Attenuation of ischemia-reperfusion injury by intracoronary chelating agent administration.

Ischemia-reperfusion (IR) injury accelerates myocardial injury sustained during the myocardial ischemic period and thus abrogates the benefit of reperfusion therapy in patients with acute myocardial infarction. We investigated the efficacy of intracoronary ethylenediaminetetraacetic acid (EDTA) administration as an adjunctive treatment to coronary intervention to reduce IR injury in a swine model. We occluded the left anterior descending artery for 1 h. From the time of reperfusion, we infused 50 mL of EDTA-based chelating agent via the coronary artery in the EDTA group and normal saline in the control group. IR injury was identified by myocardial edema on echocardiography. Tetrazolium chloride assay revealed that the infarct size was significantly lower in the EDTA group than in the control group, and the salvage percentage was higher. Electron microscopy demonstrated that the mitochondrial loss in the cardiomyocytes of the infarcted area was significantly lower in the EDTA group than in the control group. Echocardiography after 4 weeks showed that the remodeling of the left ventricle was significantly less in the EDTA group than in the control group: end-diastolic dimension 38.8 ± 3.3 mm vs. 43.9 ± 3.7 mm (n = 10, p = 0.0089). Left ventricular ejection fraction was higher in the EDTA group (45.3 ± 10.3 vs. 34.4 ± 11.8, n = 10, respectively, p = 0.031). In a swine model, intracoronary administration of an EDTA chelating agent reduced infarct size, mitochondrial damage, and post-infarct remodeling. This result warrants further clinical study evaluating the efficacy of the EDTA chelating agent in patients with ST-segment elevation myocardial infarction.

Copper-lowering agents as an adjuvant in chemotherapy.

Copper is an important element essential for metabolism and normal human body function. Although it is an essential element, related imbalance leads to toxic effects. Studies have proved that there is an increase in copper level in cancer cells. Evidences suggest the link between increase in copper levels and progression of various types of cancers. Different strategies have been utilized to decrease the level of copper in various types of cancer cells. However, it was observed that cell machinery involved in copper homeostasis plays critical factor in lowering copper levels in cancer cells. The outcomes of many monotherapies consisting copper-lowering agents for the treatment of different types of cancers showed that the inhibition of single factor is not sufficient to inhibit the growth of cancer cells. The combination of copper-lowering agent with chemotherapeutic agent showed synergistic effect. Interestingly, the presence of copper-lowering agent in such combinations significantly improved the efficacy of chemotherapeutic agent. The present work has focused on the discussion of outcomes of studies involving anti-copper agent and chemotherapeutic agent and related future strategies.

Phosphate, Microbiota and CKD.

Phosphate is a key uremic toxin associated with adverse outcomes. As chronic kidney disease (CKD) progresses, the kidney capacity to excrete excess dietary phosphate decreases, triggering compensatory endocrine responses that drive CKD-mineral and bone disorder (CKD-MBD). Eventually, hyperphosphatemia develops, and low phosphate diet and phosphate binders are prescribed. Recent data have identified a potential role of the gut microbiota in mineral bone disorders. Thus, parathyroid hormone (PTH) only caused bone loss in mice whose microbiota was enriched in the Th17 cell-inducing taxa segmented filamentous bacteria. Furthermore, the microbiota was required for PTH to stimulate bone formation and increase bone mass, and this was dependent on bacterial production of the short-chain fatty acid butyrate. We review current knowledge on the relationship between phosphate, microbiota and CKD-MBD. Topics include microbial bioactive compounds of special interest in CKD, the impact of dietary phosphate and phosphate binders on the gut microbiota, the modulation of CKD-MBD by the microbiota and the potential therapeutic use of microbiota to treat CKD-MBD through the clinical translation of concepts from other fields of science such as the optimization of phosphorus utilization and the use of phosphate-accumulating organisms.

Role of Tris-CaEDTA as an adjuvant with nebulised tobramycin in cystic fibrosis patients with Pseudomonas aeruginosa lung infections: A randomised controlled trial.

