Adverse Effects on the Thyroid of Chinese Pregnant Women Exposed to Long-Term Iodine Excess: Optimal and Safe Tolerable Upper Intake Levels of Iodine.

Ensuring optimal iodine nutrition in pregnant women is a global public health concern. However, there is no direct data on safe tolerable upper intake levels (ULs) for pregnant women. A cross-sectional study was performed to determine the ULs of pregnant women. A total of 744 pregnant women were enrolled in this study. The median (IQR) urinary iodine concentration (UIC) in pregnant women was 150.2 (87.6, 268.0) µg/L, and the urinary iodine excretion (UIE) over 24 h was 204.2 (116.0, 387.0) µg/day. Compared with those with a UIE figure of between 150-250 µg/day, the reference group, the prevalence of thyroid dysfunction was 5.7 times higher (95%CI: 1.7, 19.2) in pregnant women with a UIE figure of between 450-550 µg/day, and 3.9 times higher (95%CI: 1.5, 10.3) in pregnant women with a UIE figure of ≥550 µg/day. Compared with an estimated iodine intake (EII) of between 100-200 µg/day, the reference group, the prevalence of thyroid dysfunction was 4.3 times higher (95%CI: 1.3, 14.4) in pregnant women with a UIE figure of between 500-600 µg/day, and 3.6 times higher (95%CI: 1.5, 8.9) in pregnant women with UIE of ≥600 µg/day. In general, our cross-sectional study found that excessive iodine intake during pregnancy appears to directly increase the risk of thyroid dysfunction. Avoiding chronic iodine intakes of 500 µg/day or higher or having a UIE figure of ≥450 µg/day is recommended for pregnant women in China.

Switching across direct oral anticoagulants: a real-life-setting pilot prospective study.

AIMS: Crossover between direct oral anticoagulants (DOACs) has been underinvestigated, but happens frequently in clinical practice. The purpose of this study was to evaluate causes, rates and outcomes of a DOAC-to-DOAC switch. METHODS: Patients receiving their first DOAC prescription at the Anticoagulation Center, Cardiology Dept, Bologna-Bellaria Hospital in 2017-2018 were consecutively included and prospectively followed up. DOAC-to-DOAC switch was the main outcome; causes of switch (cardiovascular events and noncardiovascular drug-related adverse events) had direct biannual assessment before and after the switch. RESULTS: Among 300 patients enrolled (mean age = 79.3 years, mean follow-up = 1.5 years), with no difference in cardiovascular risk factors depending on index DOAC, 13% underwent DOAC-to-DOAC switch, minor bleeding and noncardiovascular adverse events being the most frequent causes. Dabigatran carried a three-fold increase in risk of switch compared with other DOACs, but the mean age of patients who switched was 83. Factors leading to switch resolved in 87% of cases afterwards. Annual rates of cardiovascular/noncardiovascular V events did not differ before and after the switch. CONCLUSION: DOAC-to-DOAC switch happens in 9% of patients using DOAC each year, and seems not to impact rates of cardiovascular events after switch. Dabigatran, in the elderly, might be associated with a higher risk of DOAC-to-DOAC switch. Further studies are needed to confirm the long-term safety and effectiveness of switching paradigm.

Viscerotropic disease and acute uveitis following yellow fever vaccination: a case report.

BACKGROUND: Yellow fever vaccine exists for over 80 years and is considered to be relatively safe. However, in rare cases it can produce serious neurotropic and viscerotropic complications. We report a case of a patient who presented both viscerotropic and neurological manifestations after yellow fever vaccination. CASE PRESENTATION: We describe the case of a 37 years old man who developed after the yellow fever vaccination a yellow fever vaccine-associated viscerotropic disease followed by acute uveitis. Prolonged detection of yellow fever RNA in blood and urine was consistent with yellow fever vaccine-associated adverse event. The final outcome was good, although with persistent fatigue over a few months. CONCLUSIONS: Even if the yellow fever vaccine is relatively safe, physicians should be aware of its possible serious adverse effects.

