Drug-drug interaction assessment based on a large-scale spontaneous reporting system for hepato- and renal-toxicity, and thrombocytopenia with concomitant low-dose methotrexate and analgesics use.

BACKGROUND: Methotrexate (MTX) is the cornerstone of rheumatoid arthritis (RA) treatment and is highly effective with low-dose intermittent administration. MTX is occasionally used in combination with non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (APAP)/paracetamol for pain or inflammation control. With MTX treatment, the side effects, such as hepatotoxicity, renal failure, and myelosuppression should be considered. These are also seen with analgesics treatment. METHODS: We used a large spontaneously reported adverse event database (FAERS [JAPIC AERS]) to analyze whether the reporting of adverse events increased upon MTX and analgesic therapy in patients with RA. RESULTS: After identifying RA cases, the crude reporting odds ratios (cRORs) for hepatotoxicity, renal failure, and thrombocytopenia associated with the use of MTX, APAP, or NSAIDs were calculated by disproportionality analysis, which revealed significantly higher cRORs for these events. No analgesics showed consistent positive signals for drug-drug interaction (DDI) with concomitant low-dose MTX analyzed using four algorithms for DDI interaction (the Ω shrinkage measure, additive or multiplicative, and combination risk ratio models). However, in renal failure and thrombocytopenia, loxoprofen (Ω025 = 0.08) and piroxicam (Ω025 = 0.46), and ibuprofen (Ω025 = 0.74) and ketorolac (Ω025 = 3.52), respectively, showed positive signals in the Ω shrinkage measure model, and no consistency was found among adverse events or NSAIDs. CONCLUSIONS: Studies using spontaneous reporting systems have limitations such as reporting bias or lack of patient background; however, the results of our comprehensive analysis support the results of previous clinical or epidemiological studies. This study also demonstrated the usefulness of FAERS for DDI assessment.

Ameliorating effects of ethanol extract of root bark of Salacia nitida on blood electrolyte and renal perturbations in Plasmodium berghei-infected mice

Abstract Malaria, a disease of public health concern is a known cause of kidney failure, and dependence on herbal medicines for its treatment is increasing due to the high cost of drugs. So this study is designed to evaluate the ameliorating effect of ethanol extract from Salacia nitida root bark on electrolyte and renal perturbations in Plasmodium berghei-infected mice. Thirty malariainfected mice divided into five groups of six mice each and another group of six uninfected mice were used for the study. 280, 430, and 580 mg/kg of extract were given to infected mice in groups B, C, and D, 4 mg/kg of artesunate given to group E mice, and 4 ml/kg of physiological saline given to group A and uninfected group F mice for five days. Serum Na+, K+, HCO3, Cl-, TB, urea, creatinine, BUN concentrations, and BUN/creatinine ratio were determined using standard methods. Results showed significant increases (p < 0.05) in Na+, K+, and HCO3 and decreases in Cl-, TB, urea, creatinine, BUN, and BUN/creatinine ratio in the infected treated mice in groups B - E. This study showed that ethanol extract of S. nitida root bark is efficient in the treatment of renal disorders and blood electrolyte perturbations

Adverse Events and Economic Burden Among Patients Receiving Systemic Treatment for Mantle Cell Lymphoma: A Real-World Retrospective Cohort Study.

BACKGROUND/AIM: Limited published real-world data describe adverse events (AEs) among patients treated for mantle-cell lymphoma (MCL). The aim of this retrospective study was to describe treatment patterns, AEs, and associated healthcare costs. PATIENTS AND METHODS: Patients had two or more claims coded for MCL diagnosis, the first claim date (07/01/2012-05/31/2017) was the index date. Patients with pre-index MCL diagnosis or systemic treatment, or hematopoietic stem cell transplantation were excluded. Cohorts by regimen were followed for up to three lines of therapy. RESULTS: Patients (n=395; median age 72 years; 31% female) were observed over a total of 576 lines of therapy, the most common being bendamustine plus rituximab; rituximab monotherapy; R-CHOP; and ibrutinib. The most frequent AEs were hypertension (40.5%), anemia (37.7%), and infection (36.1%). However, hepatotoxicity ($19,645), stroke ($18,893), and renal failure ($9,037) were associated with the highest medical costs per patient per month. CONCLUSION: Among patients receiving common systemic treatments for MCL, AEs occurred frequently; some imposed substantial inpatient care costs.

Monitoring the use of dabigatran etexilate for stroke prevention: compliance with renal function guidelines.

