target was used for rapid isolation of the (63)Zn radioisotope from the parent (63)Cu ions. Initial biologic evaluation was performed by biodistribution and PET imaging in normal mice., Methods: To produce (63)Zn, solutions of (63)Cu-copper nitrate in dilute nitric acid were irradiated by 14-MeV protons in a low-energy cyclotron. An automated module was used to purify (63)Zn from (63)Cu in the target solution. The (63)Cu-(63)Zn mixture was trapped on a cation-exchange resin and rinsed with water, and the (63)Zn was eluted using 0.05 N HCl in 90% acetone. The resulting solution was neutralized with NaHCO3, and the (63)Zn was then trapped on a carboxymethyl cartridge, washed with water, and eluted with isotonic 4% sodium citrate. Standard quality control tests were performed on the product according to current good manufacturing practice, including radionuclidic identity and purity, and measurement of nonradioactive Zn(+2), Cu(+2), Fe(+3), and Ni(+2) by ion-chromatography high-performance liquid chromatography. Biodistribution and PET imaging studies were performed in B6.SJL mice after intravenous administration of (63)Zn-zinc citrate. (63)Cu target material was recycled by eluting the initial resin with 4N HNO3., Results: Yields of 1.07 ± 0.22 GBq (uncorrected at 30-36 min after end of bombardment) of (63)Zn-zinc citrate were obtained with a 1.23 M (63)Cu-copper nitrate solution. Radionuclidic purity was greater than 99.9%, with copper content lower than 3 μg/batch. Specific activities were 41.2 ± 18.1 MBq/μg (uncorrected) for the (63)Zn product. PET and biodistribution studies in mice at 60 min showed expected high uptake in the pancreas (standard uptake value, 8.8 ± 3.2), liver (6.0 ± 1.9), upper intestine (4.7 ± 2.1), and kidney (4.2 ± 1.3)., Conclusion: A practical and current good manufacturing practice-compliant preparation of radionuclidically pure (63)Zn-zinc citrate has been developed that will enable PET imaging studies in animal and human studies. (63)Zn-zinc citrate showed the expected biodistribution in mice., (© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

The purpose of the study was to develop and internally validate a nonlinear in vitro-in vivo correlation model for a chronotherapeutically programmed HPMC based propranolol HCl (PHCl) mini-tablet. A simple and sensitive HPLC method was developed for the determination of PHCl content in rabbit plasma. The influence of tri-sodium citrate (TSC) on release behaviour was investigated through in vitro dissolution and in vivo absorption. Linear and nonlinear (quadratic, cubic, sigmoid functions) deconvolution based in vitro-in vivo correlation (IVIVC) models were developed using in vitro dissolution data and bioavailability profile. Prediction errors were investigated for Cmax and AUC in the light of US FDA guidelines for average percent prediction error. Release rate indicated that TSC was directly proportional to its concentration in the formulation. In vitro optimized formulation showed nearly 4.5h lag time and 5.24 ± 1.74% drug releases in initial 4.5h following rapid release 97.11 ± 1.87% in 6h. The deconvolution based IVIVC model appeared to be curvilinear for all three pulsatile formulations. Among various functions investigated the model using cubic function showed a better correlation (r>0.99) and satisfies the US FDA guidelines for average percent prediction error of less than 10%., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The water-soluble zinc salts gluconate, sulfate, and acetate are commonly used as supplements in tablet or syrup form to prevent zinc deficiency and to treat diarrhea in children in combination with oral rehydration. Zinc citrate is an alternative compound with high zinc content, slightly soluble in water, which has better sensory properties in syrups but no absorption data in humans. We used the double-isotope tracer method with (67)Zn and (70)Zn to measure zinc absorption from zinc citrate given as supplements containing 10 mg of zinc to 15 healthy adults without food and compared absorption with that from zinc gluconate and zinc oxide (insoluble in water) using a randomized, double-masked, 3-way crossover design. Median (IQR) fractional absorption of zinc from zinc citrate was 61.3% (56.6-71.0) and was not different from that from zinc gluconate with 60.9% (50.6-71.7). Absorption from zinc oxide at 49.9% (40.9-57.7) was significantly lower than from both other supplements (P < 0.01). Three participants had little or no absorption from zinc oxide. We conclude that zinc citrate, given as a supplement without food, is as well absorbed by healthy adults as zinc gluconate and may thus be a useful alternative for preventing zinc deficiency and treating diarrhea. The more insoluble zinc oxide is less well absorbed when given as a supplement without food and may be minimally absorbed by some individuals. This trial was registered at clinicaltrials.gov as NCT01576627.

