Comprehensive in vitro cardiac safety assessment using human stem cell technology: Overview of CSAHi HEART initiative.

J Pharmacol Toxicol Methods. 2017 Jan - Feb;83:42-54

Authors: Takasuna K, Asakura K, Araki S, Ando H, Kazusa K, Kitaguchi T, Kunimatsu T, Suzuki S, Miyamoto N

Abstract
Recent increasing evidence suggests that the currently-used platforms in vitro IKr and APD, and/or in vivo QT assays are not fully predictive for TdP, and do not address potential arrhythmia (VT and/or VF) induced by diverse mechanisms of action. In addition, other cardiac safety liabilities such as functional dysfunction of excitation-contraction coupling (contractility) and structural damage (morphological damage to cardiomyocytes) are also major causes of drug attrition, but current in vitro assays do not cover all these liabilities. We organized the Consortium for Safety Assessment using Human iPS cells (CSAHi; http://csahi.org/en/), based on the Japan Pharmaceutical Manufacturers Association (JPMA), to verify the application of human iPS/ES cell-derived cardiomyocytes in drug safety evaluation. The main goal of the CSAHi HEART team has been to propose comprehensive screening strategies to predict a diverse range of cardiotoxicities by using recently introduced platforms (multi-electrode array (MEA), patch clamp, cellular impedance, motion field imaging [MFI], and Ca transient systems) while identifying the strengths and weaknesses of each. Our study shows that hiPS-CMs used in these platforms have pharmacological responses more relevant to humans in comparison with existent hERG, APD or Langendorff (MAPD/contraction) assays, and not only MEA but also other methods such as impedance, MFI, and Ca transient systems would offer paradigm changes of platforms for predicting drug-induced QT risk and/or arrhythmia or contractile dysfunctions. Furthermore, we propose a potential multi-parametric platform in which field potential (MEA)-Ca transient-contraction (MFI) could be evaluated simultaneously as an ideal novel platform for predicting a diversity of cardiac toxicities, namely whole effects on the excitation-contraction cascade.

PMID: 27646297 [PubMed - indexed for MEDLINE]

Assessment of extracellular field potential and Ca(2+) transient signals for early QT/pro-arrhythmia detection using human induced pluripotent stem cell-derived cardiomyocytes.

J Pharmacol Toxicol Methods. 2017 Jan - Feb;83:1-15

Authors: Abi-Gerges N, Pointon A, Oldman KL, Brown MR, Pilling MA, Sefton CE, Garside H, Pollard CE

Abstract
Cardiovascular toxicity is a prominent reason for failures in drug development, resulting in the demand for assays that can predict this liability in early drug discovery. We investigated whether iCell® cardiomyocytes have utility as an early QT/TdP screen. Thirty clinical drugs with known QT/TdP outcomes were evaluated blind using label-free microelectrode array (parameters measured were beating period (BP), field potential duration (FPD), fast Na(+) amplitude and slope) and live cell, fast kinetic fluorescent Ca(2+) transient FLIPR® Tetra (parameters measured were peak count, width, amplitude) systems. Many FPD-altering drugs also altered BP. Correction for BP, using a Log-Log (LL) model, was required to appropriately interpret direct drug effects on FPD. In comparison with human QT effects and when drug activity was to be predicted at top test concentration (TTC), LL-corrected FPD and peak count had poor assay sensitivity and specificity values: 13%/64% and 65%/11%, respectively. If effective free therapeutic plasma concentration (EFTPC) was used instead of TTC, the values were 0%/100% and 6%/100%, respectively. When compared to LL-corrected FPD and peak count, predictive values of uncorrected FPD, BP, width and amplitude were not much different. If pro-arrhythmic risk was to be predicted using Ca(2+) transient data, the values were 67%/100% and 78%/53% at EFTPC and TTC, respectively. Thus, iCell® cardiomyocytes have limited value as an integrated QT/TdP assay, highlighting the urgent need for improved experimental alternatives that may offer an accurate integrated cardiomyocyte safety model for supporting the development of new drugs without QT/TdP effects.

PMID: 27622857 [PubMed - indexed for MEDLINE]

Supporting the global initiative of preventing childhood hearing loss: Act now, here's how!

Noise Health. 2016 Sep-Oct;18(84):280-281

Authors: Shrivastava SR, Shrivastava PS, Ramasamy J

PMID: 27762258 [PubMed - indexed for MEDLINE]

A phase 2 study of nanoparticle albumin-bound paclitaxel plus nedaplatin for patients with advanced, recurrent, or metastatic cervical carcinoma.

