Citrate pharmacokinetics in critically ill liver failure patients receiving CRRT.

Citrate has been proposed as anticoagulation of choice in continuous renal replacement therapy (CRRT). However, little is known about the pharmacokinetics (PK) and metabolism of citrate in liver failure patients who require CRRT with regional citrate anticoagulation (RCA). This prospective clinical PK study was conducted at King Chulalongkorn Memorial Hospital between July 2019 to April 2021, evaluating seven acute liver failure (ALF) and seven acute-on-chronic liver failure (ACLF) patients who received CRRT support utilizing RCA as an anticoagulant at a citrate dose of 3 mmol/L. For evaluation of the citrate PK, we delivered citrate for 120 min and then stopped for a further 120 min. Total body clearance of citrate was 152.5 ± 50.9 and 195.6 ± 174.3 mL/min in ALF and ACLF, respectively. The ionized calcium, ionized magnesium, and pH slightly decreased after starting citrate infusion and gradually increased to baseline after stopping citrate infusion. Two of the ACLF patients displayed citrate toxicity during citrate infusion, while, no ALF patient had citrate toxicity. In summary, citrate clearance was significantly decreased in critically ill ALF and ACLF patients receiving CRRT. Citrate use as an anticoagulation in these patients is of concern for the risk of citrate toxicity.

Citrate activates autophagic death of prostate cancer cells via downregulation CaMKII/AKT/mTOR pathway.

AIM: The aim of this study was to explore the antitumor effect of citrate on prostate cancer and its underlying mechanism. MAIN METHODS: CCK-8 and Colony formation assay were performed to detect the anti-proliferative effect of citrate on prostate cancer. Flow cytometry analysis was conducted to investigate the pro-apoptosis effect of citrate on prostate cancer. Immunofluorescence assay was taken to detect whether citrate induced autophagy in prostate cancer. Western blot and Immunohistochemical assay were performed to explore the underlying mechanism by which citrate activates autophagic death in prostate cancer cells. Xenograft tumorigenicity assay was conducted to explore whether citrate suppressed the growth of xenograft prostate tumors in vivo. KEY FINDINGS: We found citrate could significantly induce apoptosis and autophagy of prostate cancer cells in vitro and in vivo. Furthermore, treatment with autophagy inhibitor (chloroquine) drastically suppresses the apoptosis rate of prostate cancer induced by citrate. Based on the Ca2+-chelating property of citrate, the further study suggested that citrate activates autophagic cell death in prostate cancer cells via downregulation CaMKII/AKT/mTOR pathway. Finally, citrate suppresses the growth of xenograft prostate tumors without remarkable toxicity in mice. SIGNIFICANCE: Our study elucidated a novel molecular mechanism about the anti-cancer activities of citrate. That citrate activates autophagic cell death of prostate cancer via downregulation CaMKII/AKT/mTOR pathway and without remarkable toxicity in mice. This study suggests that citrate might be a promising therapeutic agent for the treatment of prostate cancer.

Surface modifications affect iron oxide nanoparticles' biodistribution after multiple-dose administration in rats.

Iron oxide nanoparticles (IONPs) possess many utilizable physical and chemical properties and have an acceptable level of biocompatibility. Therefore, they are extensively used in different medical applications. Hence, the challenge is to modify the surfaces of prepared iron oxide nanoformulations with a biocompatible coat to enhance their biosafety. In this study, different formulations of IONPs with different capping agents (citrate [Cit-IONPs], curcumin [Cur-IONPs], and chitosan [CS-IONPs]) were prepared and characterized using various physicochemical techniques. The biodistribution of iron and the histopathology of affected tissues were assessed after Cit-IONPs, Cur-IONPs, CS-IONPs, and commercial ferrous sulfate were orally administered to adult female Wistar rats for 10 consecutive days at a dose of 4 mg/kg of body weight/day. The results were compared with a control group injected orally with saline. The iron content in the kidneys, liver, and spleen was measured by atomic absorption spectroscopy. Histopathological alterations were also examined. The biodistribution results demonstrate that iron accumulated mainly in the liver tissue, whereas the lowest liver accumulation was observed after the administration of Cit-IONPs or CS-IONPs, respectively. In contrast, the administration of CS-IONPs displayed the highest spleen iron accumulation. The ferrous sulfate (FeSO4 )-treated group showed the highest kidney iron accumulation as compared with the other groups. The histopathological examination revealed that signs of toxicity were predominant for groups treated with Cit-IONPs or commercial FeSO4 . However, Cur-IONPs and CS-IONPs showed mild toxicity when administered at the same doses. The results obtained in the present study will provide insights into the expected in vivo effects after administration of each nanoformulation.