Sodium picosulfate (PICO-Na) is a member of the polyphenolic group of stimulant laxatives. Its major metabolites in humans are its active aglycone BHPM (bis-(p-hydroxyphenyl)-pyridyl-2-methane), the monoglucuronide (M1) and the monosulfate (M2) of BHPM. A sensitive, specific and rapid liquid chromatography-tandem mass spectrometry method was established and validated for the simultaneous determination of picosulfate (PICO) and its three major metabolites in human plasma to investigate the pharmacokinetics of PICO and its major metabolites. Following protein precipitation with acetonitrile, chromatographic separation was achieved on a Luna 5u C(18)(2) column using gradient elution starting with 10% of 10mM ammonium acetate followed by increasing percentages of acetonitrile to eliminate interferences due to in-source conversion of the conjugated metabolites. Detection was performed on a tandem mass spectrometer equipped with an electrospray ionization source operated in the positive mode, using the transitions of m/z 438.1→m/z 278.1 for PICO, m/z 278.1→m/z 184.2 for BHPM, m/z 454.1→m/z 184.2 for M1, and m/z 358.1→m/z 184.2 summed with m/z 358.1→m/z 278.1 for M2. Deuterium labeled compounds of the analytes were used as the internal standard, two of which, M1-d(12) and M2-d(12), were synthesized in-house. The method was validated in concentration ranges of 0.150-40.0 ng/mL for PICO and M2, 0.600-160 ng/mL for BHPM, and 0.045-12.0 ng/mL for M1 with acceptable accuracy and precision. The method was successfully applied to characterize the pharmacokinetic profiles of PICO and its metabolites in healthy volunteers after a single oral administration of 5mg PICO-Na., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Hepatitis C virus (HCV) infection represents a serious health-care problem. Previously we reported the identification of NA255 from our natural products library using a HCV sub-genomic replicon cell culture system. Herein, we report how the absolute stereochemistry of NA255 was determined and an enantioselective synthetic method for NA255 derivatives was developed. The structure-activity relationship of the NA255 derivatives and rat pharmacokinetic profiles of the representative compounds are disclosed., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

This study evaluated the effective dose of Ga-67 for a patient undergoing Ga-67 citrate nuclear examination by applying thermoluminescent dosimeter (TLD) technique and an indigenous water phantom. The Ga-67 radionuclide remaining in the body inevitably generated a measurable internal dose even though gamma camera scanning took only minutes to complete the clinical examination. For effective simulation of the cumulated effective dose for a patient undergoing examination, 150 TLDs were placed inside the water phantom for 6 days to monitor the gamma ray dose from the distributed Ga-67 citrate solution. The inserted TLDs represented internal organs, and the effective dose was calculated according to data in the ICRP-60 report. The water phantom was designed to model the body of a healthy human weighing 70 kg, and the water that was mixed with Ga-67 citrate solution was slowly replaced with fresh feed water to yield the required biological half life of the phantom. After continuously feeding in fresh water throughout the 6 days of TLD exposure, the TLDs were analyzed to determine the effective doses from the various biological half lives of the phantom. The derived effective dose of 185 MBq Ga-67 citrate solution for male/female (M/F) was 10.7/12.2, 10.7/12.0, 8.7/9.9 and 6.0/6.8 mSv, of biological half lives of 6.0, 4.5, 3.0 and 1.5 days, respectively. Although these experimental results correlated well with earlier empirical studies, they were lower than most calculated values. The cumulated uncertainty in the effective dose was 12.5-19.4%, which was acceptable in terms of both TLD counting statistic and reproducibility.

