Intravenous Exposure Research Articles

Acute kidney injury following intravenous acyclovir in children

ObjectiveThe objective of this study was to describe the incidence of acute kidney injury (AKI) in children receiving intravenous acyclovir and determine risk factors that may be associated with it.DesignThis...

A novel bovine beta-lactoglobulin-induced passive systemic anaphylaxis model using humanized NOG hIL-3/GM-CSF Tg mice

Abstract Background Food allergy is a common disease that is caused by intake of allergen-containing foods such as milk, eggs, peanuts, and wheat. Systemic anaphylaxis is a severe hypersensitive allergic reaction resulting from degranulation of mast cells or basophils after crosslinking of their surface high affinity IgE receptors (Fce-RI) by allergen-specific IgE and allergens. In this study, we developed a novel human mast cell/basophil-engrafted mouse model that recapitulates systemic anaphylaxis by milk’s major allergen beta-lactoglobulin (BLG). Method Human CD34+ hematopoietic stem cells were transferred into NOG (nonTg) or NOG hIL-3/GM-CSF Tg mice. After 14–16 weeks, mature human basophils and mast cells increased in Tg mice, and bovine BLG specific human IgE was intravenously injected in these humanized mice, followed by either intravenous or oral bovine BLG protein exposure, 1 day later. Subsequently, allergic reactions were monitored by measuring body temperature, serum histamine level, and anaphylaxis scoring. Furthermore, the adrenaline agent, ‘epinephrine’ was used to investigate whether the allergic symptoms could be suppressed. Results After bovine BLG exposure, body temperature in Tg mice, but not in nonTg mice, gradually decreased within 10 minutes and 80 % of Tg mice died within 60 minutes. Serum histamine levels and anaphylaxis scores in Tg mice were markedly increased compared to nonTg mice after 30 minutes BLG challenge. These allergic symptoms were significantly inhibited by epinephrine treatment in Tg mice. Discussion The current hIL-3/GM-CSF Tg mouse model could possibly be used to develop novel anaphylaxis drugs in food allergy.

Nanocapsule pH Regulator: Sustained Continuous Alkali Release from Thermosensitive Liposomes Reduces Acid Erosion.

Thermosensitive liposomes are major drug delivery carriers, which enable targeting of drugs and burst release of the drugs from the liposomes at the site of action by applying a local heat stimulation above body temperature. Although the burst release is significant for a one-shot high-rate release of drugs at the target site, this type of release has a limited sustained action of the drugs. In this study, we report the alkali-encapsulating thermosensitive liposomes enabling environment pH regulation by sustained continuous cargo release at human body temperature. The liposomes encapsulating alkalis successfully neutralized the environmental acids for hours by releasing the alkalis and prevented acid erosion of hydroxyapatite matrix. Taken together, the present liposomes are effective for the sustained release of cargo at body temperature, specifically the alkali-encapsulating liposomes can be a preventing agent for dental caries in the oral cavity. The sustained release under endogenous body heat characteristics of thermosensitive liposomes showcased in this study can also be extended for prolonged intravenous drug exposure from targeted liposomal drug nanotherapeutics in the near future.

Coexposed nanoparticulate Ag alleviates the acute toxicity induced by ionic Ag+in vivo

Health concerns of silver nanoparticles (AgNPs) emerged with the increase of their industrial and biomedical application and thus human exposure. The highly dynamic properties of AgNPs lead to coexposure to nanoparticulate and ionic silver, and the combined effects of different Ag species might alter their individual toxicity. Herein, the toxicity of AgNPs combined with ionic Ag+ toward the rat was investigated after intravenous (i.v.) exposure to either AgNPs (5 mg/kg), Ag+ (5 mg/kg), or a mixture of Ag+ and AgNPs (5 mg/kg for both). Comparable results by histopathological and biochemical studies revealed that the exposure to individual AgNPs causes no apparent toxicity in rats, while Ag+ ions at the same dose induced marked acute toxicity. More importantly, while there was a negligible combined effect on the Ag accumulation, the less toxic AgNPs ameliorated Ag+ induced toxicity to rat organs after coexposure to the mixture of Ag+ and AgNPs, which might result from the complexation of Ag+ with the thiols like metallothioneins. Therefore, the combined toxicity of particulate and ionic Ag was complicated by their individual toxicities and also their interaction with intracellular detoxification biomolecules, regardless of differences in Ag accumulation. Although further investigations are still needed for the potential toxic mechanisms of the coexposed AgNPs and Ag+, considerations of the combined toxicity of different Ag species will reflect more accurate assessments of their health impacts.