A pH-responsive citric-acid/α-cyclodextrin-functionalized Fe3O4 nanoparticles as a nanocarrier for quercetin: An experimental and DFT study.

Developing new nanocarriers and understanding the interactions between the drug and host molecules in the nanocarrier at the molecular level is of importance for future of nanomedicine. In this work, we synthesized and characterized a series of iron oxide nanoparticles (IONPs) functionalized with different organic molecules (citric acid, α-cyclodextrin, and citric acid/α-cyclodextrin composite). It was found that incorporation of citric acid into the α-cyclodextrin had negligible effect on the adsorption efficiency (<5%) of citric acid/α-cyclodextrin functionalized IONPs, while the isotherm adsorption data were well described by the Langmuir isotherm model (qmax = 2.92 mg/g at T = 25 °C and pH = 7). In addition, the developed nanocarrier showed pH-responsive behavior for releasing the quercetin molecules as drug model, where the Korsmeyer-Peppas model could describe the release profile with Fickian diffusion (n < 0.45 for at all pH and temperatures). Then, Density functional theory was applied to calculate the absolute binding energies (ΔEb) of the complexation of quercetin with different host molecules in the developed nanocarriers. The calculated energies are as follow: 1) quercetin and citric acid: ΔEb = -16.58 kcal/mol, 2) quercetin and α-cyclodextrin: ΔEb = -46.98 kcal/mol, and 3) quercetin and citric acid/α-cyclodextrin composite: ΔEb = -40.15 kcal/mol. It was found that quercetin tends to interact with all hosts via formation of hydrogen bonds and van der Waals interactions. Finally, the cytotoxicity of the as-developed nanocarriers was evaluated using MTT assay and both normal NIH-3T3 and cancereous HeLa cells. The cell viability results showed that the quercetin could be delivered effectively to the HeLa cells due to the acidic environment inside the cells with minimum effect on the viability of NIH-3T3 cells. These results might open a new window to design of stimuli-responsive nanocarriers for drug delivery applications.

Aluminium toxicokinetics after intramuscular, subcutaneous, and intravenous injection of Al citrate solution in rats.

Knowledge of dose linearity, plasma clearance, rate and extent of subcutaneous (SC) and intramuscular (IM) absorption of soluble aluminium (Al) citrate is considered a prerequisite for evaluation of toxicokinetic data obtained from SC or IM administration of Al adjuvants in medicinal products. Therefore, total Al plasma kinetics was investigated after SC, IM, and IV administration of single Al doses (36 and 360 µg/kg IM or SC; 30 and 300 µg/kg IV) given as citrate solution in rats. Control groups receiving vehicle (saline) were run in parallel to monitor background plasma Al levels over time resulting from dietary intake. Evaluation of Al plasma profiles was done by both non-compartmental analysis of baseline-corrected data and simultaneous model fitting to the raw data using a population kinetics approach. High and dose-independent total plasma clearance (6.6 mL/min/kg) was observed after IV administration corresponding to 60-82% of normal rat GFR. This supports the previous assumptions that parenterally administered Al citrate is more rapidly cleared from plasma than other Al species (e.g., chloride or lactate). Furthermore, plasma exposure of Al (Cmax and AUC0-inf) increased dose-proportionally at all administration routes. Fast and complete absorption of Al was observed at each dose level after both SC and IM administration (bioavailability estimates: 88 and 110%). Estimates for the first-order absorption rate constant ka correspond to absorption half-lives of 36 min (SC) and ≤ 13 min (IM). There was no increase in tissue Al content (whole bone and brain) after 36 µg/kg IM compared to control rats.

Time-course assessment of the aggregation and metabolization of magnetic nanoparticles.

