Role of Oxidative Stress in Drug-Induced Kidney Injury.

Int J Mol Sci. 2016 Nov 01;17(11):

Authors: Hosohata K

Abstract
The kidney plays a primary role in maintaining homeostasis and detoxification of numerous hydrophilic xenobiotics as well as endogenous compounds. Because the kidney is exposed to a larger proportion and higher concentration of drugs and toxins than other organs through the secretion of ionic drugs by tubular organic ion transporters across the luminal membranes of renal tubular epithelial cells, and through the reabsorption of filtered toxins into the lumen of the tubule, these cells are at greater risk for injury. In fact, drug-induced kidney injury is a serious problem in clinical practice and accounts for roughly 20% of cases of acute kidney injury (AKI) among hospitalized patients. Therefore, its early detection is becoming more important. Usually, drug-induced AKI consists of two patterns of renal injury: acute tubular necrosis (ATN) and acute interstitial nephritis (AIN). Whereas AIN develops from medications that incite an allergic reaction, ATN develops from direct toxicity on tubular epithelial cells. Among several cellular mechanisms underlying ATN, oxidative stress plays an important role in progression to ATN by activation of inflammatory response via proinflammatory cytokine release and inflammatory cell accumulation in tissues. This review provides an overview of drugs associated with AKI, the role of oxidative stress in drug-induced AKI, and a biomarker for drug-induced AKI focusing on oxidative stress.

PMID: 27809280 [PubMed - indexed for MEDLINE]

Interpretation of the evidence for the efficacy and safety of statin therapy.

Lancet. 2016 11 19;388(10059):2532-2561

Authors: Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, Blumenthal R, Danesh J, Smith GD, DeMets D, Evans S, Law M, MacMahon S, Martin S, Neal B, Poulter N, Preiss D, Ridker P, Roberts I, Rodgers A, Sandercock P, Schulz K, Sever P, Simes J, Smeeth L, Wald N, Yusuf S, Peto R

Abstract
This Review is intended to help clinicians, patients, and the public make informed decisions about statin therapy for the prevention of heart attacks and strokes. It explains how the evidence that is available from randomised controlled trials yields reliable information about both the efficacy and safety of statin therapy. In addition, it discusses how claims that statins commonly cause adverse effects reflect a failure to recognise the limitations of other sources of evidence about the effects of treatment. Large-scale evidence from randomised trials shows that statin therapy reduces the risk of major vascular events (ie, coronary deaths or myocardial infarctions, strokes, and coronary revascularisation procedures) by about one-quarter for each mmol/L reduction in LDL cholesterol during each year (after the first) that it continues to be taken. The absolute benefits of statin therapy depend on an individual's absolute risk of occlusive vascular events and the absolute reduction in LDL cholesterol that is achieved. For example, lowering LDL cholesterol by 2 mmol/L (77 mg/dL) with an effective low-cost statin regimen (eg, atorvastatin 40 mg daily, costing about £2 per month) for 5 years in 10 000 patients would typically prevent major vascular events from occurring in about 1000 patients (ie, 10% absolute benefit) with pre-existing occlusive vascular disease (secondary prevention) and in 500 patients (ie, 5% absolute benefit) who are at increased risk but have not yet had a vascular event (primary prevention). Statin therapy has been shown to reduce vascular disease risk during each year it continues to be taken, so larger absolute benefits would accrue with more prolonged therapy, and these benefits persist long term. The only serious adverse events that have been shown to be caused by long-term statin therapy-ie, adverse effects of the statin-are myopathy (defined as muscle pain or weakness combined with large increases in blood concentrations of creatine kinase), new-onset diabetes mellitus, and, probably, haemorrhagic stroke. Typically, treatment of 10 000 patients for 5 years with an effective regimen (eg, atorvastatin 40 mg daily) would cause about 5 cases of myopathy (one of which might progress, if the statin therapy is not stopped, to the more severe condition of rhabdomyolysis), 50-100 new cases of diabetes, and 5-10 haemorrhagic strokes. However, any adverse impact of these side-effects on major vascular events has already been taken into account in the estimates of the absolute benefits. Statin therapy may cause symptomatic adverse events (eg, muscle pain or weakness) in up to about 50-100 patients (ie, 0·5-1·0% absolute harm) per 10 000 treated for 5 years. However, placebo-controlled randomised trials have shown definitively that almost all of the symptomatic adverse events that are attributed to statin therapy in routine practice are not actually caused by it (ie, they represent misattribution). The large-scale evidence available from randomised trials also indicates that it is unlikely that large absolute excesses in other serious adverse events still await discovery. Consequently, any further findings that emerge about the effects of statin therapy would not be expected to alter materially the balance of benefits and harms. It is, therefore, of concern that exaggerated claims about side-effect rates with statin therapy may be responsible for its under-use among individuals at increased risk of cardiovascular events. For, whereas the rare cases of myopathy and any muscle-related symptoms that are attributed to statin therapy generally resolve rapidly when treatment is stopped, the heart attacks or strokes that may occur if statin therapy is stopped unnecessarily can be devastating.