Assessing Hepatitis B Reactivation Risk With Rituximab and Recent Intravenous Immunoglobulin Therapy.

Hepatitis B reactivation (HBR) is a complication of immunosuppression associated with significant morbidity and mortality. To further complicate interpretation of hepatitis B serologies, false positivity can occur in patients with recent intravenous immunoglobulin exposure. This scenario is not well recognized and may lead to inappropriate prescribing of HBR prophylaxis.

The acute effects of growth hormone in adipose tissue is associated with suppression of antilipolytic signals.

AimSince GH stimulates lipolysis in vivo after a 2‐hr lag phase, we studied whether this involves GH signaling and gene expression in adipose tissue (AT).MethodsHuman subjects (n = 9) each underwent intravenous exposure to GH versus saline with measurement of serum FFA, and GH signaling, gene array, and protein in AT biopsies after 30–120 min. Human data were corroborated in adipose‐specific GH receptor knockout (FaGHRKO) mice versus wild‐type mice. Expression of candidate genes identified in the array were investigated in 3T3‐L1 adipocytes.ResultsGH increased serum FFA and AT phosphorylation of STAT5b in human subjects. This was replicated in wild‐type mice, but not in FaGHRKO mice. The array identified 53 GH‐regulated genes, and Ingenuity Pathway analysis showed downregulation of PDE3b, an insulin‐dependent antilipolytic signal, upregulation of PTEN that inhibits insulin‐dependent antilipolysis, and downregulation of G0S2 and RASD1, both encoding antilipolytic proteins. This was confirmed in 3T3‐L1 adipocytes, except for PDE3B, including reciprocal effects of GH and insulin on mRNA expression of PTEN, RASD1, and G0S2. Conclusion (a) GH directly stimulates AT lipolysis in a GHR‐dependent manner, (b) this involves suppression of antilipolytic signals at the level of gene expression, (c) the underlying GH signaling pathways remain to be defined.

Does MR arthrography cause intracranial gadolinium deposition?

To determine (i) whether intra-articular gadolinium from MR arthrography (MRA) results in gadolinium deposition in the brain and (ii) whether there is a correlation between intra-articular gadolinium dose and intracranial gadolinium deposition. This retrospective study was institutional review board (IRB) approved and HIPAA compliant. The study group included consecutive adult patients who had undergone MRA of the hip or shoulder and subsequent MRI of the brain. None of the patients had a history of intravenous gadolinium exposure. A control group of patients of similar age and sex who were never exposed to gadolinium and had brain MRIs available was included. Signal intensities (SI) of four brain regions: pons, dentate nuclei (DN), globus pallidi (GP), and thalamus (Thal) normalized to cerebrospinal fluid (CSF) and expressed in SI ratios were measured on T1-weighted non-contrast MR images. Groups were compared using the student's t test. Linear correlation analysis of gadolinium dose and brain SI ratios was performed, and Pearson correlation coefficients (r) are reported. We identified 109 patients (mean age 44 ± 14years, 54% men) who had undergone MRA and 149 controls of similar age and sex distribution. There was no significant difference in mean SI ratios of the brain regions between patients and controls: pons/CSF (p = 0.7), DN/CSF (p = 0.4), GP/CSF (p > 0.99), Thal/CSF (p = 0.3). Within the MRA group, gadolinium dose was not associated with SI ratios (p > 0.2). Our study found no MR evidence of intracranial gadolinium deposition following MRA. In addition, there was no association between intra-articular gadolinium dose and SI ratios in commonly affected regions of the brain.