INTRODUCTION Dabigatran etexilate has become widely used in New Zealand, but information relating to when renal function monitoring is being undertaken is lacking. AIM To investigate if clinically appropriate renal function monitoring is being undertaken in New Zealand primary care for stroke prevention in non-valvular atrial fibrillation patients prescribed dabigatran etexilate. METHODS New Zealand non-valvular atrial fibrillation patients' prescription and primary care health data were extracted from national administrative databases for the period 1 July 2011 to 31 December 2015. The proportion of patients who had serum creatinine measurements at close proximity to treatment initiation and 12-months post initiation were assessed with 95% confidence intervals (CIs) and compared with Fisher's exact test. Log-rank tests for univariate analysis (gender, age, ethnicity and deprivation) effects on serum creatinine testing at dabigatran etexilate treatment initiation and 12-months post initiation were performed. RESULTS Overall, 1,948 patients who had been dispensed dabigatran etexilate with available primary care health data were identified. A total of 1,752 (89.9% [CI: 88.5-91.2]) patients had a renal function test at dabigatran etexilate initiation. There were 929 (72.8% [CI: 70.2-75.2]) patients who received ≥1 year supply of dabigatran etexilate and of these 207 (22.3% [CI: 19.6.6-25.1]) had a serum creatinine test 1 year after initiation. Demographic univariate analysis yielded insignificant log-rank tests for association with having serum creatinine measurements, except for Pacific Peoples. DISCUSSION There appears to be sub-optimal adherence to renal function monitoring for non-valvular atrial fibrillation patients who receive more than 12-months' treatment with dabigatran etexilate in New Zealand primary care.

An assessment of sensitivity biomarkers for urinary cadmium burden.

BACKGROUND: Excess cadmium (Cd) intake poses a general risk to health and to the kidneys in particular. Among indices of renal dysfunction under Cd burden measures are the urinary N-acetyl-ß-D-glucosidase (UNAG) and urinary ß2-microglobulin (Uß2-MG) enzymes. However, the end-pointed values and the Cd burden threshold remain controversial because the scopes fluctuate widely. METHODS: To ascertain the clinical benchmark dose of urinary Cd (UCd) burden for renal dysfunction, 1595 residents near a Cd site were surveyed. Urine was sampled and assayed. A benchmark dose low (BMDL) was obtained by fitting UCd levels and index levels. RESULTS: We found that over 50% of the subjects were suffering from Cd exposure as their UCd levels far exceeded the national standard threshold of 5.000 µg/g creatinine (cr). Further analysis indicated that Uß2-MG was more sensitive than UNAG for renal dysfunction. The BMDL for UCd was estimated as 3.486 U/g cr (male, where U is unit of enzyme) and 2.998 U/g cr (female) for UNAG. The BMDL for Uß2-MG, which is released into urine from glomerulus after Cd exposure, was found to be 2.506 µg/g cr (male, where µg is the unit of microglobulin) and 2.236 µg/g cr (female). CONCLUSIONS: Uß2-MG is recommended as the sensitivity index for renal dysfunction, with 2.2 µg/g cr as the threshold for clinical diagnosis. Our findings suggest that Uß2-MG is the better biomarker for exposure to Cd.

Therapeutic Drug Monitoring Coupled With Bayesian Forecasting Could Prevent Vancomycin-Associated Nephrotoxicity in Renal Insufficiency Patients: A Prospective Study and Pharmacoeconomic Analysis.

BACKGROUND: Vancomycin is a critical antibiotic used in important infections, and therapeutic drug monitoring (TDM) is recommended. Bayesian forecasting is demonstrated to provide an approach that can improve trough concentration monitoring for dose adjustment. The objective of this study was to determine whether TDM coupled with a Bayesian approach could increase trough concentration target attainment and prevent vancomycin-associated nephrotoxicity in patients with renal insufficiency. METHODS: A prospective study was performed using propensity score matching to provide covariate balance in renal insufficiency patients with gram-positive bacterial infections treated with vancomycin. Patients were divided into non-TDM (84 cases) and TDM (84 cases) groups, and their clinical outcomes were compared. The primary endpoints were probability of trough concentration target attainment and incidence of vancomycin-associated nephrotoxicity. A decision-tree model was developed to assess the cost effectiveness of TDM to prevent vancomycin-associated nephrotoxicity. RESULTS: Of the 168 eligible patients, 69 from each group (non-TDM and TDM) were matched based on propensity scores. In the matched cohort, trough concentration target attainment was higher with TDM (P = 0.003). Furthermore, reaching toxic trough concentrations was avoided (P = 0.027) in the TDM group. Multivariate logistic regression analysis confirmed that TDM practice independently reduced the incidence of vancomycin-associated nephrotoxicity in renal insufficiency patients (P = 0.021). According to this reduced nephrotoxicity, the incremental cost-effectiveness ratios of ¥22,638 per nephrotoxic episode prevented was found for vancomycin TDM. CONCLUSIONS: TDM coupled with Bayesian forecasting led to an increase in trough concentration target attainment and a decrease in the incidence of vancomycin-associated nephrotoxicity in renal insufficiency patients. In this high-risk population, TDM was demonstrated to be a cost-effective procedure.