PMID: 27616593 [PubMed - indexed for MEDLINE]

A systematic review of the prevalence and incidence of prescribing errors with high-risk medicines in hospitals.

J Clin Pharm Ther. 2016 Jun;41(3):239-45

Authors: Alanazi MA, Tully MP, Lewis PJ

Abstract
WHAT IS KNOWN: Prescribing errors are the most common type of error in the medication use process. However, there is a paucity of literature regarding the prevalence or incidence of prescribing errors in high-risk medicines (HRMs). HRMs bear a heightened risk of causing significant patient harm when they are used in error.
OBJECTIVE: The aim of this research was to systematically investigate the literature regarding the prevalence and incidence of prescribing errors in HRMs in inpatient settings.
METHODS: A search strategy was developed based on four categories of keywords: prescribing errors, HRMs, hospital inpatients, and prevalence or incidence. All keywords were searched for in Medline, Embase, Cochrane and the International Pharmaceutical Abstracts. The search was limited to English quantitative studies that reported the incidence or prevalence of prescribing errors by medical prescribers, whether they were seniors or juniors, since 1985.
RESULTS: Of the 3507 records identified, nine studies met the review criteria. The most frequent denominator in the included studies was medication orders, in eight studies, ranged from 0·24 to 89·6 errors per 100 orders of HRMs. Two studies reported 107 and 218 errors per 100 admissions prescribed HRMs, and one study reported 27·2 errors per 100 prescriptions with a HRM. The incidence of prescribing errors could not be calculated.
WHAT IS NEW AND CONCLUSION: The prevalence of prescribing errors in HRMs in the inpatient setting has a very wide range that reflects the different data collection methods used within the included studies. Future studies in prescribing errors should use standardized approaches to enable comparison.

PMID: 27167088 [PubMed - indexed for MEDLINE]

Bundle interventions used to reduce prescribing and administration errors in hospitalized children: a systematic review.

J Clin Pharm Ther. 2016 Jun;41(3):246-55

Authors: Bannan DF, Tully MP

Abstract
WHAT IS KNOWN AND OBJECTIVE: Bundle interventions are becoming increasingly used as patient safety interventions. The objective of this study was to describe and categorize which bundle interventions are used to reduce prescribing errors (PEs) and administration errors (AEs) in hospitalized children and to assess the quality of the published literature.
METHODS: Articles published in English and Arabic between 1985 and September 2015 were sought in MEDLINE, EMBASE and CINHAL. Bibliographies of included articles were screened for additional studies. We included any study with a comparator group reporting rates of PEs and AEs. Two authors independently extracted data, classified interventions in each bundle and assessed the studies for potential risk of bias. Constituent interventions of the bundles were categorized using both the Cochrane Effective Practice and Organization of Care Group (EPOC) taxonomy of intervention and the Behavioural Change Wheel (BCW).
RESULTS AND DISCUSSION: Seventeen studies met the inclusion criteria. All bundles contained interventions that were either professional, organizational or a mixture of both. According to the BCW, studies used interventions with functions delivering environmental restructuring (17/17), education (16/17), persuasion (4/17), training (3/17), restriction (3/17), incentivization (1/17), coercion (1/17), modelling (1/17) and enablement (1/17). Nine studies had bundles with two intervention functions, and eight studies had three or more intervention functions. All studies were low quality before/after studies. Selection bias varied between studies. Performance bias was either low or unclear. Attrition bias was unclear, and detection bias was rated high in most studies. Ten studies described the interventions fairly well, and seven studies did not adequately explain the interventions used.
WHAT IS NEW AND CONCLUSION: This novel analysis in a systematic review showed that bundle interventions delivering two or more intervention functions have been investigated but that the study quality was too poor to assess impact.