Clinical prospects of biomarkers for the early detection and/or prediction of organ injury associated with pharmacotherapy.

Several biomarkers are used to monitor organ damage caused by drug toxicity. Traditional markers of kidney function, such as serum creatinine and blood urea nitrogen are commonly used to estimate glomerular filtration rate. However, these markers have several limitations including poor specificity and sensitivity. A number of serum and urine biomarkers have recently been described to detect kidney damage caused by drugs such as cisplatin, gentamicin, vancomycin, and tacrolimus. Neutrophil gelatinase-associated lipocalin (NGAL), liver-type fatty acid-binding protein (L-FABP), kidney injury molecule-1 (KIM-1), monocyte chemotactic protein-1 (MCP-1), and cystatin C have been identified as biomarkers for early kidney damage. Hy's Law is widely used as to predict a high risk of severe drug-induced liver injury caused by drugs such as acetaminophen. Recent reports have indicated that glutamate dehydrogenase (GLDH), high-mobility group box 1 (HMGB-1), Keratin-18 (k18), MicroRNA-122 and ornithine carbamoyltransferase (OCT) are more sensitive markers of hepatotoxicity compared to the traditional markers including the blood levels of amiotransferases and total bilirubin. Additionally, the rapid development of proteomic technologies in biofluids and tissue provides a new multi-marker panel, leading to the discovery of more sensitive biomarkers. In this review, an update topics of biomarkers for the detection of kidney or liver injury associated with pharmacotherapy.

Bone Toolbox: Biomarkers, Imaging Tools, Biomechanics, and Histomorphometry.

Bone is a unique tissue with turnover, metabolic, and cellular activities that vary through development to aging and with a mineralized matrix in which the current state and the history of a bone coexist. Qualitative histopathology often lacks sensitivity to detect changes in bone formation, mineralization and resorption, which often requires chronic dosing to result in structural changes such as variation in bone mass and geometry. A large panel of modalities can be used to fully analyze the health of the skeleton, including biomarker evaluation in serum or urine, imaging techniques ranging from radiology to computed tomography, biomechanical testing, and undecalcified tissue processing with bone histomorphometry. The use of clinically relevant biomarkers provides an important noninvasive, sensitive, rapid, and real-time tool to monitor bone activity at the whole skeleton level when conducting safety assessments in a preclinical setting. Imaging modalities also allow in vivo longitudinal assessments with a powerful, noninvasive and clinically translatable tools to monitor drug effects. Different imaging modalities are used in the preclinical studies to evaluate the bone tissues: standard radiography, dual-energy X-ray absorptiometry, peripheral quantitative computed tomography (pQCT), micro-computed tomography, and high-resolution pQCT. Bone histomorphometry is an important tool that provides sensitive evaluation to detect effects of test articles on bone resorption, formation, mineralization, remodeling rates and growth to address a potential target- or class-related theoretical bone liability. Ultimately, the measurement of bone mechanical properties in pharmaceutical testing is critical to understand the potential effects of that pharmaceutical on bone health and fracture risk. Important considerations are required for including these different techniques in toxicology rodents and nonrodent studies, to actually integrate these into safety assessment.

Multiscale Mathematical Model of Drug-Induced Proximal Tubule Injury: Linking Urinary Biomarkers to Epithelial Cell Injury and Renal Dysfunction.

Drug-induced nephrotoxicity is a major cause of acute kidney injury, and thus detecting the potential for nephrotoxicity early in the drug development process is critical. Various urinary biomarkers exhibit different patterns following drug-induced injury, which may provide greater information than traditional biomarkers like serum creatinine. In this study, we developed a multiscale quantitative systems pharmacology model relating drug exposure to proximal tubule (PT) epithelial cell injury and subsequently to expression of multiple urinary biomarkers and organ-level functional changes. We utilized urinary kidney injury molecule-1 (Kim-1), alpha glutathione S-transferase, albumin (αGST), glucose, and urine volume time profiles as well as serum creatinine and histopathology data obtained from rats treated with the nephrotoxicant cisplatin to develop the model. Although the model was developed using single-dose response to cisplatin, the model predicted the serum creatinine response to multidose cisplatin regimens. Further, using only the urinary Kim-1 response to gentamicin (a nephrotoxicant with a distinctly different injury time course than cisplatin), the model detected and predicted mild to moderate PT injury, as confirmed with histopathology, even when serum creatinine was unchanged. Thus, the model is generalizable, and can be used to deconvolute the underlying degree and time course of drug-induced PT injury and renal dysfunction from a small number of urinary biomarkers, and may provide a tool to determine optimal dosing regimens that minimize renal injury.