BACKGROUND: We tested if disrupting iron utilisation by P. aeruginosa by adding the Tris-buffered chelating agent CaEDTA to nebulised tobramycin would enhance bacterial clearance and improve lung function in CF patients. METHODS: In this double-blind, randomised controlled trial, 26 episodes (25 patients) with P. aeruginosa infection admitted to two CF centres for treatment of an acute pulmonary exacerbation were randomly assigned to receive either 75 mg CaEDTA in Tris-buffered saline or placebo (Tris-buffered saline) nebulised in combination with 250 mg tobramycin twice daily for six weeks followed with four week safety follow-up. Primary endpoints were safety, tolerability, and bacterial density of P. aeruginosa. A secondary endpoint was lung function. RESULTS: The study drug was well tolerated with adverse events comparable in both groups. The mean (SD) reduction in sputum P. aeruginosa count (log10 CFU/g) in the CaEDTA vs placebo group was 2·05 (2·57) vs 0·82 (2·71) at two weeks relative to admission (p = 0·39). The mean improvement in ppFEV1 was 16 vs 5 (p = 0·16); 11 vs 2 (p = 0·28); and 6 vs 2 percentage points (p = 0·47) at two, six, and ten weeks in CaEDTA and placebo groups, respectively. CONCLUSIONS: In this pilot study in CF patients, an increase in the reduction of sputum density of P. aeruginosa and an increase in ppFEV1 was observed in the group of patients who received Tris-CaEDTA added to inhaled tobramycin compared to the group who received inhaled tobramycin alone, although these differences were not statistically significant. The treatment was also shown to be safe.

The Effects of Long-Term Magnesium Creatine Chelate Supplementation on Repeated Sprint Ability (RAST) in Elite Soccer Players.

AIM: The aim of the study was to evaluate the effects of 16 weeks of a low dose of magnesium creatine chelate supplementation on repeated sprint ability test (RAST) results in elite soccer players. MATERIALS: Twenty well-trained soccer players participated in the study. The players were divided randomly into two groups: the supplemented group (SG = 10) and placebo group (PG = 10). Out of the 20 subjects selected for the study, 16 (SG = 8, PG = 8) completed the entire experiment. The SG ingested a single dose of 5500 mg of magnesium creatine chelate (MgCr-C), in 4 capsules per day, which was 0.07 g/kg/d. The PG received an identical 4 capsules containing corn starch. Before and after the study, the RAST was performed. In the RAST, total time (TT), first and sixth 35 m sprint length (s), average power (AP) and max power (MP) were measured. Additionally, before and after the test, lactate LA (mmol/L) and acid-base equilibrium pH (-log(H+)), bicarbonates HCO3- (mmol/L) were evaluated. Also, in serum at rest, creatinine (mg/dL) concentration was measured. RESULTS: After the study, significantly better results in TT, AP and MP were observed in the SG. No significant changes in the RAST results were observed in the PG. After the study, significant changes in the first 35 m sprint, as well as the sixth 35 m sprint results were registered in the SG, while insignificant changes occurred in the PG. A significantly higher creatinine concentration was observed. Also, a higher post-RAST concentration of LA, HCO3- and lower values of pH were observed in April, May and June compared with baseline values. CONCLUSIONS: The long timeframe, i.e., 16 weeks, of the low dose of magnesium creatine chelate supplementation improved the RAST results in the SG. Despite the long period of MgCr-C supplementation, in the end of the study, the creatinine level in the SG reached higher but still reference values.

Liquid chromatography/tandem mass spectrometric analysis of penicillamine for its pharmacokinetic evaluation in dogs.

Copper storage disease occurs in multiple dog breeds and is one of the most common causes of chronic hepatitis in this species. The disease is caused by hereditary defects in copper metabolism in conjunction with high dietary copper levels. The progressive copper accumulation leads to hepatitis, cirrhosis, and eventually death if left untreated. Copper chelators are critical in modulating the effects of this disease. It is therefore of significant practicality to understand the pharmacokinetic (PK) parameters of chelating agents, particularly since they are oftentimes quite expensive. A liquid chromatography-tandem mass spectrometric (LC/MS/MS) method was developed to measure plasma levels of one of the most common chelators, d-penicillamine. The compound was discovered to exist in two forms, monomeric and dimeric, and various chemical derivatizations were tried to force the compound into one form or the other. Eventually, the simplest approach was individual determination of penicillamine and its dimer, with summation of the two quantities. This enabled determination of canine PK parameters for penicillamine based on comparison of oral and intravenous administration of the drug, including time to maximum drug level (Tmax), concentration at maximum (Cmax), clearance (Cls) and volume of distribution (Vdss). The drug was found to exist predominantly in the dimeric form in plasma, which is incapable of chelating copper owing to lack of free sulfhydryl groups and must therefore provide a storage form of the drug in equilibrium with its monomeric form in vivo. Mechanisms are discussed for the electrospray-induced fragmentation of penicillamine as well as of its dimer.