PMID: 27145467 [PubMed - indexed for MEDLINE]

Ameliorative effect of berberine against gentamicin-induced nephrotoxicity in rats via attenuation of oxidative stress, inflammation, apoptosis and mitochondrial dysfunction.

Ren Fail. 2016 Jul;38(6):996-1006

Authors: Adil M, Kandhare AD, Dalvi G, Ghosh P, Venkata S, Raygude KS, Bodhankar SL

Abstract
BACKGROUND: Gentamicin (GM) is the commonly used antibiotics against Gram-negative infection, but the nephrotoxic potential of drug limit its clinical interest. The aim of this study was to investigate the protective effect of berberine (BER) against GM-induced nephrotoxicity and possible underlying mechanisms.
MATERIAL AND METHODS: The rats were divided into various group, namely normal, GM-control, GM + BER (10, 20, and 40 mg/kg). Nephrotoxicity was induced by intraperitoneal administration of GM (120 mg/kg) for 7 consecutive days. BER (10, 20, and 40 mg/kg; p.o.) was also administered for the 7 days. Various biochemical, molecular, and histological parameters were assessed in serum and kidney.
RESULTS: GM-administration significantly increased (p < 0.001) the serum creatinine and blood urea nitrogen (BUN) as well as renal malonaldehyde (MDA), nitric oxide (NO) along with Kidney Injury Molecule-1 (KIM-1), Neutrophil gelatinase-associated lipocalin (NGAL), and nuclear factor-kappa B (NF-KB) renal mRNA expressions. In addition, GM also significantly decreased (p < 0.001) the renal superoxide dismutase (SOD), reduced glutathione (GSH), B-cell lymphoma 2 (Bcl-2) mRNA expression, and mitochondrial enzymes (NADH dehydrogenase and cytochrome c oxidase) activities. Rats treated with BER (20 and 40 mg/kg; p.o.) significantly and dose-dependently (p < 0.05 and p < 0.01) restore the altered levels of antioxidant, inflammatory, apoptosis, AKI markers as well as depleted mitochondrial enzymes. Histopathological abbreviations were also ameliorated by BER administration.
CONCLUSION: Berberine exerts renoprotective effects through its anti-oxidant, anti-inflammatory, and anti-apoptotic properties.[Formula: see text].

PMID: 27056079 [PubMed - indexed for MEDLINE]

Extrapyramidal symptoms after exposure to calcium channel blocker-flunarizine or cinnarizine.

Eur J Clin Pharmacol. 2017 Apr 06;:

Authors: Jhang KM, Huang JY, Nfor ON, Tung YC, Ku WY, Lee CT, Liaw YP

Abstract
PURPOSE: Flunarizine (fz) and cinnarizine (cz) have well-known extrapyramidal side effects (EPSEs). The aim of this study was to evaluate the incidence and occurrence time of cz- and fz-related EPSEs.
METHOD: Patients who took fz or cz for more than 1 month were identified from the longitudinal health insurance database 2005 and 2010. Excluded were patients with any of the underlying diseases that may cause parkinsonism. Drug-induced EPSEs were defined as the new diagnosis of parkinsonism, dyskinesia, or secondary dystonia during drug use or within 3 months after discontinuing the medication. Age- and sex-matched controls were included in this study.
RESULTS: Recruited for analysis were individuals who took fz (n = 26,133) and cz (n = 7186). The incidence rates of fz- and cz-induced EPSEs were 21.03 and 10.3 per 10,000 person-months, respectively. The hazard ratios (HRs) of EPSEs among fz and cz subjects were 8.03 (95% CI 6.55-9.84) and 3.41 (95% CI 2.50-4.63) when compared with the control individuals. Both fz and cz patients had a higher cumulative incidence of EPSEs than their control individuals (p < 0.001). Among subjects who took fz, the incidence of EPSEs was higher in the second than first year of drug exposure (45.59 vs 21.03 per 10,000 person-months).
CONCLUSIONS: Fz and cz significantly increased the risk of parkinsonism, dyskinesia, and dystonia. Potential benefits and risks should be weighed when considering long-term use of these drugs especially fz.