To successfully develop biomedical applications for magnetic nanoparticles, it is imperative that these nanoreagents maintain their magnetic properties in vivo and that their by-products are safely metabolized. When placed in biological milieu or internalized into cells, nanoparticle aggregation degree can increase which could affect magnetic properties and metabolization. To evaluate these aggregation effects, we synthesized citric acid-coated iron oxide nanoparticles whose magnetic susceptibility can be modified by aggregation in agar dilutions and dextran-layered counterparts that maintain their magnetic properties unchanged. Macrophage models were used for in vitro uptake and metabolization studies, as these cells control iron homeostasis in the organism. Electron microscopy and magnetic susceptibility studies revealed a cellular mechanism of nanoparticle degradation, in which a small fraction of the particles is rapidly degraded while the remaining ones maintain their size. Both nanoparticle types produced similar iron metabolic profiles but these profiles differed in each macrophage model. Thus, nanoparticles induced iron responses that depended on macrophage programming. In vivo studies showed that nanoparticles susceptible to changes in magnetic properties through aggregation effects had different behavior in lungs, liver and spleen. Liver ferritin levels increased in these animals showing that nanoparticles are degraded and their by-products incorporated into normal metabolic routes. These data show that nanoparticle iron metabolization depends on cell type and highlight the necessity to assess nanoparticle aggregation in complex biological systems to develop effective in vivo biomedical applications. STATEMENT OF SIGNIFICANCE: Magnetic iron oxide nanoparticles have great potential for biomedical applications. It is however imperative that these nanoreagents preserve their magnetic properties once inoculated, and that their degradation products can be eliminated. When placed in a biological milieu nanoparticles can aggregate and this can affect their magnetic properties and their degradation. In this work, we showed that iron oxide nanoparticles trigger the iron metabolism in macrophages, the main cell type involved in iron homeostasis in the organism. We also show that aggregation can affect nanoparticle magnetic properties when inoculated in animal models. This work confirms iron oxide nanoparticle biocompatibility and highlights the necessity to assess in vivo nanoparticle aggregation to successfully develop biomedical applications.

A Feasibility Study Showing [68Ga]Citrate PET Detects Prostate Cancer.

PURPOSE: The management of advanced or recurrent prostate cancer is limited in part by the lack of effective imaging agents. Metabolic changes in prostate cancer have previously been exploited for imaging, culminating in the recent US FDA approval of [11C]choline for the detection of subclinical recurrent disease after definitive local therapy. Despite this milestone, production of [11C]choline requires an on-site cyclotron, limiting the scope of medical centers at which this scan can be offered. In this pilot study, we tested whether prostate cancer could be imaged with positron emission tomography (PET) using [68Ga]citrate, a radiotracer that targets iron metabolism but is produced without a cyclotron. PROCEDURES: Eight patients with castrate-resistant prostate cancer were enrolled in this single-center feasibility study. All patients had evidence of metastatic disease by standard of care imaging [X-ray computed tomography (CT), bone scan, or magnetic resonance imaging (MRI)] prior to PET with [68Ga]citrate. Patients were intravenously injected with increasing doses of [68Ga]citrate (136.9 to a maximum of 259 MBq). Uptake time was steadily increased from 1 h to approximately 3.5 h for the final 4 patients, and all patients were imaged with a PET/MRI. Qualitative and semi-quantitative (maximum standardized uptake value (SUVmax)) assessment of the metastatic lesions was performed and compared to the standard of care imaging. RESULTS: At 1- and 2-h imaging times post injection, there were no detectable lesions with [68Ga]citrate PET. At 3- to 4-h uptake time, there were a total of 71 [68Ga]citrate-positive lesions (67 osseous, 1 liver, and 3 lymph node). Of these, 65 lesions were visible on the standard of care imaging (CT and/or bone scan). One PET-avid osseous vertebral body metastasis was not apparent on either CT or bone scan. Twenty-five lesions were not PET-avid but seen on CT and bone scan (17 bone, 6 lymph node, 1 pleural, and 1 liver). The average of the maximum SUVs for bone or soft tissue metastases for patients treated at higher doses and uptake time was statistically higher than the corresponding parameter in normal liver, muscle, and bone. Visually obvious blood pool activity was observed even 3-4 h post injection, suggesting that further optimization of the [68Ga]citrate imaging protocol is required to maximize signal-to-background ratios. CONCLUSIONS: Our preliminary results support that PET with [68Ga]citrate may be a novel tool for imaging prostate cancer. Future studies are needed to determine the optimal imaging protocol, the clinical significance of [68Ga]citrate uptake, and its role in therapeutic decisions.