Citric Acid Metabolism in Resistant Hypertension: Underlying Mechanisms and Metabolic Prediction of Treatment Response.

Resistant hypertension (RH) affects 9% to 12% of hypertensive adults. Prolonged exposure to suboptimal blood pressure control results in end-organ damage and cardiovascular risk. Spironolactone is the most effective drug for treatment, but not all patients respond and side effects are not negligible. Little is known on the mechanisms responsible for RH. We aimed to identify metabolic alterations in urine. In addition, a potential capacity of metabolites to predict response to spironolactone was investigated. Urine was collected from 29 patients with RH and from a group of 13 subjects with pseudo-RH. For patients, samples were collected before and after spironolactone administration and were classified in responders (n=19) and nonresponders (n=10). Nuclear magnetic resonance was applied to identify altered metabolites and pathways. Metabolites were confirmed by liquid chromatography-mass spectrometry. Citric acid cycle was the pathway most significantly altered (P<0.0001). Metabolic concentrations were quantified and ranged from ng/mL malate to µg/mL citrate. Citrate and oxaloacetate increased in RH versus pseudoresistant. Together with α-ketoglutarate and malate, they were able to discriminate between responders and nonresponders, being the 4 metabolites increased in nonresponders. Combined as a prediction panel, they showed receiver operating characteristiccurve with area under the curve of 0.96. We show that citric acid cycle and deregulation of reactive oxygen species homeostasis control continue its activation after hypertension was developed. A metabolic panel showing alteration before spironolactone treatment and predicting future response of patients is shown. These molecular indicators will contribute optimizing the rate of control of RH patients with spironolactone.

Clinical Relevance and Predictive Value of Damage Biomarkers of Drug-Induced Kidney Injury.

Nephrotoxin exposure accounts for up to one-fourth of acute kidney injury episodes in hospitalized patients, and the associated consequences are as severe as acute kidney injury due to other etiologies. As the use of nephrotoxic agents represents one of the few modifiable risk factors for acute kidney injury, clinicians must be able to identify patients at high risk for drug-induced kidney injury rapidly. Recently, significant advancements have been made in the field of biomarker utilization for the prediction and detection of acute kidney injury. Such biomarkers may have a role both for detection of drug-induced kidney disease and implementation of preventative and therapeutic strategies designed to mitigate injury. In this article, basic principles of renal biomarker use in practice are summarized, and the existing evidence for six markers specifically used to detect drug-induced kidney injury are outlined, including liver-type fatty acid binding protein, neutrophil gelatinase-associated lipocalin, tissue inhibitor of metalloproteinase-2 times insulin-like growth factor-binding protein 7 ([TIMP-2]·[IGFBP7]), kidney injury molecule-1 and N-acetyl-ß-D-glucosaminidase. The results of the literature search for these six kidney damage biomarkers identified 29 unique articles with none detected for liver-type fatty acid binding protein and [TIMP-2]·[IGFBP7]. For three biomarkers, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin and N-acetyl-ß-D-glucosaminidase, the majority of the studies suggest utility in clinical practice. While many questions need to be answered to clearly articulate the use of biomarkers to predict drug-induced kidney disease, current data are promising.

Net Reclassification Index and Integrated Discrimination Index Are Not Appropriate for Testing Whether a Biomarker Improves Predictive Performance.