Risk of Acute Kidney Injury Following Contrast-enhanced CT in Hospitalized Pediatric Patients: A Propensity Score Analysis.

Background Acute kidney injury (AKI) remains a concern in hospitalized children undergoing CT with intravenous iodinated contrast material (ICM). Adult studies have shown frequencies of AKI after CT with intravenous ICM to be similar to propensity score-matched ICM-unexposed patient groups; similar data in pediatric patients are lacking. Purpose To evaluate the association between intravenous ICM exposure and AKI in hospitalized pediatric patients with stable kidney function undergoing contrast material-enhanced CT by comparing with a propensity score-matched ICM-unexposed patient sample undergoing abdominal US. Materials and Methods In this retrospective observational study, hospitalized patients aged 18 years or younger with stable kidney function and available serum creatinine (SCr) measurement before and after imaging who underwent CT with intravenous ICM or abdominal US (control group) between January 2009 and November 2018 were identified. The 1:1 propensity score matching was performed by using 23 covariates, stratified by estimated glomerular filtration rate (eGFR) before imaging (≥60 mL/min/1.73 m2 or <60 mL/min/1.73 m2). AKI was defined by using Acute Kidney Injury Network SCr-related criteria. Multivariable logistic regression was performed to identify risk factors for AKI after imaging, including the effects of eGFR and intravenous ICM exposure before imaging. Results A total of 1850 unique patients were included in the propensity score-matched sample (925 exposed to ICM [mean age ± standard deviation, 8 years ± 6; 484 female patients]; 925 unexposed to ICM [mean age, 7 years ± 6; 484 female patients]). Frequency of AKI with eGFR greater than or equal to 60 mL/min/1.73 m2 was 2.2% (20 of 889) for CT and US (odds ratio [OR]: 0.98; 95% confidence interval [CI]: 0.52, 1.86; adjusted P = .95) and with eGFR less than 60 mL/min/1.73 m2 was 5.6% (two of 36) and 11.1% (four of 36) for CT and US, respectively (OR: 0.75; 95% CI: 0.11, 5.00; adjusted P = .76). Significant multivariable predictors of AKI included eGFR before imaging (OR: 0.99; 95% CI: 0.98, 0.995; P = .001), body mass index (OR: 1.06; 95% CI: 1.02, 1.10; P = .003), acquired kidney disease (OR: 1.95; 95% CI: 1.004, 3.78; P = .049), and nephrotoxic antibiotic exposure (OR: 2.86; 95% CI: 1.55, 5.25; P < .001). Intravenous ICM exposure was not predictive (OR: 0.91; 95% CI: 0.51, 1.64; P > .05). Conclusion Hospitalized children with stable kidney function who underwent CT with intravenous iodinated contrast material (ICM) had a similar frequency of acute kidney injury (AKI) compared with a propensity score-matched ICM-unexposed patient group. In pediatric inpatients with estimated glomerular filtration rate greater than or equal to 60 mL/min/1.73 m2, ICM was not independently associated with AKI. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Paltiel in this issue.

In Vivo Metabolic Response upon Exposure to Gold Nanorod Core/Silver Shell Nanostructures: Modulation of Inflammation and Upregulation of Dopamine.

With the increasing applications of silver nanoparticles (Ag NPs), the concerns of widespread human exposure as well as subsequent health risks have been continuously growing. The acute and chronic toxicities of Ag NPs in cellular tests and animal tests have been widely investigated. Accumulating evidence shows that Ag NPs can induce inflammation, yet the overall mechanism is incomplete. Herein, using gold nanorod core/silver shell nanostructures (Au@Ag NRs) as a model system, we studied the influence on mice liver and lungs from the viewpoint of metabolism. In agreement with previous studies, Au@Ag NRs’ intravenous exposure caused inflammatory reaction, accompanying with metabolic alterations, including energy metabolism, membrane/choline metabolism, redox metabolism, and purine metabolism, the disturbances of which contribute to inflammation. At the same time, dopamine metabolism in liver was also changed. This is the first time to observe the production of dopamine in non-neural tissue after treatment with Ag NPs. As the upregulation of dopamine resists inflammation, it indicates the activation of antioxidant defense systems against oxidative stress induced by Au@Ag NRs. In the end, our findings deepened the understanding of molecular mechanisms of Ag NPs-induced inflammation and provide assistance in the rational design of their biomedical applications.