Use of pre-ART laboratory screening to identify renal, hepatic and haematological abnormalities in Côte d'Ivoire.

BACKGROUND: High demand for HIV-services and extensive clinical guidelines force health systems in low-resource settings to dedicate resources to service delivery at the expense of other priorities. Simplifying services may reduce the burden on health systems and pre-antiretroviral therapy (ART) laboratory screening is among the services under consideration for simplification. METHODS: We assessed the frequencies of conditions linked to ART toxicities among 34,994 adult, ART-naïve patients with specimens referred to the RETRO-CI laboratory in Abidjan, Côte d'Ivoire between 1998 and 2017. Screening included tests for serum creatinine, alanine aminotransferase (ALT) and haemoglobin (Hb) to identify renal dysfunction (estimated glomerular filtration rate < 50 mL/min), hepatic abnormalities (ALT > 5× upper limit of normal) and severe anaemia (Hb < 6.5 g/dL), respectively. We considered screening results across four eras and identified factors associated with the conditions in question. RESULTS: The prevalence of renal dysfunction, hepatic abnormalities and severe anaemia were largely unchanged over time and just 8.4% of patients had any of the three conditions. Key factors associated with renal dysfunction and severe anaemia were age > 50 years (adjusted odds ratio (aOR): 2.53; 95% confidence interval (CI): 2.19-2.92; P < 0.001) and CD4 < 100 cells/µl (aOR: 2.57; 95% CI: 2.30-2.88; P < 0.001). CONCLUSION: The relative infrequency of conditions linked to toxicity in Côte d'Ivoire supports the notion that simplification of pre-ART laboratory screening may be undertaken with limited negative impact on identification of adverse events. Targeted screening may be a feasible strategy to balance detection of conditions associated with ART toxicities with simplification of services.

CONTEXTE: La forte demande de services VIH et les directives cliniques détaillées obligent les systèmes de santé des pays à faibles ressources à consacrer des ressources à la prestation de services au détriment d'autres priorités. La simplification des services peut réduire la charge pesant sur les systèmes de santé et les analyses de laboratoire avant la thérapie antirétrovirale (ART) fait partie des services envisagés pour la simplification. MÉTHODES: Nous avons évalué la fréquence des conditions liées aux toxicités dues à l'ART chez 34.994 patients adultes naïfs pour l'ART avec des échantillons référés au laboratoire RETRO-CI à Abidjan, en Côte d'Ivoire entre 1998 et 2017. Les analyses comprenaient les tests de créatinine sérique, d'alanine aminotransférase (ALT) et d'hémoglobine (Hb) pour identifier respectivement la dysfonction rénale (débit de filtration glomérulaire estimé <50 mL/min), les anomalies hépatiques (ALT >5x la limite supérieure normale) et l'anémie sévère (Hb <6,5 g/dL). Nous avons examiné les résultats des analyses sur quatre époques et identifié les conditions associées aux conditions en question. RÉSULTATS: La prévalence de la dysfonction rénale, des anomalies hépatiques et de l'anémie sévère est restée largement inchangée au fil du temps et seulement 8,4% des patients présentaient l'une des trois conditions. Les facteurs clés associés à la dysfonction rénale et à l'anémie sévère étaient l'âge >50 ans (odds ratio ajusté (aOR): 2,53; intervalle de confiance (IC) à 95%: 2,19 à 2,92; p <0,001) et les CD4 <100 cellules/µl (aOR: 2,57; IC95%: 2,30 à 2,88; P < 0,001). CONCLUSION: La relativement faible fréquence des conditions liées à la toxicité en Côte d'Ivoire soutient la notion selon laquelle une simplification des analyses de laboratoire pré-ART peut être entreprise avec un impact négatif limité sur l'identification des événements adverses. Le ciblage des analyses peut être une stratégie réalisable pour aligner la détection des conditions associées aux toxicités ART à la simplification des services.