PMID: 28386684 [PubMed - as supplied by publisher]

Recognizing and managing on toxicities in cancer immunotherapy.

Tumour Biol. 2017 Mar;39(3):1010428317694542

Authors: Yang L, Yu H, Dong S, Zhong Y, Hu S

Abstract
Over the past 4 years, cancer immunotherapy has significantly prolonged survival time of patients with prostate cancer, melanoma, lung cancer, and liver cancer, but its side effects are also impressive. Different types of the immune therapeutic agents have different on-target or off-target toxicity due to high affinity or weak specificity, respectively. Treatment toxicity spectrums vary greatly even in patients with the same type of cancer. Common toxicities are fevers, chills, diarrhea colitis, maculopapular rash, hepatitis, and hormone gland disorder; therefore, routine monitoring of thyroid function, liver function, renal function, and complete blood count are absolutely necessary once treatment begins. Some side effects are reversible, and can be processed through the standard medicines. However, serious toxicities are lethal, which should be frequently followed-up, identified at an early stage and immediately symptomatic treated by high-dose immunosuppressors. In this case, thereafter, the same agent should not be challenged again.

PMID: 28351299 [PubMed - indexed for MEDLINE]

Evaluation of sorafenib in Chinese unresectable hepatocellular carcinoma patients with prior surgery and portal vein tumor thrombosis: A subset analysis of GIDEON study data.

Tumour Biol. 2017 Mar;39(3):1010428317695030

Authors: Ye SL, Chen X, Yang J, Bie P, Zhang S, Liu F, Liu L, Zhou J, Dou K, Yip CS, Yang X

Abstract
The purpose of this study was to examine the safety and efficacy of sorafenib in Chinese patients with unresectable hepatocellular carcinoma. Data of 338 Chinese patients from the Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib study database were included. Patients were divided into those who received and did not receive sorafenib prior to surgical resection and those with and without portal vein tumor thrombosis. In the non-surgery group, the median survival was 302 days (95% confidence interval: 244-371), and the median time from diagnosis to death was 428 days (95% confidence interval: 352-556); in the surgery group, half of the patients survived for 345 days and the median time from diagnosis to death was 1000 days (95% confidence interval: 750-2816). Median progression-free survival and median time to progression were not different between the two groups. Median overall survival was 360 days (95% confidence interval: 309-435) in the non-portal vein tumor thrombosis group and 240 days (95% confidence interval: 181-296) in the portal vein tumor thrombosis group; median time between hepatocellular carcinoma diagnosis and death was 750 days (95% confidence interval: 472-1000) and 420 days (95% confidence interval: 252-567), respectively, in the two groups. Median progression-free survival was 209 days (95% confidence interval: 166-264) for patients without portal vein tumor thrombosis and 154 days (95% confidence interval: 112-202) for patients with portal vein tumor thrombosis; median time to progression was 295 days (95% confidence interval: 209-463) and 221 days, respectively. Adverse events were generally comparable regardless of prior surgery and portal vein tumor thrombosis status. We thus conclude that earlier administration of sorafenib may result in improved outcomes in patients with unresectable hepatocellular carcinoma and portal vein tumor thrombosis.

PMID: 28349781 [PubMed - indexed for MEDLINE]

Pharmacology education in nursing based on the "Patient-oriented Pharmacology".

Nihon Yakurigaku Zasshi. 2017;149(1):20-25

Authors: Yanagita T

PMID: 28049874 [PubMed - indexed for MEDLINE]

Review of Toxic Epidermal Necrolysis.