Reduction of radiation and contrast agent exposure in a cryoballoon ablation procedure with integration of electromagnetic mapping and intracardiac echocardiography: a single center experience.

Pulmonary vein isolation (PVI) with cryoballoon ablation (CBA) is routinely guided by fluoroscopy and utilizes contrast injection to ensure catheter positioning and pulmonary vein occlusion. Non-fluoroscopic imaging techniques including electromagnetic mapping (EM) and intracardiac echocardiography (ICE) have demonstrated reduced fluoroscopy times and contrast exposure. Utilization of color flow Doppler to evaluate vein occlusion with the balloon has not been evaluated as an alternative to contrast injection. In this study we evaluate the effectiveness of cryoablation guided by EM and ICE along with color Doppler to achieve PVI. We designed a retrospective cohort study comparing patients who were treated before and after implementation of EM (Carto 3, Biosense Webster) and ICE during CBA (AF Solutions, Medtronic). We analyzed patients receiving CBA with fluoroscopy plus EM and ICE (group 2; N = 24) versus fluoroscopy alone (group 1; N = 25). Procedural success was defined as freedom from atrial fibrillation or other atrial arrhythmias at 1year post ablation. Primary outcomes were radiation time and contrast exposure. Procedural success was achieved in all cases. Total fluoroscopy time was reduced from 22.4 ± 9.8min to 8.9 ± 5.1min (P < 0.001) in patients receiving CBA guided by EM and ICE. Furthermore, exposure to contrast media was significantly lower at 75.4 ± 24.1ml and 16.5 ± 21.1ml (P ≤ 0.001) in group 1 and group 2, respectively. Neither the number of required cryotherapy treatments nor procedure duration was negatively impacted by the implementation of non-fluoroscopic techniques. The 1-year success rate was identical between both groups at 72% and 79%. There was no difference in complication rates. This single-center cohort study demonstrates that CBA guided by EM and ICE can markedly reduce radiation and contrast exposure with excellent rates of acute PVI. This technique may be particularly effective in patients sensitive to intravenous contrast exposure.

Unaltered intravenous prion disease pathogenesis in the temporary absence of marginal zone B cells

Prion diseases are a unique, infectious, neurodegenerative disorders that can affect animals and humans. Data from mouse transmissions show that efficient infection of the host after intravenous (IV) prion exposure is dependent upon the early accumulation and amplification of the prions on stromal follicular dendritic cells (FDC) in the B cell follicles. How infectious prions are initially conveyed from the blood-stream to the FDC in the spleen is uncertain. Addressing this issue is important as susceptibility to peripheral prion infections can be reduced by treatments that prevent the early accumulation of prions upon FDC. The marginal zone (MZ) in the spleen contains specialized subsets of B cells and macrophages that are positioned to continuously monitor the blood-stream and remove pathogens, toxins and apoptotic cells. The continual shuttling of MZ B cells between the MZ and the B-cell follicle enables them to efficiently capture and deliver blood-borne antigens and antigen-containing immune complexes to splenic FDC. We tested the hypothesis that MZ B cells also play a role in the initial shuttling of prions from the blood-stream to FDC. MZ B cells were temporarily depleted from the MZ by antibody-mediated blocking of integrin function. We show that depletion of MZ B cells around the time of IV prion exposure did not affect the early accumulation of blood-borne prions upon splenic FDC or reduce susceptibility to IV prion infection. In conclusion, our data suggest that the initial delivery of blood-borne prions to FDC in the spleen occurs independently of MZ B cells.

A Non-ST Elevation Myocardial Infarction Associated with Alternative Medicine Ozone Infusion.