Evaluation of the geographical utility of Eastern Russell's viper (Daboia siamensis) antivenom from Thailand and an assessment of its protective effects against venom-induced nephrotoxicity.

BACKGROUND: Daboia siamensis (Eastern Russell's viper) is a medically important snake species found widely distributed across Southeast Asia. Envenomings by this species can result in systemic coagulopathy, local tissue injury and/or renal failure. While administration of specific antivenom is an effective treatment for Russell's viper envenomings, the availability of, and access to, geographically-appropriate antivenom remains problematic in many rural areas. In this study, we determined the binding and neutralizing capability of antivenoms manufactured by the Thai Red Cross in Thailand against D. siamensis venoms from four geographical locales: Myanmar, Taiwan, China and Thailand. METHODOLOGY/PRINCIPLE FINDINGS: The D. siamensis monovalent antivenom displayed extensive recognition and binding to proteins found in D. siamensis venom, irrespective of the geographical origin of those venoms. Similar immunological characteristics were observed with the Hemato Polyvalent antivenom, which also uses D. siamensis venom as an immunogen, but binding levels were dramatically reduced when using comparator monovalent antivenoms manufactured against different snake species. A similar pattern was observed when investigating neutralization of coagulopathy, with the procoagulant action of all four geographical venom variants neutralized by both the D. siamensis monovalent and the Hemato Polyvalent antivenoms, while the comparator monovalent antivenoms were ineffective. These in vitro findings translated into therapeutic efficacy in vivo, as the D. siamensis monovalent antivenom was found to effectively protect against the lethal effects of all four geographical venom variants preclinically. Assessments of in vivo nephrotoxicity revealed that D. siamensis venom (700 µg/kg) significantly increased plasma creatinine and blood urea nitrogen levels in anaesthetised rats. The intravenous administration of D. siamensis monovalent antivenom at three times higher than the recommended scaled therapeutic dose, prior to and 1 h after the injection of venom, resulted in reduced levels of markers of nephrotoxicity and prevented renal morphological changes, although lower doses had no therapeutic effect. CONCLUSIONS/SIGNIFICANCE: This study highlights the potential broad geographical utility of the Thai D. siamensis monovalent antivenom for treating envenomings by the Eastern Russell's viper. However, only the early delivery of high antivenom doses appears to be capable of preventing venom-induced nephrotoxicity.

Reappraisal of Linezolid Dosing in Renal Impairment To Improve Safety.

Linezolid is administered as a fixed dose to all patients despite evidence of increased exposure and myelosuppression in renal impairment. The objectives of these studies were to assess the risk of thrombocytopenia with standard-dose linezolid in renal impairment and to identify an alternate dosing strategy. In study 1, data from adult patients receiving linezolid for ≥10 days were retrospectively reviewed to determine the frequency of thrombocytopenia in patients with and without renal impairment. Time-to-event analyses were performed using Cox proportional-hazards models. In study 2, population pharmacokinetic modeling was employed to build covariate-structured models using an independent data set of linezolid concentrations obtained during routine therapeutic drug monitoring (TDM). Monte Carlo simulations were performed to identify linezolid dosing regimens that maximized attainment of therapeutic trough concentrations (2 to 8 mg/liter) across various renal-function groups. Toxicity analysis (study 1) included 341 patients, 133 (39.0%) with renal impairment. Thrombocytopenia occurred more frequently among patients with renal impairment (42.9% versus 16.8%; P < 0.001), and renal impairment was independently associated with this toxicity in multivariable analysis (adjusted hazard ratio [aHR], 2.37; 95% confidence interval [CI], 1.52 to 3.68). Pharmacokinetic analyses (study 2) included 1,309 linezolid concentrations from 603 adult patients. Age, body surface area, and estimated glomerular filtration rate (eGFR) were identified as covariates of linezolid clearance. Linezolid dose reductions improved the probability of achieving optimal exposures in simulated patients with eGFR values of <60 ml/min. Thrombocytopenia occurs more frequently in patients with renal impairment receiving standard linezolid doses. Linezolid dose reduction and trough-based TDM are predicted to mitigate this treatment-limiting toxicity.