Cancer. 2017 Feb 01;123(3):420-425

Authors: Li Y, Zeng J, Huang M, An J, Bai P, Wu L, Zhang R

Abstract
BACKGROUND: Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) and nedaplatin (NDP) are used for the treatment of patients with cervical cancer. However, to the authors' knowledge, the use of this combination regimen among patients with advanced, recurrent, or metastatic cervical cancer has rarely been reported.
METHODS: Patients with pathologically confirmed, stage IVB (FIGO staging 2009), recurrent or metastatic cervical cancer were eligible. Nab-paclitaxel at a dose of 175 mg/m(2) plus NDP at a dose of 80 mg/m(2) was administered intravenously every 3 weeks. The primary endpoint of the current study was the objective response rate (ORR). The secondary endpoints were progression-free survival, overall survival, and safety.
RESULTS: A total of 27 patients were included (5 with late-stage and 22 with recurrent or metastatic disease). The mean age of the patients was 48.26 ± 9.21 years. Of these 27 patients, 25 had squamous cell carcinoma (92.6%). A total of 26 patients completed 92 cycles of chemotherapy, with an average of 3.4 cycles per patient. The ORR was 50.0% (13 of 26 patients). The overall survival was 16.6 months (95% confidence interval, 12.6-20.6 months) and the progression-free survival was 9.1 months (95% confidence interval, 2.4-15.8 months).The ORR of patients with an interval of >12 months from receipt of prior chemotherapy was significantly higher than that of those with a shorter interval (71.4% vs 25.0%; P = .034). The most common adverse effects reported were myelosuppression, gastrointestinal reactions, fatigue, and peripheral neuropathy. The incidence of grade 3 neutropenia was 33.3% (adverse effects were graded on a scale from 0 to 4 according to the National Cancer Institute's Common Terminology Criteria for Adverse Events [version 3.0]). The incidence of grade 3 thrombocytopenia and anemia was 7.4% and 18.5%, respectively. The incidence of grade 1 to 2 peripheral neuropathy was reported to be as high as 51.9%. No case of hypersensitivity was observed.
CONCLUSIONS: The combination of nab-paclitaxel plus NDP for the treatment of patients with late-stage, recurrent, or metastatic cervical cancer appears to be active and tolerable. Cancer 2017;123:420-425. © 2016 American Cancer Society.

PMID: 27696395 [PubMed - indexed for MEDLINE]

N-acetyltransferase 2 (NAT2) gene polymorphism as a predisposing factor for phenytoin intoxication in tuberculous meningitis or tuberculoma patients having seizures - A pilot study.

Indian J Med Res. 2016 May;143(5):581-90

Authors: Adole PS, Kharbanda PS, Sharma S

Abstract
BACKGROUND & OBJECTIVES: Simultaneous administration of phenytoin and isoniazid (INH) in tuberculous meningitis (TBM) or tuberculoma patients with seizures results in higher plasma phenytoin level and thus phenytoin intoxication. N-acetyltransferase 2 (NAT2) enzyme catalyses two acetylation reactions in INH metabolism and NAT2 gene polymorphism leads to slow and rapid acetylators. The present study was aimed to evaluate the effect of allelic variants of N-acetyltransferase 2 (NAT2) gene as a predisposing factor for phenytoin toxicity in patients with TBM or tuberculoma having seizures, and taking INH and phenytoin simultaneously.
METHODS: Sixty patients with TBM or tuberculoma with seizures and taking INH and phenytoin simultaneously for a minimum period of seven days were included in study. Plasma phenytoin was measured by high performance liquid chromatography. NAT2 gene polymorphism was studied using restriction fragment length polymorphism and allele specific PCR.
RESULTS: The patients were grouped into those having phenytoin intoxication and those with normal phenytoin level, and also classified as rapid or slow acetylators by NAT2 genotyping. Genotypic analysis showed that of the seven SNPs (single nucleotide polymorphisms) of NAT2 gene studied, six mutations were found to be associated with phenytoin intoxication. For rs1041983 (C282T), rs1799929 (C481T), rs1799931 (G857A), rs1799930 (G590A), rs1208 (A803G) and rs1801280 (T341C) allelic variants, the proportion of homozygous mutant was higher in phenytoin intoxicated group than in phenytoin non-intoxicated group.
INTERPRETATION & CONCLUSIONS: Homozygous mutant allele of NAT2 gene at 481site may act as a predisposing factor for phenytoin intoxication among TBM or tuberculoma patients having seizures.