Int J Mol Sci. 2016 Dec 18;17(12):

Authors: Harris V, Jackson C, Cooper A

Abstract
Toxic epidermal necrolysis (TEN) is a rare but life threatening mucocutaneous reaction to drugs or their metabolites. It is characterised by widespread keratinocyte apoptosis and sloughing of the skin, erosions of the mucous membranes, painful blistering, and severe systemic disturbance. The pathophysiology of TEN is incompletely understood. Historically, it has been regarded as a drug-induced immune reaction initiated by cytotoxic lymphocytes via a human leukocyte antigen (HLA)-restricted pathway. Several mediators have been identified as contributors to the cell death seen in TEN, including; granulysin, soluble Fas ligand, perforin/granzyme, tumour necrosis factor-α (TNF-α), and TNF-related apoptosis-inducing ligand. Currently, granulysin is accepted as the most important mediator of T cell proliferation. There is uncertainty around the accepted management of TEN. The lack of definitive management guidelines for TEN is explained in part by the rarity of the disease and its high mortality rate, which makes it difficult to conduct randomised control trials on emerging therapies. Developments have been made in pharmacogenomics, with numerous HLA alleles identified; however, these have largely been ethnically specific. These associations have translated into screening recommendations for Han Chinese.

PMID: 27999358 [PubMed - indexed for MEDLINE]

Authors' responses to letter to the editor re: "Efficacy and effectiveness of anti-digoxin antibodies in chronic digoxin poisonings from the DORA study (ATOM-1)".

Clin Toxicol (Phila). 2017 01;55(1):64

Authors: Chan BS, Chiew A, Isbister GK, O'Leary M, Buckley NA

PMID: 27530430 [PubMed - indexed for MEDLINE]

Tadalafil Facilitates the Distal Ureteral Stone Expulsion: A Meta-Analysis.

J Endourol. 2017 Apr 06;:

Authors: Bai Y, Yang Y, Wang X, Tang Y, Han P, Wang J

Abstract
OBJECTIVE: To assess the efficacy and safety of tadalafil in facilitating the spontaneous passage of distal ureteral stones.
METHODS: The relevant studies were identified by searching MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials up to November 2016. Randomized controlled trials evaluating effects of tadalafil for distal ureteral stones were included.
RESULTS: Six publications involving 921 patients were included. Compared with tamsulosin monotherapy, tadalafil monotherapy or combined with tamsulosin has a significantly higher stone expulsion rate (relative risk [RR], 1.16; 95% confidence interval [CI], 1.05 to 1.29; p = 0.004; RR, 1.24; 95% CI, 1.09 to 1.42; p = 0.001, respectively) and shorter time to stone expulsion (mean difference [MD], -1.33 days; 95% CI, -2.44 to -0.23; p = 0.02; MD, -1.98 days; 95% CI, -3.08 to -0.88; p = 0.0004, respectively). Statistically significant differences were noted in pain episodes and analgesic use in favor of group tadalafil alone compared to group tamsulosin alone. The analgesic use was significantly lower in the combined group than in the tamsulosin alone group. Although the occurrence of drug-related adverse events in the tadalafil alone or combined with tamsulosin was higher than that in the use of tamsulosin-alone group, the most common adverse events were mild and tolerable.
CONCLUSIONS: Our study suggested that medical expulsive therapy for the distal ureteral stones using tadalafil alone or combined with tamsulosin is safe, efficacious, and well tolerated.

PMID: 28384011 [PubMed - as supplied by publisher]

Adverse drug reactions in therapeutic hypothermia after cardiac arrest.