Assessment of renal function in routine care of people living with HIV on ART in a resource-limited setting in urban Zambia.

INTRODUCTION: Data on renal impairment in sub-Saharan Africa (SSA) remains scarce, determination of renal function is not part of routine assessments. We evaluated renal function and blood pressure in a cohort of people living with HIV (PLWH) on antiretroviral treatment (ART) in the Renal Care Zambia project (ReCaZa). METHODS: Using routine data from an HIV outpatient clinic from 2011-2013, we retrospectively estimated the glomerular filtration rate (eGFR, CKD-Epi formula) of PLWH on ART in Lusaka, Zambia. Data were included if adults had had at least one serum creatinine recorded and had been on ART for a minimum of three months. We investigated the differences in eGFR between ART subgroups with and without tenofovir disproxil fumarate (TDF), and applied multivariable linear models to associate ART and eGFR, adjusted for eGFR before ART initiation. RESULTS AND DISCUSSION: Among 1118 PLWH (63,3% female, mean age 41.8 years, 83% ever on TDF; median duration 1461 [range 98 to 4342] days) on ART, 28.3% had an eGFR <90 ml/min, and 5.5% <60 ml/min at their last measurement. Information on other conditions associated with renal impairment was not systematically documented. Fourteen per cent of the PLWH who later switched to TDF-free ART had an initial eGFR lower 60ml/min. Nineteen percent had first-time hypertensive readings at their last visit. The multivariable models suggest that physicians acted according to guidelines and replaced TDF-containing ART if patients developed moderate/severe renal impairment. CONCLUSIONS: Assessment of renal function in SSA remains a challenge. The vast majority of PLWH benefit from long-term ART, including improved renal function. However, approximately 5% of PLWH on ART may have clinically relevant decreased eGFR, and 27% hypertension. While a routine renal assessment might not be feasible, strategies to identify patients at risk are warranted. Targeted monitoring prior and during ART is recommended, however, should not delay ART access.

Economic evaluation among Chinese patients with nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus and treated with linezolid or vancomycin: a secondary, post-hoc analysis based on a Phase 4 clinical trial study.

OBJECTIVE: To assess cost-effectiveness of linezolid vs vancomycin in treating nosocomial pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA-NP) in China and the impact of renal failure on healthcare resource utilization (HCRU) and costs. METHODS: Cost-effectiveness analysis was conducted based on data from the ZEPHyR trial, with efficacy measured by treatment success and costs calculated from HCRU. Confidence intervals (CI) for cost, efficacy and incremental cost-effectiveness ratios (ICER) were calculated by non-parametric bootstrap. Chi-square test was used for renal failure rate and t-test for HCRU/cost comparisons. Impact of renal failure was assessed using regression model. RESULTS: Data from 448 patients (1:1 linezolid:vancomycin) were analyzed. More patients treated with linezolid achieved success (55% [95% CI = 48-62%]) than with vancomycin (45% [38-52%]). Treatment cost were ¥79,551 (95% CI = ¥72,421-¥86,680) for linezolid vs ¥77,587 (¥70,656-¥84,519) for vancomycin in Beijing, ¥90,995 (¥82,598-¥99,393) vs ¥89,448 (¥81,295-¥97,601) in Guangzhou, ¥82,383 (¥74,956-¥89,810) vs ¥80,799 (¥73,545-¥88,054) in Nanjing and ¥59,413 (¥54,366-¥64,460) vs ¥57,804 (¥52,613-¥62,996) in Xi'an. Per successful treatment, the ICER of linezolid over vancomycin were ¥19,719 (-¥143,553 to ¥320,980) (Beijing), ¥15,532 (-¥185,411 to ¥349,693) (Guangzhou), ¥15,904 (-¥161,935 to ¥314,987) (Nanjing) and ¥16,145 (-¥100,738 to ¥234,412) (Xi'an). From simulations, the majority of linezolid cases had greater efficacy and higher costs and more than one third had greater efficacy and lower costs. More vancomycin patients developed renal failure (15% vs 4%, p < 0.001). Patients with renal failure had higher cost (Nanjng: ¥100,449 (SD = ¥65,080) vs ¥74,944 (SD = ¥49,632), p = 0.002). CONCLUSION: Linezolid was more cost-effective than vancomycin in treating MRSA-NP from a Chinese payer's perspective, and associated with less renal failure, HCRU and cost.

panobinostat (FARYDAK°). Multiple myeloma: too toxic!