PMID: 27488001 [PubMed - indexed for MEDLINE]

Efficacy and safety of fosaprepitant for the prevention of nausea and emesis during 5 weeks of chemoradiotherapy for cervical cancer (the GAND-emesis study): a multinational, randomised, placebo-controlled, double-blind, phase 3 trial.

Lancet Oncol. 2016 Apr;17(4):509-18

Authors: Ruhlmann CH, Christensen TB, Dohn LH, Paludan M, Rønnengart E, Halekoh U, Hilpert F, Feyer P, Kristensen G, Hansen O, Keefe D, Herrstedt J

Abstract
BACKGROUND: The role of the neurokinin-1 (NK-1) receptor antagonists in the prevention of radiation-induced nausea and vomiting has not been established. The purpose of the GAND-emesis study was to investigate the efficacy and safety of fosaprepitant in combination with palonosetron and dexamethasone in the prevention of nausea and vomiting during 5 weeks of fractionated radiotherapy and concomitant weekly cisplatin in patients with cervical cancer.
METHODS: This investigator initiated, multinational, randomised, double-blind, placebo-controlled phase 3 trial, included women with cervical cancer scheduled to receive fractionated radiotherapy and weekly cisplatin 40 mg/m(2) for 5 weeks. Patients had to be naive to chemotherapy and radiotherapy. Patients were randomly assigned to receive either single doses of fosaprepitant 150 mg intravenously or placebo (saline) in combination with palonosetron 0·25 mg intravenously and dexamethasone 16 mg orally before cisplatin administration. Randomisation was done by the unmasked pharmacist, who used a list of six numbers (a block) provided in a sealed envelope. A web-based randomisation number generator was used to generate the full list of randomisation numbers that was split up in blocks of six numbers. All patients received oral dexamethasone 8 mg twice a day on day 2, 4 mg twice a day on day 3, and 4 mg once on day 4. The treatment was repeated for 5 weeks. The primary endpoint was the proportion of patients with sustained no emesis after 5 weeks of treatment. The modified intention-to-treat population (all patients who received study medication) was used for the statistical analyses. The study was registered with ClinicalTrials.gov, number NCT01074697.
FINDINGS: Between June 15, 2010, and March 8, 2015, 246 patients from four countries consented to the study and were randomly assigned. Of these, 234 patients were eligible, having received study medication (118 received fosaprepitant, 116 received placebo). The proportion of patients with sustained no emesis at 5 weeks (competing risk analysis) was 48·7% (95% CI 25·2-72·2) for the placebo group compared with 65·7% (42·2-89·2) of patients for the fosaprepitant group. There was a significantly lower cumulative risk of emesis in the fosaprepitant group compared with the placebo group (subhazard ratio 0·58 [95% CI 0·39-0·87]; p=0·008). Treatments were generally well tolerated with few grade 3 adverse events none of which were related to the study treatment; the most common grade 3 adverse event during the 5 weeks of treatment was diarrhoea (11 [9%] of 118 patients in the fosaprepitant group vs six [5%] of 116 patients in the placebo group). There was only one report of a grade 4 adverse event (neutropenia), in the fosaprepitant group. No deaths were recorded in either group.
INTERPRETATION: To our knowledge, this is the first study to investigate safety and efficacy of a NK-1 receptor antagonist during 5 weeks of radiotherapy and concomitant weekly cisplatin. Patients receiving fosaprepitant in addition to palonosetron and dexamethasone were less likely to experience emesis and nausea compared with those receiving palonosetron and dexamethasone alone. Both treatments were safe and well tolerated. Further investigations in other radiotherapy settings are warranted.
FUNDING: Private and hospital or university funding, unrestricted grants from Biovitrum and Helsinn Healthcare SA.

PMID: 26952945 [PubMed - indexed for MEDLINE]

Dopamine D2 receptors and the circadian clock reciprocally mediate antipsychotic drug-induced metabolic disturbances.