Ther Adv Drug Saf. 2017 Mar;8(3):101-111

Authors: Witcher R, Dzierba AL, Kim C, Smithburger PL, Kane-Gill SL

Abstract
BACKGROUND: Therapeutic hypothermia (TH) improves survival and neurologic function in comatose survivors of cardiac arrest. Many medications used to support TH have altered pharmacokinetics and pharmacodynamics during this treatment. It is unknown if or at what frequency the medications used during TH cause adverse drug reactions (ADRs).
METHODS: A retrospective chart review was conducted for patients admitted to an intensive care unit (ICU) after cardiac arrest and treated with TH from January 2009 to June 2012 at two urban, university-affiliated, tertiary-care medical centres. Medications commonly used during TH were screened for association with significant ADRs (grade 3 or greater per Common Terminology Criteria for Adverse Events) using three published ADR detection instruments.
RESULTS: A total of 229 patients were included, the majority being males with median age of 62 presenting with an out-of-hospital cardiac arrest in pulseless electrical activity or asystole. The most common comorbidities were hypertension, coronary artery disease, and diabetes mellitus. There were 670 possible ADRs and 69 probable ADRs identified. Of the 670 possible ADRs, propofol, fentanyl, and acetaminophen were the most common drugs associated with ADRs. Whereas fentanyl, insulin, and propofol were the most common drugs associated with a probable ADR. Patients were managed with TH for a median of 22 hours, with 38% of patients surviving to hospital discharge.
CONCLUSIONS: Patients undergoing TH after cardiac arrest frequently experience possible adverse reactions associated with medications and the corresponding laboratory abnormalities are significant. There is a need for judicious use and close monitoring of drugs in the setting of TH until recommendations for dose adjustments are available to help prevent ADRs.

PMID: 28382198 [PubMed - in process]

Sappanone A protects mice against cisplatin-induced kidney injury.

Int Immunopharmacol. 2016 Sep;38:246-51

Authors: Kang L, Zhao H, Chen C, Zhang X, Xu M, Duan H

Abstract
Cisplatin (CP) is an anti-cancer drug that often causes nephrotoxicity due to enhanced inflammatory response and oxidative stress. Sappanone A (SA), a homoisoflavanone isolated from the heartwood of Caesalpinia sappan, has been known to have antioxidant and anti-inflammatory effects. In this study, we aimed to investigate the protective effects and mechanism of SA on CP-induced kidney injury in mice. The results showed that treatment of SA improved CP-induced histopathalogical injury and renal dysfunction. SA also inhibited CP-induced MPO, MDA, TNF-α and IL-1β production and up-regulated the activities of SOD and GSH-PX decreased by CP. SA significantly inhibited the apoptosis rate of kidney tissues induced by CP. Furthermore, SA was found to inhibit CP-induced NF-κB activation. Treatment of SA up-regulated the expression of Nrf2 and HO-1 in a dose-dependent manner. In vitro, SA dose-dependently inhibited CP-induced TNF-α and IL-1β production and NF-κB activation in HK-2 cells. In conclusion, these results suggested that SA inhibited CP-induced kidney injury through activating Nrf2 and inhibiting NF-κB activation. SA was a potential therapeutic drug for treating CP-induced kidney injury.

PMID: 27318179 [PubMed - indexed for MEDLINE]

Improving drug safety with a systems pharmacology approach.

Eur J Pharm Sci. 2016 Oct 30;94:84-92

Authors: Schotland P, Bojunga N, Zien A, Trame MN, Lesko LJ

Abstract
Systems pharmacology is used to mechanistically analyze drug-adverse drug reaction (ADRs) pairs and is a promising solution to the complex problem of understanding mechanisms of toxicity. In this research, we have explored the feasibility of retrospectively mapping population-level adverse events from the FDA Adverse Event Reporting System (FAERS) to chemical and biological databases to identify drug safety signals and the underlying molecular mechanisms. We used an analytic platform - Molecular Analysis of Side Effects (MASE™). For this purpose, we selected the adverse event of severe and potentially fatal cutaneous reactions (SCARs) that are associated with acetaminophen (APAP). SCARs encompass the continuum between Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). We found a statistically significant association between APAP and TEN, the most severe form of SCARs. We also explored the influence of APAP on other classes of drugs commonly associated with SCARs. We found that APAP significantly reduced the risk of SCARs commonly associated with carbamazepine (CBZ). We used molecular docking simulations to propose a mechanism for APAP's reduction in CBZ-induced SCARs which is competitive inhibition of the binding of CBZ to HLA-B*15:02. We conclude that systems pharmacology can complement established surveillance methodologies by providing a means to undertake an independent investigation and review of the mechanisms by which drugs cause adverse events.

PMID: 27287422 [PubMed - indexed for MEDLINE]

Systems pharmacology to predict drug safety in drug development.