Patients with relapsed or refractory multiple myeloma who have received several lines of therapy have no satisfactory treatment options. High-dose corticosteroid therapy or a combination of low-dose dexamethasone and pomaildomide may be proposed. Panobinostat is the first histone deacetylase (HDAC) inhibitor to be authorised in the European Union for use in this indication. A randomised, double-blind, placebo-controlled trial evaluated panobinostat in 768 patients with relapsed or refractory multiple myeloma who were also receiving bortezomib + dexamethasone. Panobinostat did not prolong survival. The median time to myeloma progression, relapse, or death was prolonged by about 3 months with the panobinostat-containing combination, and by a median of about 8 months in the subgroup of patients who had received at least two lines of chemotherapy including bortezomib and an "immunomodulatory" drug. There was no statistically significant increase in survival, however. In this trial, adverse events led one in six patients to discontinue panobinostat and resulted in numerous hospital admissions. The proportion of patients who died from causes unrelated to myeloma was 6.8% in the panobinostat group versus 3.2% In the placebo group. The toxicity of panobinostat affects most vital functions, resulting in a risk of infections as well as haematological, gastrointestinal, cardiac, renal, hepatic and thyroid disorders. These adverse effects are often severe and sometimes fatal. Panobinostat is subject to pharmacokinetic interactions via cytochrome P450 enzymes and P-glycoproteln, and also to pharmacodynamic Interactions. Panobinostat was teratogenic in animal studies. In practice, even when several previous lines of treatment have failed, panobinostatis more toxic than useful In patients with myeloma. It should therefore not be used.

Vitamin E supplementation ameliorates aflatoxin B1-induced nephrotoxicity in rats.

Fungal toxins in nutrition can cause organ dysfunction or even failure. Aflatoxin B1 (AFB1)-induced renal impairment is not sufficiently studied regarding its extent and prevention. The aim of this experiment was to study the effect of AFB1 on renal cortical tissue and whether its possible harmful effect could be prevented by the conventional economical antioxidant, vitamin E. Forty rats were divided into four groups; I-IV. Group I represented the control while the others received vitamin E (Vit E), AFB1 and AFB1+Vit E, respectively. Renal cortex specimens were taken from each group after 25 days. Then, specimens were prepared for histological study by hematoxlyin and eosin (H&E), Masson's trichrome, caspase-3 as well as for ultrastructural examination and oxidative stress parameters evaluation. Data were morphometrically and statistically analyzed. In AFB1-treated group, focal tubulo-interstitial affection in the form of tubular cytoplasmic vacuolation, mitochondrial disruption, numerous lysosomes, marked increase in collagen deposition and in caspase-3 expression were observed. Glomerular impairment in the form of fusion of podocytes enlarged foot processes and thickening of the glomerular basement membrane (GBM) with loss of its trilaminar appearance were detected. In the group treated by AFB1+Vit E, there were minimal affection of the histological structure of the renal cortex as well as significant increase in the anti-oxidative parameters which were significantly decreased in the AFB1-treated group. Therefore, Vit E could be considered in wide experimental studies to be a first choice antioxidant of high cost-effectiveness in prevention of fungal toxins pro-oxidant-induced renal impairment.

The incidence of contrast medium-induced nephropathy following endovascular aortic aneurysm repair: assessment of risk factors.

PURPOSE: The aim of the study was to investigate the incidence of contrast medium-induced nephropathy (CIN) and risk factors for CIN following endovascular abdominal aortic aneurysm repair or thoracic endovascular aortic aneurysm repair. MATERIALS AND METHODS: After exclusion criteria, 139 (121 males, 18 females) patients aged 20-86 (median 65.5) years who underwent endovascular aortic aneurysm repair between January 2002 and September 2013 were included in this retrospective study. CIN, with ≥25% increase in serum creatinine levels within 3 days after contrast medium administration, was compared to the patients' demographics, risk factors, type and complexity of the endovascular operation, parameters regarding to the contrast medium, preoperative estimated glomerular filtration rate (eGFR), and preoperative and early postoperative serum parameters. Statistical analyses were performed with Kolmogorov-Smirnov, χ (2) and Student's t tests. RESULTS: CIN, detected in 39 of 139 patients (28%), was correlated with preoperative eGFR <60 ml/min/1.73 m(2) (P = 0.04) and high preoperative and postoperative serum urea and creatinine levels. Postoperative serum urea levels (P < 0.001) were significant in multivariate analysis. CONCLUSION: In patients undergoing endovascular aortic aneurysm repair, CIN was correlated with preoperative and postoperative renal impairment, while it was not correlated with the contrast medium dose.