Characteristics of Patients Who Achieve Serum Phosphorus Control on Sucroferric Oxyhydroxide or Sevelamer Carbonate: A post hoc Analysis of a Phase 3 Study.

INTRODUCTION: Control of hyperphosphatemia in patients on dialysis remains a major challenge. OBJECTIVE: This study evaluated predictors of serum phosphorus (sP) control among dialysis patients treated with noncalcium, oral phosphate binder therapy in a phase 3 clinical trial. METHODS: Post hoc analyses were performed using data for patients with hyperphosphatemia who received 52 weeks of treatment with sucroferric oxyhydroxide (SFOH) or sevelamer carbonate (sevelamer). Patients were categorized into those who achieved sP control (n = 302; defined as sP ≤ 5.5 mg/dL at week 52), and those with uncontrolled sP (n = 195; sP >5.5 mg/dL at week 52). Because SFOH and sevelamer have previously demonstrated similar effects on chronic kidney disease-mineral-bone disorder parameters in this study, the treatment groups were pooled. RESULTS: Average age at baseline was higher among sP-controlled versus sP-uncontrolled patients (56.9 vs. 53.4 years; p = 0.005). Baseline sP levels were significantly lower among sP-controlled versus sP-uncontrolled patients (7.30 vs. 7.85 mg/dL; p < 0.001), and sP reductions from baseline were significantly greater in the sP-controlled group (-2.89 vs. -0.99 mg/dL at week 52; p < 0.001). Logistic regression analysis identified higher baseline sP levels (odds ratio [OR] = 0.86, 95% confidence interval [CI]: 0.765-0.960), no concomitant active vitamin D therapy use (OR = 0.51, 95% CI: 0.328-0.804), and higher body mass index at baseline (OR = 0.96, 95% CI: 0.937-0.992) as significant predictors of uncontrolled sP. CONCLUSION: This analysis indicates that sP control may be more challenging in younger patients with high sP levels. Closer monitoring and management of serum phosphorus levels may be required in this population.

How to improve adherence the captors of phosphorus on hemodialysis: Experience in real life with sucroferric oxyhydroxide.

INTRODUCTION: The lack of adherence to phosphate -binders (PB) is the most important factor in not achieving the objectives of serum phosphorus (sP). Studies in the real-world population are needed to understand the influence of PBs on adherence and how to modify it. METHODS: Prospective study conducted during 3 months in usual clinical practice. Out of 105 hemodialysis patients, 57 were switched to SFOH and 48 maintained their baseline treatment (control group). sP levels and the percentage of patients with sP levels <5mg/dl were compared. Adherence before and after introduction of SFOH, number of pills of PB, preferences in the administration mode and side effects were analyzed. RESULTS: The percentage of patients with controlled sP (<5mg/dl) increased significantly in the SFOH users' group (62.1-92.9%, p<0.001), but not in the control group (83-83.3%, p=NS). The average of daily tablets decreased significantly in the SFOH group (7.2-2.3 comp, p<0.001), but not in the control group (5.6-5.6, p=NS) and 100% of the patients used only one PB in SFOH group. The use of SFOH increased the adherence according to the SMAQ questionnaire (57.8-84.3%; OR 13.1, p<0.001). The possibility to choose the preferred mode of administration (split-swallowing 89% compared to chewing 11%), improved the acceptance (44.7-78%). 14% of the patients experienced side effects and in 5.2% SFOH was discontinued for this reason. CONCLUSIONS: SFOH controlled serum sP in 93% of patients, 100% in monotherapy, and with fewer tablets. The exploration and adaptation of preferences in the mode of administration influenced the acceptance of the drug by the patient and, probably, the future adherence.

Dietary calcium intake does not meet the nutritional requirements of children with chronic kidney disease and on dialysis.