Alternative medicine is frequently used by patients even though most treatments are without demonstrable benefit and have not been properly evaluated for medical safety. Intravenous ozone is a modern form of alternative medicine. Even though ozone has been used medically for more than a century, ozone as an infusion is scientifically untested and potentially dangerous. This case notes a patient who underwent an ozone infusion who experienced syncope and a non-ST elevation myocardial infarction immediately thereafter. A 50-year-old white woman presented after experiencing syncope after completion of ozone infusion therapy. The ozone infusion consisted of her blood being drawn and ozone gas being injected into the sample. This blood was subsequently transfused back into the patient's blood stream via peripheral intravenous catheter. An initial electrocardiogram revealed no signs of infarction or ischemia, but her initial troponin I was elevated and continued to rise. She was admitted for a non-ST elevation myocardial infarction and underwent an extensive cardiac evaluation. It was determined that the oxidative myocardial stress secondary to ozone was associated with the non-ST elevation myocardial infarction. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: More patients are turning to alternative medicine. Unfortunately, the published literature regarding intravenous ozone exposure is scant; however, a multitude of studies have shown that ozone can have hazardous effects, including that of detrimental cardiovascular oxidative stress. Emergency physicians need to be aware of these novel treatments and their potential undetermined effects.

Prediction of Oral Bioavailability in Rats: Transferring Insights from in Vitro Correlations to (Deep) Machine Learning Models Using in Silico Model Outputs and Chemical Structure Parameters.

Oral administration of drug products is a strict requirement in many medical indications. Therefore, bioavailability prediction models are of high importance for prioritization of compound candidates in the drug discovery process. However, oral exposure and bioavailability are difficult to predict, as they are the result of various highly complex factors and/or processes influenced by the physicochemical properties of a compound, such as solubility, lipophilicity, or charge state, as well as by interactions with the organism, for instance, metabolism or membrane permeation. In this study, we assess whether it is possible to predict intravenous (iv) or oral drug exposure and oral bioavailability in rats. As input parameters, we use (i) six experimentally determined in vitro and physicochemical endpoints, namely, membrane permeation, free fraction, metabolic stability, solubility, pKa value, and lipophilicity; (ii) the outputs of six in silico absorption, distribution, metabolism, and excretion models trained on the same endpoints, or (iii) the chemical structure encoded as fingerprints or simplified molecular input line entry system strings. The underlying data set for the models is an unprecedented collection of almost 1900 data points with high-quality in vivo experiments performed in rats. We find that drug exposure after iv administration can be predicted similarly well using hybrid models with in vitro- or in silico-predicted endpoints as inputs, with fold change errors (FCE) of 2.28 and 2.08, respectively. The FCEs for exposure after oral administration are higher, and here, the prediction from in vitro inputs performs significantly better in comparison to in silico-based models with FCEs of 3.49 and 2.40, respectively, most probably reflecting the higher complexity of oral bioavailability. Simplifying the prediction task to a binary alert for low oral bioavailability, based only on chemical structure, we achieve accuracy and precision close to 70%.

639 A Multimodal Intervention Reduces Intravenous Opioid Exposure Among Hospitalized Patients With Inflammatory Bowel Disease