Eur J Pharm Sci. 2016 Oct 30;94:93-95

Authors: Trame MN, Biliouris K, Lesko LJ, Mettetal JT

Abstract
Ensuring that drugs are safe and effective is a very high priority for drug development and the US Food and Drug Administration review process. This is especially true today because of faster approval times and smaller clinical trials, especially in oncology and rare diseases. In light of these trends, systems pharmacology is seen as an essential strategy to understand and predict adverse drug events during drug development by analyzing interactions between drugs and multiple targets rather than the traditional "one-drug-one-target" approach. This commentary offers an overview of the current trends and challenges of using systems pharmacology to reduce the risks of unintended adverse events.

PMID: 27251780 [PubMed - indexed for MEDLINE]

A Systematic Approach to Assess the Burden of Drug Interactions in Adult Kidney Transplant Patients.

Curr Drug Saf. 2016;11(2):156-63

Authors: Bril F, Castro V, Centurion IG, Espinosa J, Keller GA, Gonzalez CD, Riera MC, Saubidet CL, Di Girolamo G, Pujol GS, Alvarez PA

Abstract
AIM: Renal transplant patients are frequently subject to polypharmacy and drug-drug interactions. However, no previous study has systematically assessed the risk of drug interactions and Adverse Drug Reactions (ADRs) in this population.
METHODS: A total of 138 consecutive adult kidney transplant recipients admitted to our hospital between August 2010 and February 2012 were prospectively and systematically assessed by our pharmacovigilance team, within 24 hours of admission, to identify potential drug-drug interactions and probable ADRs.
RESULTS: As a consequence of the high number of medications per patient (7.8±0.2 drugs), a considerable number of drugdrug interactions were observed in this population, with an average of 5.6±0.4 drug interactions per patient. Moreover, a significant percentage of admissions (~10%) of kidney transplant patients were related to probable ADRs. Almost all these patients had at least one drug interaction that could have potentially contributed to the probable ADR. Of note, clinically significant (i.e. severe) drug interactions were more frequent among patients with ADRs (29% vs. 15%, p<0.01). Also, patients with ADRs were more likely to have started a medication 30 days before admission (38.5% vs. 10.4%, p < 0.01). Non-immunosuppressive drugs most commonly involved in severe interactions were omeprazole, magnesium sulphate, and statins. The most commonly observed interactions were: tacrolimus and omeprazole, mycophenolate and omeprazole, sirolimus and enalapril, mycophenolate and antivirals, and mycophenolate and magnesium sulphate.
CONCLUSION: Drug interactions were extremely frequent among kidney transplant recipients, and responsible for potentially avoidable ADRs. They should be carefully considered when following kidney transplant recipients.

PMID: 27194037 [PubMed - indexed for MEDLINE]

Computed Biological Relations among Five Select Treatment-Related Organ/Tissue Toxicities.

Chem Res Toxicol. 2016 05 16;29(5):914-23

Authors: Sakellaropoulos T, Herod TJ, Alexopoulos LG, Bai JP

Abstract
Drug toxicity presents a major challenge in drug development and patient care. We set to build upon previous works regarding select drug-induced toxicities to find common patterns in the mode of action of the drugs associated with these toxicities. In particular, we focused on five disparate organ toxicities, peripheral neuropathy (PN), rhabdomyolysis (RM), Stevens-Johnson syndrome/toxic epidermal necrosis (SJS/TEN), lung injury (LI), and heart contraction-related cardiotoxicity (CT), and identified biological commonalities between and among the toxicities in terms of pharmacological targets and nearest neighbors (indirect effects) using the hyper-geometric test and a distance metric of Spearman correlation. There were 20 significant protein targets associated with two toxicities and 0 protein targets associated with three or more toxicities. Per Spearman distance, PN was closest to SJS/TEN compared to other pairs, whereas the pairs involving RM were more different than others excluding RM. The significant targets associated with RM outnumbered those associated with every one of the other four toxicities. Enrichment analysis of drug targets that are expressed in corresponding organ/tissues determined proteins that should be avoided in drug discovery. The identified biological patterns emerging from the mode of action of these drugs are statistically associated with these serious toxicities and could potentially be used as predictors for new drug candidates. The predictive power and usefulness of these biological patterns will increase with the database of these five toxicities. Furthermore, extension of our approach to all severe adverse reactions will produce useful biological commonalities for reference in drug discovery and development.