BACKGROUND: Adequate calcium (Ca) intake is required for bone mineralization in children. We assessed Ca intake from diet and medications in children with CKD stages 4-5 and on dialysis (CKD4-5D) and age-matched controls, comparing with the UK Reference Nutrient Intake (RNI) and international recommendations. METHODS: Three-day prospective diet diaries were recorded in 23 children with CKD4-5, 23 with CKD5D, and 27 controls. Doses of phosphate (P) binders and Ca supplements were recorded. RESULTS: Median dietary Ca intake in CKD4-5D was 480 (interquartile range (IQR) 300-621) vs 724 (IQR 575-852) mg/day in controls (p = 0.00002), providing 81% vs 108% RNI (p = 0.002). Seventy-six percent of patients received < 100% RNI. In CKD4-5D, 40% dietary Ca was provided from dairy foods vs 56% in controls. Eighty percent of CKD4-5D children were prescribed Ca-based P-binders, 15% Ca supplements, and 9% both medications, increasing median daily Ca intake to 1145 (IQR 665-1649) mg/day; 177% RNI. Considering the total daily Ca intake from diet and medications, 15% received < 100% RNI, 44% 100-200% RNI, and 41% > 200% RNI. Three children (6%) exceeded the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) upper limit of 2500 mg/day. None with a total Ca intake < RNI was hypocalcemic, and only one having > 2 × RNI was hypercalcemic. CONCLUSIONS: Seventy-six percent of children with CKD4-5D had a dietary Ca intake < 100% RNI. Restriction of dairy foods as part of a P-controlled diet limits Ca intake. Additional Ca from medications is required to meet the KDOQI guideline of 100-200% normal recommended Ca intake. Graphical abstract.

Ameliorative effect of curcumin on lead-induced hematological and hepatorenal toxicity in a rat model.

INTRODUCTION: Lead (Pb) is a ubiquitous toxic heavy metal that inflicts numerous clinical consequences on humans. Curcumin is the principal component of turmeric, which is reported to have antioxidative properties. This study aimed at evaluating the ameliorative effects of curcumin on Pb-induced hepatorenal toxicity in a rat model. METHODS: Thirty-six male Sprague-Dawley rats were randomly assigned into five groups with 12 rats in the control (normal saline) and six rats each for the lead-treated group (LTG) (50 mg/kg lead acetate [Pb acetate] for 4 weeks), recovery group (50 mg/kg Pb acetate for 4 weeks and left with no treatment for another 4 weeks), treatment group 1 (Cur100) (50 mg/kg Pb acetate for 4 weeks, followed by 100 mg/kg curcumin for 4 weeks), and treatment group 2 (Cur200) (50 mg/kg Pb acetate for 4 weeks, followed by 200 mg/kg curcumin for 4 weeks). All the experimental groups received oral treatments via orogastric-tube on alternate days. Pb concentration in the liver and kidney of the rats were evaluated using inductive-coupled plasma mass spectrometry techniques. RESULTS: Pb-administered rats revealed significant alteration in oxidative status and increased Pb concentration in their liver and kidney with obvious reduction of hemogram and increased in leukogram as well as aberration in histological architecture of the liver and kidney. However, treatment with curcumin reduces the tissue Pb concentrations and ameliorates the above mention alterations. CONCLUSIONS: The results in this study suggested that curcumin attenuates Pb-induced hepatorenal toxicity via chelating activity and inhibition of oxidative stress.

Inhibition of Amyloid ß Aggregation Using Optimized Nano-Encapsulated Formulations of Plant Extracts with High Metal Chelator Activities.

BACKGROUND: The role of Fe+2, Cu+2 and Zn+2 in facilitating aggregation of Amyloid ß (Aß) and consequently, the progression of Alzheimer's disease (AD) is well established. OBJECTIVE: Development of non-toxic metal chelators is an emerging era in the treatment of AD, in which complete success has not been fully achieved. The purpose of this study was to determine plant extracts with high metal chelator and to encapsulate them in nano-micellar systems with the ability to pass through the Blood Brain Barrier (BBB). METHODS: Extracts of 36 different Anatolian plants were prepared, total phenolic and flavonoid contents were determined, and the extracts with high content were examined for their Fe+2, Cu+2 and Zn+2 chelating activities. Apolipoprotein E4 (Apo E) decorated nano-formulations of active extracts were prepared using Poly (Lactide-co-Glycolide) (PLGA) (final product ApoEPLGA) to provide BBB penetrating property. RESULTS: Verbascum flavidum aqueous extract was found as the most active sample, incubation of which, with Aß before and after metal-induced aggregation, resulted in successful inhibition of aggregate formation, while re-solubilization of pre-formed aggregates was not effectively achieved. The same results were obtained using ApoEPLGA. CONCLUSION: An optimized metal chelator nano-formulation with BBB penetrating ability was prepared and presented for further in-vivo studies.