Cytotoxicity, intracellular localization and exocytosis of citrate capped and PEG functionalized gold nanoparticles in human hepatocyte and kidney cells.

Surface-modified gold nanoparticles (AuNPs) are nanomaterials that hold promise in drug delivery applications. In this study, the cytotoxicity, uptake, intracellular localization, and the exocytosis of citrate-stabilized (Cit-AuNP) and polyethylene glycol (PEG)-modified gold nanoparticles with the carboxyl (COOH) terminal functional group were assessed in human embryonic kidney (HEK 293) and the human caucasian hepatocytes carcinoma (Hep G2) cell systems, representing two major accumulation sites for AuNPs. The zeta (ζ)-potential measurements confirmed the negative surface charge of the AuNPs in water and in cell growth medium. The transmission electron microscopy confirmed the size and morphology of the AuNPs. Both types of AuNPs were shown to induce cytotoxic effects in cells. The Hep G2 cells were more sensitive cell type, with the COOH-PEG-AuNPs inducing the highest toxicity at higher concentrations. Dark field microscopy and TEM images revealed that the AuNPs were internalized in cells, mostly as agglomerates. TEM micrographs further revealed that the AuNPs were confined as agglomerates inside vesicle-like compartments, likely to be endosomal and lysosomal structures as well as in the cytosol, mostly as individual particles. The AuNPs were shown to remain in cellular compartments for up to 3 weeks, but thereafter, clearance of the gold nanoparticles from the cells by exocytosis was evident. The results presented in this study may therefore give an indication on the fate of AuNPs on long-term exposure to cells and may also assist in safety evaluation of AuNPs.

Development of tailored and self-mineralizing citric acid-crosslinked hydrogels for in situ bone regeneration.

Bone tissue engineering demands alternatives overcoming the limitations of traditional approaches in the context of a constantly aging global population. In the present study, elastin-like recombinamers hydrogels were produced by means of carbodiimide-catalyzed crosslinking with citric acid, a molecule suggested to be essential for bone nanostructure. By systematically studying the effect of the relative abundance of reactive species on gelation and hydrogel properties such as functional groups content, degradation and structure, we were able to understand and to control the crosslinking reaction to achieve hydrogels mimicking the fibrillary nature of the extracellular matrix. By studying the effect of polymer concentration on scaffold mechanical properties, we were able to produce hydrogels with a stiffness value of 36.13 ± 10.72 kPa, previously suggested to be osteoinductive. Microstructured and mechanically-tailored hydrogels supported the growth of human mesenchymal stem cells and led to higher osteopontin expression in comparison to their non-tailored counterparts. Additionally, tailored hydrogels were able to rapidly self-mineralize in biomimetic conditions, evidencing that citric acid was successfully used both as a crosslinker and a bioactive molecule providing polymers with calcium phosphate nucleation capacity.

Alternating magnetic field-induced hyperthermia increases iron oxide nanoparticle cell association/uptake and flux in blood-brain barrier models.

PURPOSE: Superparamagnetic iron oxide nanoparticles (IONPs) are being investigated for brain cancer therapy because alternating magnetic field (AMF) activates them to produce hyperthermia. For central nervous system applications, brain entry of diagnostic and therapeutic agents is usually essential. We hypothesized that AMF-induced hyperthermia significantly increases IONP blood-brain barrier (BBB) association/uptake and flux. METHODS: Cross-linked nanoassemblies loaded with IONPs (CNA-IONPs) and conventional citrate-coated IONPs (citrate-IONPs) were synthesized and characterized in house. CNA-IONP and citrate-IONP BBB cell association/uptake and flux were studied using two BBB Transwell(®) models (bEnd.3 and MDCKII cells) after conventional and AMF-induced hyperthermia exposure. RESULTS: AMF-induced hyperthermia for 0.5 h did not alter CNA-IONP size but accelerated citrate-IONP agglomeration. AMF-induced hyperthermia for 0.5 h enhanced CNA-IONP and citrate-IONP BBB cell association/uptake. It also enhanced the flux of CNA-IONPs across the two in vitro BBB models compared to conventional hyperthermia and normothermia, in the absence of cell death. Citrate-IONP flux was not observed under these conditions. AMF-induced hyperthermia also significantly enhanced paracellular pathway flux. The mechanism appears to involve more than the increased temperature surrounding the CNA-IONPs. CONCLUSIONS: Hyperthermia induced by AMF activation of CNA-IONPs has potential to increase the BBB permeability of therapeutics for the diagnosis and therapy of various brain diseases.