One of the goals of the Critical Path Institute's Predictive Safety Testing Consortium (PSTC) is to promote best practices for evaluating novel markers of drug induced injury. This includes the use of sound statistical methods. For rat studies, these practices have centered around comparing the area under the receiver-operator characteristic curve for each novel injury biomarker to those for the standard markers. In addition, the PSTC has previously used the net reclassification index (NRI) and integrated discrimination index (IDI) to assess the increased certainty provided by each novel injury biomarker when added to the information already provided by the standard markers. Due to their relatively simple interpretations, NRI and IDI have generally been popular measures of predictive performance. However recent literature suggests that significance tests for NRI and IDI can have inflated false positive rates and thus, tests based on these metrics should not be relied upon. Instead, when parametric models are employed to assess the added predictive value of a new marker, following (Pepe, M. S., Kerr, K. F., Longton, G., and Wang, Z. (2013). Testing for improvement in prediction model performance. Stat. Med. 32, 1467-1482), the PSTC recommends that likelihood based methods be used for significance testing.

[Investigations of the distribution of aripiprazole in the internal organs and biological fluids of the laboratory animals in case of acute intoxication].

Despite the present-day extensive application of aripiprazole, there are many cases of its overdose and of poisoning with this compound. The objective of the present study was to detect and quantify aripiprazole in the internal organs and biological fluids of the laboratory animals in case of acute intoxication. The experiments were carried out on white mice of both sexes weighing 20.5 and 25.7 g. Aripiprazole was isolated from the liver, kidneys, brain, and heart as described by A.A. Vasil'eva and from the plasma and urine by the newly developed original methods. Aripiprazole was identified and quantitatively determined in the extracts from the aforementioned organs and tissues with the use of HPLC. The data obtained on the completeness of extraction from the liver, kidneys , and brain of the laboratory animals indicate that aripiprazole accumulated in the highest concentrations in the brain and kidneys within 24 hours after acute poisoning. Ist content was significantly lower in the liver while no traces of aripiprazole were found in the heart of the mice. The methods for aripiprazole isolation from the urine and blood plasma are described. The maximum amounts of aripiprazole were detected in blood plasma within 24 hours after acute intoxication. It is concluded that the proposed methods for aripiprazole isolation from the biological fluids (blood plasma and urine) can be included in the scheme of the chemical toxicological analysis of this compound.

Systems level metabolic phenotype of methotrexate administration in the context of non-alcoholic steatohepatitis in the rat.

Adverse drug reactions (ADRs) represent a significant clinical challenge with respect to patient morbidity and mortality. We investigated the hepatotoxicity and systems level metabolic phenotype of methotrexate (MTX) in the context of a prevalent liver disease; non-alcoholic steatohepatitis (NASH). A nuclear magnetic resonance spectroscopic-based metabonomic approach was employed to analyze the metabolic consequences of MTX (0, 10, 40, and 100 mg/kg) in the urine and liver of healthy rats (control diet) and in a model of NASH (methionine-choline deficient diet). Histopathological analysis confirmed baseline (0 mg/kg) liver necrosis, liver inflammation, and lipid accumulation in the NASH model. Administration of MTX (40 and 100 mg/kg) led to liver necrosis in the control cohort, whereas the NASH cohort also displayed biliary hyperplasia and liver fibrosis (100 mg/kg), providing evidence of the synergistic effect of MTX and NASH. The complementary hepatic and urinary metabolic phenotypes of the NASH model, at baseline, revealed perturbation of multiple metabolites associated with oxidative and energetic stress, and folate homeostasis. Administration of MTX in both diet cohorts showed dose-dependent metabolic consequences affecting gut microbial, energy, nucleobase, nucleoside, and folate metabolism. Furthermore, a unique panel of metabolic changes reflective of the synergistic effect of MTX and NASH was identified, including the elevation of hepatic phenylalanine, urocanate, acetate, and both urinary and hepatic formiminoglutamic acid. This systems level metabonomic analysis of the hepatotoxicity of MTX in the context of NASH provided novel mechanistic insight of potential wider clinical relevance for further understanding the role of liver pathology as a risk factor for ADRs.