The clinical benefit of implementing Bayesian approach for lithium drug monitoring was evaluated. Intervention group (N = 42) and historical control group (N = 55) patients were each divided into two groups: Dosage with immediate-release lithium carbonate or a sustained-release formulation, lithium citrate. Bayesian approach was performed in the intervention groups, and estimation of lithium steady-state trough concentration was obtained from non-steady-state blood sample, collected about 12 hr after the first lithium study dose. The estimate was compared with the actually measured steady-state concentration. In the control group, lithium monitoring was traditionally performed as steady-state blood sampling. Predicted and measured lithium concentrations were comparable. The desired lithium dose was reached significantly faster in the intervention group compared to control; 2.47 ± 2.22 days versus 9.96 ± 11.24 days (mean ± S.D.) (p = 0.0003). Bayesian approach was an advantage for the clinicians as a fast and safe aid to obtain the optimal lithium treatment dose., (© 2011 The Authors. Basic & Clinical Pharmacology & Toxicology © 2011 Nordic Pharmacological Society.)

Objective: Gastric uptake of (67)Ga may be observed in patients with no obvious gastric lesions, as well as those with gastric malignancy. The aim of this study was to investigate whether the use of an effervescent agent aids in evaluating gastric (67)Ga uptake., Methods: Twenty patients having or suspected of having gastric uptake on whole-body (67)Ga scintigrams were studied. Anterior abdominal images were obtained at baseline and after the oral intake of the effervescent agent (gas contrast image). The presence or absence of malignant gastric uptake was judged visually using the baseline image or gas contrast image. The judgment was compared with the clinical diagnosis, and the clinical usefulness of the gas contrast technique was assessed., Results: In all patients, successful distension of the stomach was indicated in the gas contrast image. Clinical assessment showed gastric lesions in six patients (gastric involvement of lymphoma in 3, primary gastric lymphoma in 2, and adenocarcinoma in 1). The gas contrast image yielded accurate judgments of malignant gastric uptake in all patients except one with adenocarcinoma. Imaging after gastric distension induced by the oral effervescent agent contributed to excluding malignant gastric uptake in eight patients and demonstrating malignant gastric uptake in four patients., Conclusions: Benign gastric uptake may complicate the assessment of gastric lesions in (67)Ga scintigraphy. Additional spot imaging after oral intake of an effervescent agent can aid in evaluating malignant gastric lesions through gastric distension.

Objectives: 67Ga-Citrate has been extensively used for infection and inflammation imaging for the past four decades but has limitations. In the present study, we explored the ability of 68Ga-Citrate to detect Staphylococcus aureus (Staph A) infection in rats and further studied its ability to localize intra-abdominal infection in a patient., Methods: An infection was induced in male Wistar rats by injecting Staph A in the right thigh muscle. In this study a simple method was described for the preparation of 68Ga-Citrate with > 99% yield and purity. 68Ga-Citrate (15 MBq/rat and 150 MBq/patient) was injected intravenously and the images were acquired for 10 min each., Results: 68Ga-Citrate uptake was moderate at the infection lesion within 5 min post injection but intense focal uptake was visualized from 30 min to 6 hr post-injection in rats. Cardiac blood pool and liver activity decreased during the same period of study. In the patient studied, an infected area in the abdomen at the site of recent appendectomy was detected within 30min post-injection of 68Ga-Citrate, which was consistent with CT and microbiology findings., Conclusion: A simple method of preparation of 68Ga-Citrate with > 99% yield and purity was described, suitable for routine clinical work. Our results showed 68Ga-Citrate is capable of detecting Staph A infection in rats and an intraabdominal infection in a post-operative patient. These findings indicate the high potential of 68Ga-Citrate for clinical utility.