Toxicity, bioaccumulation, and biotransformation of silver nanoparticles in marine organisms.

The toxicity, bioaccumulation, and biotransformation of citrate and polyvinylpyrrolidone (PVP) coated silver nanoparticles (NPs) (AgNP-citrate and AgNP-PVP) in marine organisms via marine sediment exposure was investigated. Results from 7-d sediment toxicity tests indicate that AgNP-citrate and AgNP-PVP did not exhibit toxicity to the amphipod (Ampelisca abdita) and mysid (Americamysis bahia) at ≤75 mg/kg dry wt. A 28-d bioaccumulation study showed that Ag was significantly accumulated in the marine polychaete Nereis virens (N. virens) in the AgNP-citrate, AgNP-PVP and a conventional salt (AgNO3) treatments. Synchrotron X-ray absorption spectroscopy (XAS) results showed the distribution of Ag species in marine sediments amended with AgNP-citrate, AgNP-PVP, and AgNO3 was AgCl (50­65%) > Ag2S (32­42%) > Ag metal (Ag0) (3­11%). In N virens, AgCl (25­59%) and Ag2S (10­31%) generally decreased and, Ag metal (32­44%) increased, relative to the sediments. The patterns of speciation in the worm were different depending upon the coating of the AgNP and both types of AgNPs were different than the AgNO3 salt. These results show that the AgNP surface capping agents influenced Ag uptake, biotransformation, and/or excretion. To our knowledge, this is the first demonstration of the bioaccumulation and speciation of AgNPs in a marine organism (N. virens).

The bioavailability of different zinc compounds used as human dietary supplements in rat prostate: a comparative study.

The normal human prostate accumulates the highest levels of zinc (Zn) of any soft tissue in the body. The pool of zinc available to the body is known to significantly decrease with age. It is suggested that dietary Zn supplementation protects against oxidative damage and reduces the risk of cancer. Zinc sulfate and zinc gluconate were the most frequently mentioned in per os administration in studies on Zn supplementation. The major aim of the study was to compare the bioavailability of different Zn compounds (sulfate, gluconate and citrate) in the prostate after their daily administration to male rats at three different doses (3.0; 15.0; and 50.0 mg Zn/kg b.w.) for 30 days. The results show that bioavailability in the prostate differs significantly between individual zinc preparations. A significantly elevated Zn concentration in the dorso-lateral lobe of the prostate, compared to controls, was found in the rats supplemented with two compounds only: zinc gluconate and zinc citrate. However, after administration of zinc gluconate, this effect occurred even at the lowest dose. The lowest zinc bioavailability in the prostate was found in the rats administered zinc sulfate: no significant Zn increase was seen in particular zones of the prostate. To sum up, the use of zinc gluconate is worth considering as a possible means of zinc supplementation in men.

Penetration into dentin of sodium hypochlorite associated with acid solutions.

OBJECTIVE: The objective of this study was to evaluate the penetration of 2.5% NaOCl associated with 17.0% EDTA, 1.0% citric acid, and 1.0% peracetic acid into dentin tubules. STUDY DESIGN: The roots of 44 bovine incisors were cross-sectioned and 5-mm-long fragments were produced from their middle thirds. The specimens were instrumented with ProTaper hand files, stained in crystal violet, then sectioned mesiodistally. The buccal fragments were divided into 4 groups (n = 9) and subjected to 2 consecutive 10-minute immersion periods in one of the following acid solutions combined with 2.5% NaOCl: 17.0% EDTA (group 1), 1.0% citric acid (group 2), and 1.0% peracetic acid (group 3). Nine fragments were immersed in 2.5% NaOCl (group 4). The analysis of the penetration of NaOCl solutions into dentin was performed by measuring the depth of crystal violet stain that was bleached using a steromicroscope under ×50 magnification. Statistical comparisons were carried out by Kruskal-Wallis and Dunn's tests at the 5% significance level. RESULTS: Group 1 showed less penetration into dentin than group 4 (P < .05). No statistically significant differences were observed among groups 2, 3, and 4 (P > .05). CONCLUSIONS: Association of NaOCl with acid solutions did not increase its penetration depth into root dentin.