NPJ Schizophr. 2017;3:17

Authors: Freyberg Z, McCarthy MJ

Abstract
Antipsychotic drugs are widely prescribed medications, used for numerous psychiatric illnesses. However, antipsychotic drugs cause serious metabolic side effects that can lead to substantial weight gain and increased risk for type 2 diabetes. While individual drugs differ, all antipsychotic drugs may cause these important side effects to varying degrees. Given that the single unifying property shared by these medications is blockade of dopamine D2 and D3 receptors, these receptors likely play a role in antipsychotic drug-induced metabolic side effects. Dopamine D2 and dopamine D3 receptors are expressed in brain regions critical for metabolic regulation and appetite. Surprisingly, these receptors are also expressed peripherally in insulin-secreting pancreatic beta cells. By inhibiting glucose-stimulated insulin secretion, dopamine D2 and dopamine D3 receptors are important mediators of pancreatic insulin release. Crucially, antipsychotic drugs disrupt this peripheral metabolic regulatory mechanism. At the same time, disruptions to circadian timing have been increasingly recognized as a risk factor for metabolic disturbance. Reciprocal dopamine and circadian signaling is important for the timing of appetitive/feeding behaviors and insulin release, thereby coordinating cell metabolism with caloric intake. In particular, circadian regulation of dopamine D2 receptor/dopamine D3 receptor signaling may play a critical role in metabolism. Therefore, we propose that antipsychotic drugs' blockade of dopamine D2 receptor and dopamine D3 receptors in pancreatic beta cells, hypothalamus, and striatum disrupts the cellular timing mechanisms that regulate metabolism. Ultimately, understanding the relationships between the dopamine system and circadian clocks may yield critical new biological insights into mechanisms of antipsychotic drug action, which can then be applied into clinical practice.

PMID: 28560263 [PubMed - in process]

Ceftazidime-induced thrombocytopenia.

Rev Esp Anestesiol Reanim. 2017 May 27;:

Authors: Domingo-Chiva E, Díaz-Rangel M, Monsalve-Naharro JÁ, Cuesta-Montero P, Catalá-Ripoll JV, García-Martínez EM

Abstract
Ceftazidime is an antibiotic belonging to the group of third generation cephalosporins, frequently used in clinical practice for its broad antibacterial spectrum. A case report is presented on a 78-year-old man who entered the intensive care unit due to respiratory failure secondary to nosocomial pneumonia in the postoperative period of a laparoscopic hepatic bisegmentectomy for a hepatocarcinoma. It required invasive mechanical ventilation and was treated with ceftazidime, developing a progressive decrease in platelet count after the onset of this drug and after re-exposure to it, not coinciding with the introduction of other drugs. The adverse reaction was reported to the Spanish pharmacosurveillance system and according to the Naranjo algorithm the causal relationship was probable. Since no case of ceftazidime-induced thrombocytopenia was found in the literature, we consider knowledge of it relevant as an adverse effect to be taken into account given its potential severity, especially when it cannot be explained by other causes.

PMID: 28559046 [PubMed - as supplied by publisher]

Is gender still a predisposing factor in contrast-media associated adverse drug reactions? A systematic review and meta-analysis of randomized trials and observational studies.

Eur J Radiol. 2017 Apr;89:81-89

Authors: Lee H, Song S, Oh YK, Kang W, Kim E

Abstract
OBJECTIVE: To evaluate the role of gender as a risk factor for developing contrast media-associated adverse drug reactions (CM-ADRs) by comparing the incidence of CM-ADR between male and female patients according to study design, ADR type, and computed tomography (CT) examination.
MATERIAL AND METHODS: We systematically searched three electronic databases for eligible studies. In the studies included (n=18), we assessed effect estimates of the relative incidence of CM-ADR, analysed by experimental design, ADR type and CT examination. This was calculated by using a random effects model if clinical conditions showed heterogeneity; otherwise, a fixed effects model was used.
RESULTS: We identified 10,776 patients administered CM. According to the designs, studies were classified into randomised controlled trials (RCTs) and observational studies. Results were as follows: risk ratio (RR)=1.07 (95% confidence interval (CI): 0.79-1.46, P=0.66) for RCTs, and RR=0.77 (95% CI: 0.58-1.04, P=0.09) for observational studies. The results of analysis according to ADR type and for undergoing CT demonstrated that the incidence of CM-ADR did not differ between males and females.
CONCLUSIONS: We found no significant difference in the incidence of CM-ADRs between male and female patients according to study design, ADR type, or CT examination. Future studies to determine why gender has shown different roles as a risk factor between CM-ADRs and non-CM ADRs are needed.

PMID: 28267554 [PubMed - indexed for MEDLINE]

Review of Childhood Obesity: From Epidemiology, Etiology, and Comorbidities to Clinical Assessment and Treatment.