Background: Single-dwell studies in rats and humans have shown that supplementing citrate for lactate in peritoneal dialysis (PD) fluids improves ultrafiltration (UF). ♢, Methods: The long-term effects of citrate-substituted PD fluids on PD catheter patency, UF, and peritoneal morphology were evaluated in a rat model over 5 weeks of daily PD fluid exposure. A standard 2.5% glucose 40 mmol/L lactate PD fluid and a corresponding 10/30 mmol/L citrate/lactate PD fluid were compared. In a control group, rats with catheters received no PD fluid. ♢, Results: The average patency time (% of 36 days) of silicone rubber PD catheters was significantly longer in the citrate PD group (98.8% ± 1.2%) and the control group (100% ± 0%) compared to the lactate PD group (54.7% ± 9.5%). In a separate experiment, heparin-coated polyurethane catheters were used to study peritoneal morphology and fluid transport. The citrate group had a higher net UF than the lactate group at the beginning and at the end of the 5 weeks. During the experiment, both fluid-treated groups suffered from UF loss; the control group showed the highest net UF at the end of the 5 weeks. Peritoneal vascular density and submesothelial thickness, indicators of angiogenesis and fibrosis, were not significantly different among the groups. Fibrosis was significantly negatively correlated to osmotic UF. ♢, Conclusion: A positive acute effect of citrate on UF was confirmed and conserved over time. Citrate PD strongly improved PD catheter patency time compared with lactate. Both citrate PD and lactate PD induced negative long-term effects on UF compared with control animals.

Background: Regional citrate anticoagulation is a very effective anticoagulation method for haemodialysis. However, it is not widely used, primarily due to the risk of hypocalcaemia. We studied citrate and calcium kinetics to better understand safety aspects of this anticoagulation method., Methods: During 15 haemodialysis treatments with a calcium-free dialysis solution, citrate was infused pre-dialyser and calcium was substituted post-dialyser. Systemic and extracorporeal citrate and calcium concentrations were repeatedly measured to calculate citrate and calcium pharmacokinetics., Results: Removal by dialysis constituted the major elimination pathway of citrate (83 +/- 5%). Systemic citrate load and concentrations were low (17 +/- 7 mmol/4 h, 0.3 +/- 0.15 mmol/l). Combined use of calcium-free dialysate and citrate infusion increased diffusible calcium to 80% of total calcium and induced substantial dialytic loss of calcium (43 +/- 4 mmol/4 h). Since calcium was substituted, systemic calcium balances were positive (approximately +5 mmol) and concentrations stable. Calcium supplementation correlated with calcium dialytic losses, which in turn were dependent on total calcium and haematocrit., Conclusions: When using calcium-free dialysate during citrate anticoagulation, hypocalcaemia is very likely unless calcium is re-infused, because large amounts of calcium are lost in the dialysate. However, an accumulation of citrate in the patient's systemic circulation is an unlikely cause of hypocalcaemia since most of the citrate is removed by dialysis. Calcium substitution and monitoring are the most important safety measures. We propose a rational approach based on haematocrit and total calcium for the choice of the starting calcium supplementation rate.

Purpose: To evaluate the association of gallium-67 ((67)Ga)-citrate thyroid uptake with the presence of thyroid disorders in patients with sarcoidosis (S patients)., Methods: Eighty-four S patients were evaluated by a complete thyroid work-up (neck ultrasound, circulating thyroid hormones and anti-thyroid antibodies, fine-needle aspiration)., Results: In S patients with (67)Ga thyroid uptake (respect those without): serum thyroid-stimulating hormone, the titre of anti-thyroid peroxidase (AbTPO) and/or anti-thyroglobulin antibodies (AbTg), and the prevalence of S patients with hypothyroidism or with positive AbTg or AbTPO was significantly higher; a thyroid hypoechoic pattern was more frequent. The prevalence of thyroid nodules was not significantly different between the two groups. Two cases of papillary thyroid cancer were observed in S patients without (67)Ga thyroid uptake, whilst no case in those with (67)Ga thyroid uptake., Conclusions: (67)Ga thyroid uptake is associated with the presence of aggressive autoimmune thyroiditis and hypothyroidism in S patients; thyroid function and ultrasonography should be performed in the presence of (67)Ga thyroid uptake.