Changes in lognormal shape parameter guide design of patient-specific radiochemotherapy cocktails.

UNLABELLED: Uptake of radiopharmaceuticals and chemotherapeutic drugs is nonuniform at the microscopic level. Their distributions are typically lognormal, suggesting that failure in chemotherapy and targeted radionuclide therapy may be attributable, in part, to the characteristics of this biologically ubiquitous distribution. The lognormal problem can be overcome by using cocktails of 2 or more agents, tailored such that at least 1 agent is strongly incorporated by every cell in the target population. Therefore, critical assessment of the tissue uptake of each cocktail component is warranted. METHODS: Cellular incorporation of the α-particle-emitting radiochemical ((210)Po-citrate) and 2 anticancer drugs (daunomycin and doxorubicin) was determined using flow cytometry. The role of their lognormal distribution in clonogenic cell survival was evaluated. RESULTS: The shape parameter of the lognormal distribution was found to be correlated to both intracellular agent concentration and cell survival. Although no difference emerged between the shape parameters for citrate within the first 2 logs of cell kill, those for daunomycin and doxorubicin changed significantly. CONCLUSION: Changes in the value of the lognormal shape parameter and slope of the cellular drug uptake curves can be used to rapidly screen radiopharmaceuticals and other cytotoxic agents to formulate more effective cocktails for cancer therapy.

Comparative in vitro study of the intestinal absorption of titanium and iron in rats.

Rat Everted Gut Sac (EGS) model was employed to study the intestinal uptake of titanium and iron. Incubation of freshly prepared rat EGS in Earle's medium pH = 7.4 containing titanium showed that the absorption of titanium as well as iron was a dose dependent process. Ascorbic acid enhanced the absorption of both metal ions, while NaF (1 mM) as an inhibitor of glycolytic energy supply, decreased their absorption. The Na+-K+ ATPase inhibitor, ouabain (1 mM) reduced intestinal absorption of Titanium. This suggests that titanium uptake is an active transport process as is iron uptake. Iron absorption was reduced approximate by 17% when titanium was presented to incubation medium EGS whereas, the absorption of titanium was decreased by 35% when iron was added to the reaction mixture.

Establishment of simultaneous treatment model with citrate for preventing nephropathy induced by FYX-051, a xanthine oxidoreductase inhibitor, in rats.

As a precedent study for elucidating the mechanism of possible urinary bladder carcinogenesis due to xanthine crystals induced by FYX-051, a xanthine oxidoreductase inhibitor, we have determined the experimental conditions suitable for the 52-week simultaneous treatment with citrate in F344 rats. Simultaneous treatment with citrate and FYX-051 produced both increased urinary citrate excretion and suppression of urinary xanthine deposition at around 4 hours after a single dosing, but these effects disappeared 2 hours later, indicating a lack of the durability of citrate effects. Next, we carried out a 7-day simultaneous treatment study by two daily treatments, that is, FYX-051 (6 mg/kg) and citrate (2,000 mg/kg), followed by citrate-alone treatment, under the conditions of selected dosing intervals, the second dose of citrate, and dosing volume. As a result, the dosing interval of citrate was found to be optimal at 4 hours, but not at 3 or 5 hours, because this treatment completely inhibited intrarenal xanthine deposition. The dose of citrate for the second treatment and the dosing volume were found to be sufficient at 1,500 mg/kg and 10 mL/kg, respectively. Subsequently, a 4-week study by simultaneous treatment at 3 mg/kg of FYX-051 and citrate (2,000 mg/kg) + citrate (1,500 mg/kg), under the improved conditions, revealed that renal lesions could be drastically inhibited. Thus, the present study demonstrated that the interval of two citrate treatments is pivotal and indicated that the improved model would be useful for the mechanistic study of FYX-051-induced urinary bladder carcinogenesis because of an easier treatment method than our previous model.

68Ga-citrate PET/CT for evaluating patients with infections of the bone: preliminary results.