Chelation Treatment by Early Inhalation of Liquid Aerosol DTPA for Removing Plutonium after Rat Lung Contamination.

Occupational contamination is a potential health risk associated with plutonium inhalation. DTPA remains the chelating drug of choice to decorporate plutonium. In this study, plutonium was found to be more effectively removed from lungs by a single inhalation of nebulized DTPA solution at only 1.1 µmol.kg-1 than by a single intravenous (i.v.) dose of DTPA at 15 µmol.kg-1. When DTPA was inhaled promptly after contamination, it removed the transportable fraction of plutonium prior blood absorption, thereby preventing both liver and bone depositions. Conversely, DTPA injection was better than inhalation at reducing the extrapulmonary burden, probably due to the much greater circulating dose, favoring the mobilization of plutonium already translocated. Thus, prompt inhalation, concomitantly supplemented with i.v. injection, of DTPA induced an important decrease in extrapulmonary deposits. Repeated DTPA inhalations over several weeks were more efficient than a single inhalation in limiting both pulmonary and extrapulmonary plutonium retention, due at least in part to the chelation of the transportable fraction of lung plutonium. Furthermore, repeated DTPA injections remained better at reducing liver and bone plutonium retentions. Taken together, our results suggest that multiple DTPA inhalations may be considered an effective treatment after inhalation of plutonium, particularly given the ease of this needle-free delivery, for the two following conditions: 1. A treatment combining i.v. injection and inhalation should be given in an emergency scenario to efficiently chelate the activity already absorbed; 2. Inhalations should be administered daily to effectively trap the early transferable fraction.

Impacts of lead exposure and chelation therapy on bone metabolism during different developmental stages of rats.

OBJECTIVE: To explore the impacts of Pb exposure and the dimercaptosuccinic acid (DMSA) chelation therapy on bone metabolisms in young rats of different ages, as well as the potential mechanisms. METHOD: Young rats were exposed to 0.05%-0.1% Pb acetate for 19 days, during infanthood (postnatal day, PND2-20), childhood (PND21-39) and adolescenthood (PND40-58) respectively. In each developmental stage, rats were further divided into three subgroups: lead-exposed, one-course and two-course DMSA chelation therapy subgroups. Blood/bone lead concentrations, serum calciotropic hormones concentrations, and mRNA and protein expressions of bone turnover markers in the serum and bones were measured. Bone microstructures were analyzed using Micro-CT. RESULTS: Compared with lead-exposed during childhood and adolescenthood, increases in blood/bone lead levels, and the changes of blood/bone lead and trabecular bone microstructures after one-course DMSA chelation were most significant in rats lead-exposed during infanthood (P < .05). The serum osteocalcin (OC) concentrations, mRNA/protein expressions of OC and runt-related transcription factor 2 (RUNX2) in bones all decreased after Pb exposure, along with significant increases in serum C-terminal telopeptide of type I collagen (CTX) concentrations (P < .05). These effects were accompanied by changes of serum parathormone (PTH) and 1,25-dihydroxyvitamin D3 (1,25-(OH2)-D3) concentrations. DMSA chelation partially reversed the changes of bone microarchitectures, bone formation and resorption markers, and calciotropic-hormones, and the efficiency was greatest when the therapy was provided during infanthood. CONCLUSION: Developmental Pb exposure impaired bone microstructures and interfered bone metabolism, and the exposure effect was more obvious during infanthood than during childhood and adolescenthood. Lead effects were partially reversed by chelation therapy, and the efficacy may be most significant when the therapy was provided at younger ages.

A 3,2-Hydroxypyridinone-based Decorporation Agent that Removes Uranium from Bones In Vivo.