INTRODUCTION: Opioids (OPIs) are associated with increased mortality and infections in patients with IBD (AJG 2012;107(9):1409–22). Prior interventions targeting reductions in intravenous (IV) OPI exposure for all patients admitted to a general medical unit have decreased total OPI use without compromising pain control (JAMA IM 2018;178(6):759-63). We therefore performed a prospective evaluation of a multimodal intervention to reduce IV OPI exposure among IBD patients hospitalized at our institution. METHODS: This prospective study was conducted on a general medical unit at a large urban academic medical center from 1/1/19 to 5/31/19. Interventions to decrease IV OPI use were implemented in stages (Figure 1): 1. protocol for IV acetaminophen for IBD patients lacking enteral access 2. EHR “smartphrase” with analgesia guidance for use in gastroenterology consult notes 3. online IBD pain management pathway 4. automated text message alerts with analgesia guidance sent to providers. IV and total (IV+PO+TD) OPI exposures were measured in IV morphine mg equivalents (IVMME)/patient-day and compared to pre-intervention (1/1/18-12/31/18) data abstracted retrospectively from the EHR. IV acetaminophen and ketorolac use, length of stay (LOS), 30-day readmission rates (RRs), and pain scores (1-10 scale) were also assessed. RESULTS: Our study included 332 IBD patient encounters with similar baseline characteristics in pre-intervention (n = 241) and intervention (n = 91) periods (Table 1A). Between study periods, we observed a significant reduction in the proportion of patients receiving IV OPIs (43.6% vs. 30.1%, P = 0.03) and non-significant reductions in mean IV and total OPI exposures/patient-day (Table 1B). The proportion with highest OPI exposure (&gt;39.0 IVMME/d, top quartile of non-zero total OPI exposure in 2018) was significantly reduced (13.7% vs. 5.5%, P = 0.04). Run charts were performed to correlate the timing of interventions to changes in OPI exposure (Fig 2). We observed appropriately increased IV acetaminophen use (0.8% vs. 14.3%, P &lt; 0.01), similar mean pain scores (3.9 vs. 3.8, P = 0.74), non-significantly reduced IV ketorolac use (8.7% vs. 3.3%, P = 0.09), and significantly reduced mean LOS (7.2 vs. 5.2 d, P = 0.04) and 30-day RRs (21.6% vs. 11.0%, P = 0.03). CONCLUSION: A multimodal intervention successfully reduced IV OPI exposure for hospitalized IBD patients. This was associated with reduced LOS and 30-day RRs. Additional research is needed to determine long-term benefits of reduced OPI exposure in this population.

Repeated intravenous administration of silica nanoparticles induces pulmonary inflammation and collagen accumulation via JAK2/STAT3 and TGF-β/Smad3 pathways in vivo.

BackgroundThe health hazards of silica nanoparticle (SiNP) are raising worldwide concern as SiNPs has become the second largest manufactured nanomaterial in global markets. However, insufficient data for the adverse health effects and safety evaluation of SiNPs are remaining a big question.PurposeWe evaluated the effects and related mechanism of SiNPs on pulmonary inflammation and collagen production through repeated intravenous administration in mice in a 45-day observation period.MethodsMorphological and ultrastructural change, ultradistribution of SiNPs in lungs were observed in ICR mice through intravenous administration. Oxidative damage, pro-inflammatory cytokines, hydroxyproline content, the marker of fibroblasts and epithelial-mesenchymal transition (EMT), and JAK2/STAT3 and TGF-β1/Smad3 signaling pathways were detected to explore the lung injuries and related mechanism.ResultsThe results showed repeated intravenous exposure of SiNPs increased the weight of lung tissues and destroyed pulmonary histomorphological structure. The increased MDA content, depletion of SOD and GSH-Px in lungs were observed in SiNP-treated mice. The protein expressions of JAK2/STAT3 pathway were upregulated in lungs, and the levels of inflammatory cytokines TNF-α, IL-1β, and IL-6 in serum and lungs were also elevated in SiNPs treated group. The increased hydroxyproline content indicated collagen accumulation in lungs of SiNP-treated mice. Meanwhile, the protein expressions of the marker of myofibroblast (a-SMA), the regulators in connective tissue remodeling (CTGF), TGF-β, and p-Smad3 were all upregulated in lungs. In addition, we found intravenous administration of SiNPs-induced ultrastructural changes in type II alveolar epithelial cells but without downregulation of the protein expression of the key markers of epithelial cells (E-Cadherin).ConclusionOur results revealed that oxidative stress and inflammation contributed to the collagen accumulation through activation of JAK2/STAT3 and TGF-β/Smad3 pathways. It suggests that pulmonary aberrant inflammation and collagen accumulation induced by nanoparticles should be seriously considered for the safety application in diagnostics or therapeutics.

Characterization of the Pharmacokinetics of Samidorphan in Healthy Volunteers: Absolute Bioavailability and the Effect of Food and Age.