UNLABELLED: The aim of this work was to preliminarily evaluate the sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy of (68)Ga-citrate PET/CT in a population of patients with suspected bone infections. METHODS: We enrolled 31 patients with suspected osteomyelitis or diskitis who underwent a total of forty (68)Ga-citrate PET/CT scans. The results were compared with different combinations of diagnostic procedures (MRI, radiography, CT, or white blood cell scintigraphy), biopsy (when diagnostic), and follow-up data (at least 1 y) to determine the performance of (68)Ga-citrate PET/CT. RESULTS: We found a sensitivity of 100%, a specificity of 76%, a positive predictive value of 85%, a negative predictive value of 100%, and an overall accuracy of 90%. CONCLUSION: Although preliminary, these data confirm a possible role for (68)Ga-citrate in the diagnosis of bone infections, especially in consideration of its favorable characteristics.

Automated regional citrate anticoagulation: technological barriers and possible solutions.

BACKGROUND: Large-scale adoption of regional citrate anticoagulation (RCA) is prevented by risks of the technique as practiced traditionally. Safe RCA protocols with automated delivery on customized dialysis systems are needed. METHODS: We applied kinetic analysis of solute fluxes during RCA to design a protocol for sustained low-efficiency dialysis (SLED) for critically ill patients. We used a high-flux hemodialyzer, a zero-calcium (Ca) dialysate, a dialysis machine with online clearance and access recirculation monitoring, and a separate optical hematocrit (Hct) sensor. Flow rates were Q(B) = 200 ml/min for blood; Q(D) = 400 ml/min for dialysate, with Na = 140 mmol/l and HCO(3) = 32 mmol/l; Q(citrate) = 400 ml/h of acid citrate dextrose A; ultrafiltration as indicated. The Q(Ca) was infused into the return blood line, adjusted hourly based on online Hct and a <24-hour-old albumin level. RESULTS: Using the SLED-RCA protocol in an anhepatic, ex vivo dialysis system, ionized Ca (iCa) was >1 mmol/l in the blood reservoir and <0.3 mmol/l in the blood circuit after citrate but before Ca infusion (Q(Ca)) with normal electrolyte composition of the blood returning to the reservoir. Clinically, SLED-RCA completely abrogated clotting, without adverse electrolyte effects. The Q(Ca) prediction algorithm maintained normal systemic iCa (0.95-1.4 mmol/l) in all patients. The high citrate extraction on the dialyzer prevented systemic citrate accumulation even in shock liver patients. Safety analysis shows that building a dialysis system for automated SLED-RCA is feasible. CONCLUSION: Using predictive Q(Ca) dosing and integrating control of the infusion pumps with the dialysis machine, SLED-RCA can be near-automated today to provide a user-friendly and safe system.

Effect of dentin treatment time with tetraclean on its residual antibacterial activity.

The goal of this study was to evaluate the effect of dentin treatment duration (10 minutes, 24 hours, and seven days) with Tetraclean on its residual antibacterial activity in bovine root dentin. Results showed that the number of colony-forming units in all three experimental groups was zero at the first culture. Furthermore, the 10-minute group and seven-day group demonstrated the highest and the lowest number of colony-forming units, respectively.

Sodium picosulfate/magnesium citrate: a review of its use as a colorectal cleanser.