The objective of this study was to develop a population model of the pharmacokinetics (PK) of caffeine after orogastric or intravenous administration to extremely premature neonates with apnea of prematurity who were to undergo extubation from ventilation. Infants of gestational age <30 weeks were randomly allocated to receive maintenance caffeine citrate dosing of either 5 or 20 mg/kg/d. Four blood samples were drawn at prerandomized times from each infant during caffeine treatment. Serum caffeine was assayed by enzyme-multiplied immunoassay technique. Concentration data (431 samples, median: 4 per subject) were obtained from 110 (52 male) infants of mean birth weight of 1009 g, current mean weight (WT) of 992 g, mean gestational age of 27.6 weeks, and mean postnatal age (PNA) of 12 days. Of 1022 doses given, 145 were orogastric, permitting estimation of absolute bioavailability. A 1-compartment model with first-order absorption was fitted to the data in NONMEM. Patient characteristics were screened (P < 0.01) in nested models for pharmacokinetic influence. Model stability was assessed by nonparametric bootstrapping. Clearance (CL) increased nonlinearly with increasing PNA, whereas volume of distribution (Vd) increased linearly with WT, according to the following allometric models: CL (L/h) = 0.167 (WT/70) (PNA/12); Vd (L) = 58.7 (WT/70). The mean elimination half-life was 101. Interindividual variability (IIV) of CL and Vd was 18.8 % and 22.3 %, respectively. Interoccasion variability (IOV) of CL and Vd was 35.1% and 11.1%, respectively. This study established that the elimination of caffeine was severely depressed in extremely premature infants but increased nonlinearly after birth up to age 6 weeks. Caffeine was completely absorbed, which has favorable implications for switching between intravenous and orogastric routes. The interoccasion variability about CL was twice the interindividual variability, which, among other factors, indicates that routine serum concentration monitoring of caffeine in these patients is not warranted.

Indium-111 ((111)In) has a strong binding affinity for transferrin (Tf), and the (111)In-Tf complex binds to Tf receptor in various tissues. In partial hepatectomy (PH), a part of blood in circulation is lost along with removed liver tissues; consequently, the number of blood cells and the amount of Tf in circulation decreases. These decreases should greatly affect the uptake of (111)In in the liver and bone marrow. In order to investigate this effect, we compared the uptake in partially hepatectomized rats with that in venesectioned rats, in which only the volume of blood in circulation had been decreased. Our data show that fewer blood cells and smaller amount of Tf in circulation due to venesection increased the uptake of (111)In in bone marrow, but not in the liver, whereas PH increased the uptake of (111)In in both bone marrow and liver. The higher bone marrow uptake of (111)In must be related to the increase of the hematopoietic function resulted from the smaller amount of blood; the higher uptake in liver may be closely related to liver regeneration.

Erdheim-Chester disease (E-C D) is a rare clinicopathologic entity with nearly pathognomonic radiographic features. About half of the affected exhibit extraskeletal manifestations, including involvement of the hypothalamus-pituitary axis, lung, heart, retroperitoneum, skin, liver, kidneys, spleen and orbit. This disease usually affects individuals in their fifties to their seventies and has a male preponderance. The lesions of E-C D consist of lipid-storing CD68 (+) and CD1a (-) non-Langerhans cell histiocytes, either localized to the bone or involving multiple systems of the body as well. Skeletal involvement is characteristically bilateral and symmetric, exhibiting an osteosclerotic pattern in the metaphysis and diaphysis of the long bones, usually sparing epiphysis. We recently had a 68 years old male patient with E-C D, with a mild and persistent knee pain, who was subjected to a 3-phase technetium-99m methylene diphosphonate ((99m)Tc-MDP) bone-scan and subsequently to gallium-67 citrate ((67)Ga-C) whole body scan. The characteristic symmetric pattern of these scans raised the question of E-CD disease. The patient showed an excellent symptomatic response to high-dose steroids. However, the symptoms recurred after discontinuation of treatment.