Di-22:6-bis(monoacylglycerol)phosphate: A clinical biomarker of drug-induced phospholipidosis for drug development and safety assessment.

The inability to routinely monitor drug-induced phospholipidosis (DIPL) presents a challenge in pharmaceutical drug development and in the clinic. Several nonclinical studies have shown di-docosahexaenoyl (22:6) bis(monoacylglycerol) phosphate (di-22:6-BMP) to be a reliable biomarker of tissue DIPL that can be monitored in the plasma/serum and urine. The aim of this study was to show the relevance of di-22:6-BMP as a DIPL biomarker for drug development and safety assessment in humans. DIPL shares many similarities with the inherited lysosomal storage disorder Niemann-Pick type C (NPC) disease. DIPL and NPC result in similar changes in lysosomal function and cholesterol status that lead to the accumulation of multi-lamellar bodies (myeloid bodies) in cells and tissues. To validate di-22:6-BMP as a biomarker of DIPL for clinical studies, NPC patients and healthy donors were classified by receiver operator curve analysis based on urinary di-22:6-BMP concentrations. By showing 96.7-specificity and 100-sensitivity to identify NPC disease, di-22:6-BMP can be used to assess DIPL in human studies. The mean concentration of di-22:6-BMP in the urine of NPC patients was 51.4-fold (p ≤ 0.05) above the healthy baseline range. Additionally, baseline levels of di-22:6-BMP were assessed in healthy non-medicated laboratory animals (rats, mice, dogs, and monkeys) and human subjects to define normal reference ranges for nonclinical/clinical studies. The baseline ranges of di-22:6-BMP in the plasma, serum, and urine of humans and laboratory animals were species dependent. The results of this study support the role of di-22:6-BMP as a biomarker of DIPL for pharmaceutical drug development and health care settings.

A prospective stratified case-cohort study on statins and multiple adverse events in Japan.

PURPOSE: To assess the association between statins and diverse adverse events in Japanese population. METHODS: New users of statin who started statin after 6-month period of non-use were identified in 68 hospitals between January 2008 and July 2010. In addition to the random sample subcohort, we selected additional subcohort members to make the stratified sample subcohort have at least one patient in all subgroups stratified by each combination of statin and hospital. By abstraction from medical records, detailed information was obtained for all potential cases and pre-selected subcohort members. The event review committee consisting of 3 specialists judged whether possible cases met the definition of one of the adverse events of interest, and for adjudicated cases the committee further judged whether statin was a certain, probable or possible cause of the occurrence of the event. Adjusted for covariates including age, gender, status of "switcher", use of high daily dose and comorbidities at baseline, hazard ratio (HR) was estimated by the Cox proportional hazards model with Barlow's weighting method. Data were also analyzed by the method proposed by Breslow in 2009. RESULTS: A total of 6,877 new users of a statin were identified (median age: 66 years; males: 52%). The hazard ratios of increase in serum creatinine for atorvastatin and fluvastatin have wide confidence intervals, but both of the point estimates were around 2.5. Estimates of hazard ratios by the method of Barlow (1999) were similar to those by the method of Breslow (2009). CONCLUSIONS: Use of statin was not associated with a significant increased risk for renal, liver and muscle events. However, the hazard ratio of increase in serum creatinine tended to be high with atorvastatin and fluvastatin to require further studies.

Urinary Neutrophil Gelatinase-Associated Lipocalin predicts the severity of contrast-induced acute kidney injury in chronic kidney disease patients undergoing elective coronary procedures.

BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) particularly in high risk patients with chronic kidney disease (CKD), increases morbidity and mortality. Neutrophil gelatinase-associated lipocalin (NGAL) is a protein excreted by the kidney during AKI. There are no urine (u) NGAL data as an early CI-AKI marker in CKD patients undergoing coronary procedures. METHODS: This prospective study enrolled 130 patients with estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m² undergoing elective coronary procedures. Serial urine samples, obtained at baseline and 3, 6, 12, 18, and 24 h post contrast administration were analyzed by NGAL ELISA kit. AKI was defined as an increase in serum creatinine (SCr) of ≥ 0.3 mg/dl or ≥ 1.5 times baseline SCr within 48 h per 2012 KDIGO guidelines. Receiver operator characteristic curve analyses identified optimal uNGAL and delta of uNGAL values for diagnosing CI-AKI. RESULTS: The uNGAL was significantly and inverse correlated with eGFR (R = 0.25, P < 0.005). CI-AKI developed in 16/130 (12.31%) patients: 13 and 3 in CI-AKI stages I and II, respectively. uNGAL and delta of uNGAL were significantly higher in the CI-AKI group when compared with the No CI-AKI group (P < 0.05). The best uNGAL cut-off for optimal sensitivity 94%, specificity 78%, and area under the curve 0.84 for predicting CI-AKI was 117 ng/mL at 6 h, respectively. Corresponding values for predicting CI-AKI stage II were 100%, 87% and 0.9 when using an uNGAL of 264 ng/mL at 6 h. CONCLUSIONS: Monitoring of uNGAL levels not only provide the early detecting CI-AKI but also predict the severity of CI-AKI in CKD patients undergoing elective coronary procedures.

Emergence of biomarkers in nephropharmacology.

Blood-urea nitrogen, serum creatinine and urine output have long been used as markers of kidney function despite their known limitations. In the past few years, a number of novel biomarkers have been identified in the urine and blood that can detect kidney injury early. Although, to date, none of these biomarkers are in clinical use, many have been validated as reliable and sensitive, allowing detection of kidney injury before serum creatinine levels rise and urine output drops. These markers have been evaluated in great detail in animal models and to a lesser extent in humans in postcardiopulmonary bypass and sepsis. There is relatively scarse data on the use of these biomarkers in the detection of kidney injury associated with the use of pharmacologic agents. The purpose of this article is to summarize these data and highlight the potential utility of these biomarkers in nephropharmacology.

Biomarkers - SMi's Third Summit: discovery, validation & qualification.

SMi's Third Summit on Biomarkers, held in London, included topics covering new technological and therapeutic developments in the field of biomarkers. This conference report highlights selected presentations on the development of biomarkers, novel biomarkers for cancer and other diseases, and safety issues relating to biomarkers.

Tissue-specific, non-invasive toxicity biomarkers: translation from preclinical safety assessment to clinical safety monitoring.

Limited sensitivity and limited target organ specificity are the major drawbacks for most peripheral clinical pathology parameters traditionally used for monitoring organ integrity both during preclinical toxicological assessment and clinical safety testing of investigational drugs. Several novel toxicity biomarkers have emerged as sensitive tools for detection, monitoring, quantification and prediction of solid organ toxicity. These tissue-specific, non-invasive biomarkers may provide valuable information for decision making during toxicological assessment and may be used for sensitive and specific target organ monitoring during clinical trials. This review critically discusses the opportunities and limitations of these biomarkers with respect to their translation into (first-in-human) clinical trials. A comprehensive overview is provided on serum- and urine-based biomarkers for hepatotoxicity, nephrotoxicity, cardiotoxicity, gonadotoxicity, pancreatic toxicity, vascular toxicity and phospholipidosis including species-specific assay availabilities and sampling regimens. In addition, the current regulatory status is presented and discussed in view of recent changes in regulatory acceptance by health authorities.

Sample classification based on Bayesian spectral decomposition of metabonomic NMR data sets.

1H NMR spectra of biofluids provides a wealth of biochemical information on the metabolic status of an organism. Through the application of pattern recognition and classification algorithms, the data have been shown to provide information on disease diagnosis and the beneficial and adverse effects of potential therapeutics. Here, a novel approach is described for identifying subsets of spectral patterns in databases of NMR spectra, and it is shown that the intensities of these spectral patterns can be related to the onset and recovery from a toxic lesion in both a time-related and dose-related fashion. These patterns form a new type of combination biomarker for the biological effect under study. The approach is illustrated with a study of liver toxicity in rats using NMR spectra of urine following administration of a model hepatotoxin hydrazine.