Mayo Clin Proc. 2017 Feb;92(2):251-265

Authors: Kumar S, Kelly AS

Abstract
Childhood obesity has emerged as an important public health problem in the United States and other countries in the world. Currently 1 in 3 children in the United States is afflicted with overweight or obesity. The increasing prevalence of childhood obesity is associated with emergence of comorbidities previously considered to be "adult" diseases including type 2 diabetes mellitus, hypertension, nonalcoholic fatty liver disease, obstructive sleep apnea, and dyslipidemia. The most common cause of obesity in children is a positive energy balance due to caloric intake in excess of caloric expenditure combined with a genetic predisposition for weight gain. Most obese children do not have an underlying endocrine or single genetic cause for their weight gain. Evaluation of children with obesity is aimed at determining the cause of weight gain and assessing for comorbidities resulting from excess weight. Family-based lifestyle interventions, including dietary modifications and increased physical activity, are the cornerstone of weight management in children. A staged approach to pediatric weight management is recommended with consideration of the age of the child, severity of obesity, and presence of obesity-related comorbidities in determining the initial stage of treatment. Lifestyle interventions have shown only modest effect on weight loss, particularly in children with severe obesity. There is limited information on the efficacy and safety of medications for weight loss in children. Bariatric surgery has been found to be effective in decreasing excess weight and improving comorbidities in adolescents with severe obesity. However, there are limited data on the long-term efficacy and safety of bariatric surgery in adolescents. For this comprehensive review, the literature was scanned from 1994 to 2016 using PubMed using the following search terms: childhood obesity, pediatric obesity, childhood overweight, bariatric surgery, and adolescents.

PMID: 28065514 [PubMed - indexed for MEDLINE]

Ceftriaxone-induced hemolytic anemia in a child successfully managed with intravenous immunoglobulin.

Turk J Pediatr. 2016;58(2):216-219

Authors: Vehapoğlu A, Göknar N, Tuna R, Çakır FB

Abstract
Drug-induced hemolytic anemia is an immune-mediated phenomenon that leads to the destruction of red blood cells. Here, we present a case of life-threatening ceftriaxone-induced hemolytic anemia (CIHA) in a previously healthy 3-year-old girl. We also reviewed the literature to summarize the clinical features and treatment of hemolytic anemia. Acute hemolysis is a rare side effect of ceftriaxone therapy associated with high mortality. Our patient had a sudden loss of consciousness with macroscopic hematuria and her hemoglobin dropped from 10.2 to 2.2 g/dl over 4 hours, indicating that the patient had life-threatening hemolysis after an intravascular dose of ceftriaxone who had previously been treated with ceftriaxone in intramuscular form for six days. CIHA is associated with a positive direct antiglobulin test, revealing the presence of IgG in all cases and C3d in most cases. Our patient's direct antiglobulin test was positive for IgG (3+) and for C3d (4+). The case was managed successfully with supportive measures and intravenous immunoglobulin therapy. Ceftriaxone is used very frequently in children; an early diagnosis and proper treatment of hemolytic anemia are essential to improve the patient outcome. The pathophysiological mechanism is the same as for non-drug autoimmune hemolytic anemia. However, there is still no consensus treatment for CIHA. Intravenous immunoglobulin can be used in clinical emergencies, such as our case, or in refractory cases.

PMID: 27976566 [PubMed - indexed for MEDLINE]

A computational model predicts adjunctive pharmacotherapy for cardiac safety via selective inhibition of the late cardiac Na current.

J Mol Cell Cardiol. 2016 Oct;99:151-161

Authors: Yang PC, El-Bizri N, Romero L, Giles WR, Rajamani S, Belardinelli L, Clancy CE