Background and ObjectivesSamidorphan (SAM) is a novel μ-opioid receptor antagonist. We report clinical pharmacokinetic (PK) properties of SAM following different routes of administration, and the effects of food and age on the PK of SAM following oral administration in healthy volunteers.MethodsAn open-label, fixed-sequence study (study 1, N = 10) examined the PK parameters following intravenous, sublingual, and oral exposure to SAM to determine absolute bioavailability. A double-blind, placebo-controlled study (study 2, N = 45) compared the PK in participants aged 18–40 years (cohort 1, n = 30) and ≥ 65 years (cohort 2, n = 15) who received a single oral dose of SAM 10 mg under fed (cohort 1 only) or fasted conditions.ResultsIn study 1, intravenous SAM had a plasma clearance of 33.7 L/h, volume of distribution of 341 L, and elimination half-life of 7–8 h. SAM was well-absorbed following sublingual or oral administration and reached peak concentrations (Cmax) within 2 h, with absolute bioavailability of 71% (sublingual) and 69% (oral). In study 2, concentration–time profiles were similar under fed and fasted conditions (cohort 1) and for young and elderly participants from both cohorts; 90% confidence intervals for the geometric least squares mean ratios for Cmax and area under the concentration–time curve from time zero extrapolated to infinity indicated equivalence.ConclusionsSAM has high bioavailability that is comparable following sublingual and oral administration and is not subject to extensive first-pass metabolism. The PK of orally administered SAM are not affected by food or age.

Association between intravenous contrast media exposure and non-recovery from dialysis-requiring septic acute kidney injury: a nationwide observational study.

This study aimed to examine the association between the use of intravenous contrast and non-recovery from dialysis-requiring acute kidney injury (AKI-D) and in-hospital mortality among patients with sepsis. This was a retrospective observational study using the Japanese Diagnosis Procedure Combination inpatient database between January 2011 and December 2016. We identified patients with septic AKI who began continuous renal replacement therapy (RRT) within 2-days of admission and underwent computed tomography. We compared patients with AKI-D with and without the use of intravenous contrast for computed tomography and performed propensity score matching to adjust for confounders for the association between exposure to intravenous contrast and outcomes, including a composite outcome of in-hospital mortality and RRT dependence at discharge and RRT duration. From 3782 and 6619 patients with septic AKI-D with and without intravenous contrast exposure, respectively, 3485 propensity score-matched pairs were generated. No significant differences were found in the outcomes between the propensity score-matched groups: a composite outcome of in-hospital mortality and RRT dependence, 49.6% vs. 50.2% (odds ratio (OR) 0.98; 95% CI (confidence interval) 0.88, 1.07); in-hospital mortality, 45.3% vs. 46.1% (OR 0.97; 95% CI 0.87, 1.06); RRT dependence, 4.4% vs 4.1% (OR 1.08; 95% CI 0.85, 1.31); and median (interquartile range) of RRT duration, 4 [2-11]days vs. 4 [2-11]days (P = 0.58). This large observational study did not support an association between intravenous contrast media and adverse in-hospital outcomes in patients with septic AKI-D. Further studies are warranted to assess the generalizability.

Intravenous iron supplementation does not increase infectious disease risk in hemodialysis patients: a nationwide cohort-based case-crossover study

BackgroundStudies have reported conflicting findings on the infection risk posed by intravenous iron supplementation among hemodialysis (HD) patients. We used a novel study design to assess associations between intravenous iron and infectious diseases.MethodsPatients initiating HD between 1998 and 2008 were extracted from Taiwan’s National Health Insurance Research Database. Their first infectious disease in the period between 1.5 years after dialysis initiation and 2010 was identified and defined as the index date. Through the case-crossover design, the odds of exposure to intravenous iron within the 1-month period immediately preceding the index date (i.e., the case period) were compared with iron exposure in three different matched control periods for the same enrollee, thus possibly reducing some unmeasured confounders.ResultsA total of 1410 patients who met our enrollment criteria were extracted from incident HD patients. The odds of intravenous iron exposure during the case period versus total control periods exhibited no significant difference (odds ratio: 1.000, 95% confidence interval: 0.75–1.33). In subgroup analyses, this association remained nonsignificant across patients with diabetes mellitus, heart failure, chronic lung disease, venous catheter for HD, and higher iron load.ConclusionsWe found that intravenous iron supplementation did not increase short-term infection risk among HD patients.