Searching for actinide decorporation agents with advantages of high decorporation efficiency, minimal biological toxicity, and high oral efficiency is crucial for nuclear safety and the sustainable development of nuclear energy. Removing actinides deposited in bones after intake is one of the most significant challenges remaining in this field because of the instantaneous formation of highly stable actinide phosphate complexes upon contact with hydroxyapatite. Here we report a hydroxypyridinone-based ligand (5LIO-1-Cm-3,2-HOPO) exhibiting stronger affinity for U(VI) compared with the reported tetradentate hydroxypyridinone ligands. This is further revealed by the first principles calculation analysis on bonding between the ligand and uranium. Both in vitro uranium removal assay and in vivo decorporation experiments with mice show that 5LIO-1-Cm-3,2-HOPO can remove uranium from kidneys and bones with high efficiencies, while the decorporation efficiency is nearly independent of the treatment time. Moreover, this ligand shows a high oral decorporation efficiency, making it attractive for practical applications.

The effect of EDTA-based chelation on patients with diabetes and peripheral artery disease in the Trial to Assess Chelation Therapy (TACT).

OBJECTIVE: Approximately 1 in 7 US adults have diabetes; and over 60% of deaths in patients with diabetes have cardiac disease as a principal or contributing cause. Both coronary and peripheral artery disease (PAD) identify high-risk cohorts among patients with diabetes. We have previously demonstrated improved cardiovascular outcomes with edetate disodium-based chelation in post-MI patients with diabetes, enrolled in the Trial to Assess Chelation Therapy (TACT). In these analyses we further studied the effect size of patients with diabetes and severe disease in 2 vascular beds; coronaries, and lower extremity arteries. We questioned whether greater atherosclerotic burden would attenuate the observed beneficial effect of edetate disodium infusions. RESEARCH DESIGN AND METHODS: The multicenter TACT used a double blind, placebo controlled, 2 × 2 factorial design with 1708 participants, randomly assigned to receive edetate disodium-based chelation, or placebo and high dose oral vitamins or placebo. There were 162 (9.5% of 1708) post-MI patients with a diagnosis of diabetes mellitus and PAD for this post hoc analysis. Patients received up to 40 double-blind intravenous infusions of edetate disodium-based chelation, or placebo. The composite primary endpoint of TACT consisted of death from any cause, myocardial infarction, stroke, coronary revascularization and hospitalization for angina. RESULTS: The median age was 66 years, 15% female, 5% non-Caucasian, and BMI was 31. Insulin was used by 32% of patients. Active infusions significantly reduced the primary endpoint compared with placebo infusions (HR, 0.52; 95% CI, 0.30-0.92; P = 0.0069), with a 30% absolute risk reduction in the primary endpoint. There was a marked reduction in total mortality from 24% to 11%, although of borderline significance (P = 0.052). CONCLUSION: Atherosclerotic disease in multiple vascular beds did not attenuate the beneficial effect of edetate disodium infusions in post MI patients with diabetes. Studies now in progress will prospectively test this post hoc finding.

Natural antidotes and management of metal toxicity.

The global burden of heavy metal especially mercury, arsenic, lead, and cadmium toxicities remains a significant public health challenge. Developing nations are particularly at high risk and carry the highest burden of this hazard. Chelation therapy has been the mainstay for treatment of heavy metal poisoning where the chelating agent binds metal ions to form complex ring-like structures called "chelates" to enhance their elimination from the body. Metal chelators have some drawbacks such as redistribution of some heavy metals from other tissues to the brain thereby increasing its neurotoxicity, causing loss of essential metals such as copper and zinc as well as some serious adverse effects, e.g., hepatotoxicity. The use of natural antidotes, which are easily available, affordable, and with little or no side effects compared to the classic metal chelators, is the focus of this review and suggested as cheaper options for developing nations in the treatment of heavy metal poisoning.

Modeled Daily Ingested, Absorbed and Bound Phosphorus: New Measures of Mineral Balance in Hemodialysis Patients.