Role of toxicogenomics in the development of safe, efficacious and novel anti-microbial therapies.

Over the last two decades, occurrence of bacterial resistance to commonly used antibiotics has necessitated the development of safer and more potent anti-microbial drugs. However, the development of novel antibiotics is severely hampered by adverse side effects, such as drug-induced liver toxicity. Several antibacterial drugs are known to have the potential to cause severe liver damage. The major challenge in developing novel anti-microbial drugs is to predict, with certain amount of probability, the drug-induced toxicity during the pre-clinical stages, thus optimizing and reducing the time and cost of drug development. Toxicogenomics approach is generally used to harness the potential of genomic tools and to understand the physiological basis of drug-induced toxicity based on the in-depth analysis of Metagenomic data sets, i.e., transcriptional, translational or metabolomic profiles. Toxicogenomics, therefore, represents a new paradigm in the drug development process, and is anticipated to play an invaluable role in future to develop safe and efficacious medicines, by predicting the toxic potential of a new chemical entity (NCE) in early stages of drug discovery. This review examines the toxicogenomic approach in predicting the safety/toxicity of novel anti-microbial drugs, and analyses the promises, pitfalls and challenges of applying this powerful technology to the drug development process.

Statins of high versus low cholesterol-lowering efficacy and the development of severe renal failure.

BACKGROUND: The objective of this nationwide retrospective cohort study was to examine the renal outcomes of HMG-CoA reductase inhibitor (statin) initiators. METHODS: The patients who started to take statins with high cholesterol-lowering efficacy (atorvastatin and rosuvastatin) and low efficacy (lovastatin, simvastatin, pravastatin, and fluvastatin) between 1 January 2001 and 31 December 2008 were identified from the Taiwan National Health Insurance claims database. The outcome of interest was severe renal failure, defined as the composite endpoint of hemodialysis, peritoneal dialysis, and kidney transplantation. A proportional hazard regression model was applied to estimate the incidence ratio between the two groups, adjusted for the propensity scores based upon baseline characteristics. RESULTS: Among of the 26,007 and 42,249 statin initiators, the crude incidence rate for developing severe renal failure was 0.65 and 0.46 per 100 person-years for the high-efficacy and low-efficacy groups, respectively. Despite that these two groups had comparable risk for myocardial infarction (hazard ratio: 1.06, 95%CI: 0.92­1.21), there was a 13% increased hazard for developing severe renal failure in the rosuvastatin and atorvastatin initiators (hazard ratio: 1.13, 95%CI: 1.02­1.26). The increased risk associated with these two statins was consistent across different risk groups (diabetes, chronic kidney disease, and ischemic heart disease). CONCLUSIONS: Statins with high cholesterol-lowering efficacy might increase the risk for developing severe renal failure. An alternative explanation is that the renal risk cannot be ameliorated as much as cardiovascular risk. Further follow-up studies or meta-analyses are needed to solve the controversy.

Assessment of the association between colchicine therapy and serious adverse events.

STUDY OBJECTIVE: As data that prompted a 2009 labeling change detailing contraindications, precautions, and dosing recommendations for the first branded colchicine product were limited to case reports of myotoxicity and blood dyscrasias ascribed to the drug, we sought to quantify the association of colchicine therapy with serious adverse outcomes in a cohort of insured patients. DESIGN: Case-control study. DATA SOURCE: Kaiser Permanente Colorado electronic data warehouses and electronic medical records. PATIENTS: Cases were patients with a creatine kinase (CK) level of at least 2000 U/L or who developed a clinically significant non-cancer-related blood dyscrasia (thrombocytopenia, neutropenia, leukopenia, aplastic anemia, or pancytopenia) between January 1, 2006, and June 30, 2009 (954 cases). Each case was matched to up to 10 controls by age, sex, and index date (date of the increased CK level or blood dyscrasia-supporting laboratory value). Controls were patients without elevated CK levels or blood dyscrasias who had a routine health maintenance examination during the same time period (index date was the date of their health maintenance examination [9007 controls]). MEASUREMENTS AND MAIN RESULTS: The primary study outcome was colchicine exposure, defined as a colchicine prescription purchase in the 100 days before the index date. The likelihood of colchicine exposure was examined with conditional logistic regression. Cases experienced a higher rate of previous colchicine exposure compared with controls (0.6% vs 0.2%, odds ratio 3.9, 95% confidence interval 1.4-10.7). In addition, cases had higher hospitalization rates (14.9% vs 5.0%, p<0.001), higher mean chronic disease scores (2.5 vs 0.0, p<0.001), and were more likely to have been exposed to drugs that may increase the risk of adverse events due to an interaction with a CYP3A4 inhibitor drug (6.9% vs 2.3%, p<0.001). CONCLUSION: Patients with confirmed elevations in CK level and/or blood dyscrasias had a higher rate of previous colchicine exposure, although low overall, and greater hospitalization rates and exposure to drugs that may increase the risk of adverse events compared with controls. These findings support the 2009 United States Food and Drug Administration labeling for the first branded colchicine product, cautioning use in patients with liver impairment or renal dysfunction and/or those receiving concurrent drugs that may increase risk of adverse events.