Purpose: To evaluate in serial gallium-67 scans (GS) the role of semiquantitative tumor-to-background (Tm/Bg) and tumor-to-liver ratios in assessing response rates to chemotherapy, in Hodgkin's disease and non-Hodgkin's lymphoma., Materials and Methods: Twenty-seven consecutive patients (15 Hodgkin's disease and 12 non-Hodgkin's lymphoma patients) with an average age of 30 (range, 5-60) years underwent GS at prechemotherapy, early chemotherapy (after first cycle), and postchemotherapy. Average tumor, background, and liver region of interest counts obtained and Tm/Bg, tumor-to-liver, and liver region to background ratios were derived for each patient on serial GS. All patients were assessed by visual and quantitative GS and followed up clinically for more than 7 years., Results: At early visual GS, 70% (19 of 27) of the patients showed rapid response, 15% (four of 27) showed delayed response (negative at post-GS), and 15% showed no response. Mean early-GS Tm/Bg ratio of disease-free patients (1+/-0.04) was significantly different from relapsed (1.4+/-0.2) (P<0.025) and progressive disease (1.8+/-0.7) patients. A significant difference was noted (P<0.01) in serial paired comparisons of Tm/Bg ratios between pretherapy and early-therapy scans in relapsed patients, whereas progressive disease patients showed no significant change during the same time. At early-GS, 15 patients showed quantitative rapid response (Tm/Bg ratio 1.04), nine patients showed quantitative delayed response (Tm/Bg ratio >1.04 with significant serial change between pretherapy and early-therapy GS), and three patients showed quantitative no response (Tm/Bg ratio >1.04 with nonsignificant serial change between pretherapy and posttherapy GS)., Conclusion: Quantitative GS is an effective tool in the detection of early response to chemotherapy. Quantitative response rates after the first cycle can more reliably identify patients who are most likely to be disease-free or relapse after first-line therapy or those that will show no response to therapy as compared with visual analysis alone.

Objective: Single-photon emission computed tomography (SPECT) using gallium (Ga) has been frequently used for diagnosing head and neck tumors in patients. Although the usefulness of Ga-SPECT is well known, the degree of the increase in diagnostic ability with Ga-SPECT for head and neck tumors has not been reported. We compared the ability of the planar images of Ga scintigraphy, SPECT images of Ga scintigraphy, and CT images to diagnose head and neck primary tumors and neck metastases., Methods: The subjects of this study were 167 patients with malignant head/neck lesions. For Ga scintigraphy, Ga-67-citrate (74 MBq) was injected via a cubital vein. Planar and SPECT images were taken 72 h after the Ga-67-citrate injection. The rate of detection of the primary lesions was compared first between SPECT and planar images then between SPECT and CT images. The rate of detection for each stage of disease according to the TNM classification was also analyzed., Results: The rate of detection of primary lesions was 50% with planar imaging and 69% with SPECT. And similarly, regarding the rate of detection of lymph node metastases, there was a significant difference between planar imaging and SPECT. The rate of detection of primary lesions was 70% for both CT and SPECT. At T stage, the rates of detection of primary lesions with each imaging technique were 11% with planar imaging and 39% with SPECT, and 22% with CT for stage T1., Conclusions: This study revealed the marked superiority of SPECT images over planar images in terms of the ability to detect primary tumors and tumor metastasis to cervical lymph nodes. Furthermore, the primary T1 tumor detection rate of SPECT images was higher than that of CT images. On the basis of these results, the concomitant use of SPECT is highly recommended when Ga scintigraphy is performed to check for malignant head/neck tumors.