BACKGROUND: Control of predialysis serum phosphorus in hemodialysis patients is challenging. We explored the utility of a novel kinetic phosphorus modeling program. METHODS: As part of a quality assurance program, urea kinetic modeling results were combined with those from phosphorus kinetic modeling to compute modeled daily ingested phosphorus (DIP) and components making up this metric, including absorbed, bound, and nonabsorbed, nonbound phosphorus. RESULTS: In 182 hemodialysis patients, DIP averaged 1,089 ± 348 mg/day in men and 934 ± 292 in women (p < 0.002) and correlated substantially with body weight. DIP/kg bodyweight (12.8 ± 3.40 mg/kg) was not significantly different between the sexes. Prescribed equivalent binder dose (EBD) was 4.98 ± 3.61 and 4.53 ± 3.02 g/day in men and women, respectively (p NS). Protein catabolic rate (PCR) was significantly higher in men (64.4 ± 18) g/day vs. women (48.2 ± 15.6, p < 0.001), and the DIP/PCR ratio was 17.4 ± 4.81 in men vs. 20.1 ± 5.76 in women (p < 0.001). Presence of residual kidney function was associated with a lower prescribed EBD dose (4.08 ± 2.62 vs. 5.38 ± 3.81 g/day, p < 0.01). Self-reported poor binder compliance was associated with higher DIP or DIP/kg as well as higher prescribed EBD. In anuric patients, DIP/kg was increased in patients consuming diets with high phosphate additive content and those reporting poor compliance with the prescribed dose of phosphate binders. CONCLUSIONS: The combination of urea kinetic and phosphorus modeling can be used to estimate measures related to phosphorus intake. High DIP/PCR or DIP/kg body weight values in anuric patients suggest consumption of a diet high in phosphorus additives or noncompliance with the prescribed amount of phosphorus binders.

Improved Modeling of Plutonium-DTPA Decorporation.

Individuals with significant intakes of plutonium (Pu) are typically treated with chelating agents, such as the trisodium salt form of calcium diethylenetriaminepentaacetate (CaNa3-DTPA, referred to hereafter as Ca-DTPA). Currently, there is no recommended approach for simultaneously modeling plutonium biokinetics during and after chelation therapy. In this study, an improved modeling system for plutonium decorporation was developed. The system comprises three individual model structures describing, separately, the distinct biokinetic behaviors of systemic plutonium, intravenously injected Ca-DTPA and in vivo-formed Pu-DTPA chelate. The system was linked to ICRP Publication 100, "Human Alimentary Tract Model for Radiological Protection" and NCRP Report 156, Development of a Biokinetic Model for Radionuclide-Contaminated Wounds and Procedures for Their Assessment, Dosimetry and Treatment." Urine bioassay and chelation treatment data from an occupationally-exposed individual were used for model development. Chelation was assumed to occur in the blood, soft tissues, liver and skeleton. The coordinated network for radiation dosimetry approach to decorporation modeling was applied using a chelation constant describing the secondorder, time-dependent kinetics of the in vivo chelation reaction. When using the proposed system of models for plutonium decorporation, a significant improvement of the goodness-of-fit to the urinary excretion data was observed and more accurate predictions of postmortem plutonium retention in the skeleton, liver and wound site were achieved.

Dual 0.02% chlorhexidine digluconate - 0.1% disodium EDTA loaded thermosensitive ocular gel for Acanthamoeba keratitis treatment.

Poor bioavailability and low residence time limit the efficiency of conventional biguanide-based eye drops against Acanthamoeba keratitis. The aim of this work was to formulate an original anti-amoebic thermoreversible ocular gel combining biguanide and metalloproteases inhibitor - chelating agent. Chlorhexidine digluconate (CHX)-ethylenediaminetetraacetic acid disodium salt (Na2EDTA) were compounded in poloxamer 407 saline solution. 0.02% CHX - 0.1% Na2EDTA loaded thermosensitive ocular gel exhibited appropriate pH (5.73 ±â€¯0.06), iso-osmolality (314 ±â€¯5 mOsm/kg), viscosity (ranged between 15 and 25 mPa.s) and thermal gelation (26.5 °C and 33 °C) properties. Bioadhesion of gel was successfully tested onto isolated bovine eyes as well as the assessment of CHX penetration into the cornea. Intracorneal CHX concentration was found greater than trophozoite minimum amoebicidal concentration and minimal cysticidal concentration after 15-min and 2-h ocular exposure, respectively, while any CHX permeation through the cornea was detected (<51 ng/cm2/h). Improvement of CHX ocular bioavailability was attributed to probable solubilization of tear film lipid layer by poloxamer. In vitro efficiency of CHX-Na2EDTA ocular gel was confirmed from the drastic reduction of trophozoite and cyst survival (to 25% and 2%, respectively), confirming the potential of the multicomponent pharmaceutical material strategy for the treatment of Acanthamoeba keratitis.