Dose-response assessment of nephrotoxicity from a twenty-eight-day combined-exposure to melamine and cyanuric acid in F344 rats.

The adulteration of pet food with melamine and derivatives, including cyanuric acid, has been implicated in the kidney failure and death of cats and dogs in the USA and other countries. In a previous 7-day dietary study in F344 rats, we established a no-observed-adverse-effect level (NOAEL) for a co-exposure to melamine and cyanuric acid of 8.6 mg/kg bw/day of each compound, and a benchmark dose lower confidence limit (BMDL) of 8.4-10.9 mg/kg bw/day of each compound. To ascertain the role played by the duration of exposure, we treated F344 rats for 28 days. Groups of male and female rats were fed diet containing 0 (control), 30, 60, 120, 180, 240, or 360 ppm of both melamine and cyanuric acid. The lowest dose that produced histopathological alterations in the kidney was 120 ppm, versus 229 ppm in the 7-day study. Wet-mount analysis of kidney sections demonstrated the formation of melamine cyanurate spherulites in one male and two female rats at the 60 ppm dose and in one female rat at the 30 ppm dose, establishing a NOAEL of 2.1mg/kg bw/day for males and <2.6 mg/kg bw/day for females, and BMDL values as low as 1.6 mg/kg bw/day for both sexes. These data demonstrate that the length of exposure is an important component in the threshold of toxicity from a co-exposure to these compounds and suggest that the current risk assessments based on exposures to melamine alone may not reflect sufficiently the risk of a co-exposure to melamine and cyanuric acid.

Laboratory monitoring of patients treated with antihypertensive drugs and newly exposed to non steroidal anti-inflammatory drugs: a cohort study.

BACKGROUND: Drug-Drug Interactions between Non Steroidal Anti-Inflammatory Drugs (NSAIDs) and Angiotensin Converting Enzyme Inhibitors (ACEIs), Angiotensin Receptor Blocker (ARBs) or diuretics can lead to renal failure and hyperkalemia. Thus, monitoring of serum creatinine and potassium is recommended when a first dispensing of NSAID occur in patients treated with these drugs. METHODS: We conducted a pharmacoepidemiological retrospective cohort study using data from the French Health Insurance Reimbursement Database to evaluate the proportion of serum creatinine and potassium laboratory monitoring in patients treated with ACEI, ARB or diuretic and receiving a first dispensing of NSAID. We described the first dispensing of NSAID among 3,500 patients of a 4-year cohort (6,633 patients treated with antihypertensive drugs) and analyzed serum creatinine and potassium laboratory monitoring within the 3 weeks after the first NSAID dispensing. RESULTS: General Practitioners were the most frequent prescribers of NSAIDs (85.5%, 95% CI: 84.3-86.6). The more commonly prescribed NSAIDs were ibuprofen (20%), ketoprofen (15%), diclofenac (15%) and piroxicam (12%). Serum creatinine and potassium monitoring was 10.7% (95% CI: 9.5-11.8) in patients treated by ACEIs, ARBs or diuretics. Overall, monitoring was more frequently performed to women aged over 60, treated with digoxin or glucose lowering drugs, but not to patients treated with ACEIs, ARBs or diuretics. Monitoring was more frequent when NSAIDs' prescribers were cardiologists or anesthesiologists. CONCLUSION: Monitoring of serum creatinine and potassium of patients treated with ACEIs, ARBs or diuretics and receiving a first NSAID dispensing is insufficiently performed and needs to be reinforced through specific interventions.