PMID: 27063352 [PubMed - indexed for MEDLINE]

Patterns of Adverse Drug Reaction in the Medical Wards of a Teaching Hospital: A Prospective Observational Cohort Study.

Curr Drug Saf. 2016;11(2):164-71

Authors: Peter JV, Varghese GH, Alexander H, Tom NR, Swethalekshmi V, Truman C, Kumar TR, Sivakumar T

Abstract
INTRODUCTION: According to the World Health Organization (WHO) definition, an Adverse Drug Reaction (ADR) is a response to a drug that is noxious and unintended and occurs at doses normally used in humans for the prophylaxis, diagnosis, and treatment of disease. The risk factors of ADR are multi-factorial and include poly-pharmacy, age, gender, race, genetics and inter-current disease.
PATIENTS AND METHODS: This was a hospital based, prospective, observational cohort study undertaken in a tertiary care hospital in south India to assess the different patterns of adverse drug reaction in medical wards over 6 months. The severity of ADR was assessed using Hartwig Siegel scale and causality by Naranjo and WHO UMC Scale. Preventability was assessed using Schumock and Thornton scale and other parameters such as incidence, onset, duration, management and outcome were also assessed. Risk factors were assessed by bi-variate logistic regression analysis and length of hospital stay by T test.
RESULTS: The incidence of ADR was 10.42% in medicine wards. The causality of ADR done by Naranjo scale showed that most of the ADRs were probable (7.38%). Anti-tubercular agents were the leading cause of ADR. Duration of hospitalization was significantly longer (7.18 ± 2.64 vs. 5.06 ± 2.13 days) in patients with ADR (Odds ratio 1.38, 95% Confidence interval 1.26 to 1.51). 7.28% of ADRs were moderately severe. Seriousness criteria assessment showed that 0.33% were serious reactions. Most of the ADRs were definitely preventable. Most of the ADRs were managed by discontinuing the suspected drug. The present study showed female gender predominance over males for ADRs and no relationship with age.
CONCLUSION: Adverse drug reactions impose significant burden on hospitals through prolonging patient stay and by increasing admission rates. The occurrence of ADR in this study was higher when compared to that reported in previous studies. This study highlights the importance of ADR reporting among ADR reporting among health care professionals in hospital.

PMID: 26916785 [PubMed - indexed for MEDLINE]

Incidence of Adverse Drug Reactions in Indian Hospitals: A Systematic Review of Prospective Studies.

Curr Drug Saf. 2016;11(2):128-36

Authors: Patel TK, Patel PB

Abstract
This systematic review estimated the incidence of ADRs that lead to hospitalization (ADRAd) and that developed during hospitalization (ADRIn) and factors affecting in Indian population. Two independent investigators searched the electronic databases describing ADRs. Due to high heterogeneity, incidence of ADRAd and ADRIn were presented as median (interquartile range-IQR). We performed the subgroup analysis of incidence based on characteristics of the included studies. The meta-analysis (generic inverse variance method with random effect model) was possible for the fatal ADR incidence. The risk factors for ADRs were also explored from the included studies. We used 'Review manager software version 5.0' and 'Graph Pad Prism version 6.0' for the analysis. Of 77 fully evaluated references, 21 prospective studies were selected. The median incidence of ADRAd and ADRIn were 2.85% (IOR: 1.25 - 3.93%) and 6.34% (IQR: 3.36 - 16.37%), respectively. The subgroup analysis found high incidence rate with studies conducted in intensive care units, elderly age groups, with intensive monitoring, duration of > 1 year and multidisciplinary team. The fatal ADR incidence was 0.08% (95% CI: 0.00-0.15%). Important risk factors for ADRs included elderly, female sex and polypharmacy. The hospitalized patients have a significant burden of ADRs. The multiple factors may have affected their occurrence.

PMID: 26391424 [PubMed - indexed for MEDLINE]