Oral sodium picosulfate/magnesium citrate (CitraFleet; Picolax), consisting of sodium picosulfate (a stimulant laxative) and magnesium citrate (an osmotic laxative), is approved for use in adults (CitraFleet; Picolax) and/or adolescents and children (Picolax) as a colorectal cleansing agent prior to any diagnostic procedure (e.g. colonoscopy or x-ray examination) requiring a clean bowel and/or surgery. It is dispensed in powder form (sodium picosulfate 0.01 g, magnesium oxide 3.5 g, citric acid 12.0 g per sachet), with the magnesium oxide and citric acid components forming magnesium citrate when the powder is dissolved in water. In adult patients, two sachets of sodium picosulfate/magnesium citrate was at least as effective and well tolerated as oral magnesium citrate 17.7 or 35.4 g, or oral polyethylene glycol 236 g in adult patients undergoing a double-contrast barium enema procedure in three large, randomized, comparative clinical studies. In contrast, sodium picosulfate/magnesium citrate was less effective than a sodium phosphate enema preparation in two studies in patients undergoing flexible sigmoidoscopy. A similar number of patients receiving two sachets of sodium picosulfate/magnesium citrate or two 45 mL doses of oral sodium phosphate the day before a double-contrast barium enema procedure achieved satisfactory barium coating and none/minimal faecal residue in one study. However, the data from three of these studies should be interpreted with caution because the administrative regimens used differed from that recommended. Sodium picosulfate/magnesium citrate is also an effective and generally well tolerated colorectal cleansing agent in children and adolescents; the preparation was more effective than oral bisacodyl 0.01 or 0.02 g plus a sodium phosphate enema preparation in this population. Further research is thus required to accurately position sodium picosulfate/magnesium citrate and fully establish its efficacy and tolerability prior to various exploratory or surgical procedures. Nevertheless, oral sodium picosulfate/magnesium citrate provides a useful option in the preparation of the colon and rectum in adults, adolescents and children undergoing any diagnostic procedure (e.g. colonoscopy or x-ray examination) requiring a clean bowel and/or surgery. Oral sodium picosulfate/magnesium citrate acts locally in the colon as both a stimulant laxative, by increasing the frequency and the force of peristalsis (sodium picosulfate component), and an osmotic laxative, by retaining fluids in the colon (magnesium citrate component), to clear the colon and rectum of faecal contents. It is not absorbed in any detectable quantities. Sodium picosulfate is a prodrug: it is hydrolyzed by bacteria in the colon to the active metabolite 4,4'-dihydroxydiphenyl-(2-pyridyl)methane. Sodium picosulfate/magnesium citrate may be associated with a dehydrating effect, as evidenced by a reduction in bodyweight and increased haemoglobin levels; some at-risk patients may experience postural hypotension and older patients may require additional electrolytes. In three large (n >100), randomized, single-blind clinical studies, two sachets of oral sodium picosulfate/magnesium citrate was at least as effective as oral magnesium citrate 17.7 or 35.4 g, or oral polyethylene glycol 236 g as a colorectal cleansing agent in adult patients undergoing a double-contrast barium enema procedure. In contrast, sodium picosulfate/magnesium citrate was less effective than a sodium phosphate enema preparation in two studies in patients undergoing flexible sigmoidoscopy. A similar number of patients receiving two sachets of sodium picosulfate/magnesium citrate or two 45 mL doses of oral sodium phosphate the day before a double-contrast barium enema procedure achieved satisfactory barium coating and none/minimal faecal residue in one study. However, the data from three of these studies should be interpreted with caution because the administrative regimens used differed from that recommended. In children and adolescents, sodium picosulfate/magnesium citrate was significantly more effective as a colorectal cleansing agent than oral bisacodyl 0.01 or 0.02 g plus a sodium phosphate enema preparation in a randomized, single-blind study; dosages were adjusted for age in this study. Oral sodium picosulfate/magnesium citrate is generally well tolerated in adult patients undergoing various investigational colorectal procedures. Adverse events were generally mild to moderate in intensity and mainly gastrointestinal in nature (e.g. abdominal cramps/pain, nausea); other common treatment-emergent adverse events included disturbance of daily activity, headache and sleep disturbance. This combination is at least as well tolerated as oral sodium phosphate or oral polyethylene glycol, with moderate/severe nausea and vomiting occurring less frequently in sodium picosulfate/magnesium citrate recipients than in those receiving oral sodium phosphate, and abdominal bloating/pain and nausea developing less often with sodium picosulfate/magnesium citrate than polyethylene glycol therapy. The incidence of abdominal pain and sleep disturbance in sodium picosulfate/magnesium citrate versus oral magnesium citrate recipients was similar in one study, but significantly lower with sodium picosulfate/magnesium citrate in another. While the incidence of most adverse events was similar in recipients of sodium picosulfate/magnesium citrate and a sodium phosphate enema preparation, more patients receiving sodium picosulfate/magnesium citrate reported moderate/severe flatulence, incontinence and sleep disturbance, and more patients receiving the enema preparation reported rectal soreness. The tolerability profile of sodium picosulfate/magnesium citrate in patients aged >70 years is reportedly similar to that in patients aged <70 years. Abdominal pain also occurred less frequently with sodium picosulfate/magnesium citrate than with oral bisacodyl plus a sodium phosphate enema preparation in children and adolescents.