Multiple metabolic pathways are predictive of ricin intoxication in a rat model

IntroductionExposure to ricin can be lethal and treatments that are under development have short windows of opportunity for administration after exposure. It is therefore essential to achieve early detection of ricin exposure to provide the best prognosis for exposed individuals. Ricin toxin can be detected in clinical samples via several antibody-based techniques, but the efficacy of these can be limited due to the rapid processing and cellular uptake of toxin in the body and subsequent low blood ricin concentrations. Other diagnostic tools that perform, in an orthogonal manner, are therefore desirable.ObjectivesTo determine time-dependent metabolic changes in Sprague–Dawley rats following intravenous exposure to ricin.MethodsSprague–Dawley rats were intravenously exposed to ricin and multiple blood samples were collected from each animal for up to 48 h following exposure in two independent studies. Plasma samples were analysed applying HILIC and C18 reversed phase UHPLC–MS assays followed by univariate and multivariate analysis.ResultsIn Sprague–Dawley rats we have demonstrated that metabolic changes measured in blood can distinguish between rats exposed intravenously to ricin and controls prior to the onset of behavioral signs of intoxication after 24 h. A total of 37 metabolites were significantly altered following exposure to ricin when compared to controls. The arginine/proline, bile acid and triacylglyceride metabolic pathways were highlighted as being important with two triacylglycerides at 8 h post exposure giving an AUROC score of 0.94. At 16 h and 24 h the AUROC score increased to 0.98 and 1.0 with the number of metabolites in the panel increasing to 5 and 7, respectively.ConclusionsThese data demonstrate that metabolites may be a useful tool to diagnose and detect ricin exposure, thus increasing the effectiveness of supportive therapy and future ricin-specific medical treatments.

Inter-ethnic differences in CYP3A4 metabolism: A Bayesian meta-analysis for the refinement of uncertainty factors in chemical risk assessment

CYP3A4 is the major human cytochrome P450 isoform responsible for the metabolism of more than 50% of known xenobiotics. Here, inter-ethnic differences in CYP3A4 metabolism have been investigated through a systematic review of pharmacokinetic data for 15 CYP3A4 probe substrates and parameters reflecting acute (Cmax, oral route) and chronic exposure (clearance and area under the plasma concentration-time curve, oral and intravenous route). All data were extracted in a structured database and meta-analyses were performed using a hierarchical Bayesian model in the R freeware to derive parameter, route and population-specific variability distributions for CYP3A4 metabolism. Two different approaches were applied. 1) Inter-individual differences were quantified using North American healthy adults as a reference group to compare with European, Asian, Middle East, and South-American healthy adults and with ethnicity, elderly, children and neonates. 2) Intra-ethnic–specific variability distributions were derived without comparing to a reference group. Overall, subgroup-specific distributions for CYP3A4-variability provided the basis to derive CYP3A4-related uncertainty factors (UF) to cover 95th or 97.5th centiles of the population and were compared with the human default toxicokinetic UF (3.16). The results indicate that CYP3A4-related UFs in healthy adults were higher for chronic oral exposures (2.5–3.0, UF95 and UF97.5, 10 compounds) than for intravenous exposures (1.7–1.8, 2 compounds). All UFs were within the default TK UF. These distributions allow for: 1) the application of CYP3A4-related UFs in the risk assessment of compounds for which in vitro CYP3A4 metabolism evidence is available without the need for animal data; 2) the integration of CYP3A4-related variability distributions with in vitro metabolism data into physiologically based kinetic (PBK) models for quantitative in vitro to in vivo extrapolation (QIVIVE) and 3) the estimation of UFs in chemical risk assessment using variability distributions of metabolism.