Abstract
BACKGROUND: The QT interval is a phase of the cardiac cycle that corresponds to action potential duration (APD) including cellular repolarization (T-wave). In both clinical and experimental settings, prolongation of the QT interval of the electrocardiogram (ECG) and related proarrhythmia have been so strongly associated that a prolonged QT interval is largely accepted as surrogate marker for proarrhythmia. Accordingly, drugs that prolong the QT interval are not considered for further preclinical development resulting in removal of many promising drugs from development. While reduction of drug interactions with hERG is an important goal, there are promising means to mitigate hERG block. Here, we examine one possibility and test the hypothesis that selective inhibition of the cardiac late Na current (INaL) by the novel compound GS-458967 can suppress proarrhythmic markers.
METHODS AND RESULTS: New experimental data has been used to calibrate INaL in the Soltis-Saucerman computationally based model of the rabbit ventricular action potential to study effects of GS-458967 on INaL during the rabbit ventricular AP. We have also carried out systematic in silico tests to determine if targeted block of INaL would suppress proarrhythmia markers in ventricular myocytes described by TRIaD: Triangulation, Reverse use dependence, beat-to-beat Instability of action potential duration, and temporal and spatial action potential duration Dispersion.
CONCLUSIONS: Our computer modeling approach based on experimental data, yields results that suggest that selective inhibition of INaL modifies all TRIaD related parameters arising from acquired Long-QT Syndrome, and thereby reduced arrhythmia risk. This study reveals the potential for adjunctive pharmacotherapy via targeted block of INaL to mitigate proarrhythmia risk for drugs with significant but unintended off-target hERG blocking effects.

PMID: 27545042 [PubMed - indexed for MEDLINE]

In Vivo Monitoring of Sevoflurane-induced Adverse Effects in Neonatal Nonhuman Primates Using Small-animal Positron Emission Tomography.

Anesthesiology. 2016 Jul;125(1):133-46

Authors: Zhang X, Liu S, Newport GD, Paule MG, Callicott R, Thompson J, Liu F, Patterson TA, Berridge MS, Apana SM, Brown CC, Maisha MP, Hanig JP, Slikker W, Wang C

Abstract
BACKGROUND: Animals exposed to sevoflurane during development sustain neuronal cell death in their developing brains. In vivo micro-positron emission tomography (PET)/computed tomography imaging has been utilized as a minimally invasive method to detect anesthetic-induced neuronal adverse effects in animal studies.
METHODS: Neonatal rhesus monkeys (postnatal day 5 or 6, 3 to 6 per group) were exposed for 8 h to 2.5% sevoflurane with or without acetyl-L-carnitine (ALC). Control monkeys were exposed to room air with or without ALC. Physiologic status was monitored throughout exposures. Depth of anesthesia was monitored using quantitative electroencephalography. After the exposure, microPET/computed tomography scans using F-labeled fluoroethoxybenzyl-N-(4-phenoxypyridin-3-yl) acetamide (FEPPA) were performed repeatedly on day 1, 1 and 3 weeks, and 2 and 6 months after exposure.
RESULTS: Critical physiologic metrics in neonatal monkeys remained within the normal range during anesthetic exposures. The uptake of [F]-FEPPA in the frontal and temporal lobes was increased significantly 1 day or 1 week after exposure, respectively. Analyses of microPET images recorded 1 day after exposure showed that sevoflurane exposure increased [F]-FEPPA uptake in the frontal lobe from 0.927 ± 0.04 to 1.146 ± 0.04, and in the temporal lobe from 0.859 ± 0.05 to 1.046 ± 0.04 (mean ± SE, P < 0.05). Coadministration of ALC effectively blocked the increase in FEPPA uptake. Sevoflurane-induced adverse effects were confirmed by histopathologic evidence as well.
CONCLUSIONS: Sevoflurane-induced general anesthesia during development increases glial activation, which may serve as a surrogate for neurotoxicity in the nonhuman primate brain. ALC is a potential protective agent against some of the adverse effects associated with such exposures.

PMID: 27183169 [PubMed - indexed for MEDLINE]

Efficacy and safety of catheter ablation vs. rate control of atrial fibrillation in systolic left ventricular dysfunction : A meta-analysis and systematic review.

Herz. 2016 Jun;41(4):342-50

Authors: Zhang B, Shen D, Feng S, Zhen Y, Zhang G

Abstract
PURPOSE: It is unclear what constitutes the optimal strategy for management of atrial fibrillation (AF) in patients with systolic left ventricular (LV) dysfunction. We hypothesized that catheter ablation of AF had benefits compared with rate control in patients with systolic LV dysfunction.
METHODS: PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials and nonrandomized, observational studies. Weighted mean differences (WMD) and 95 % confidence intervals (CIs) were calculated to compare the improvement of left ventricular ejection fraction (LVEF), functional capacity, and quality of life between a catheter ablation group and a rate control group.
RESULTS: Six trials with 324 patients were included in the analysis. Patients in the catheter ablation group had greater improvement of LVEF (WMD: 8.89; 95 % CI: 6.93-10.86; p < 0.001), 6-min walk distance (WMD: 46.9; 95 % CI: 28.5-65.4; p < 0.001), and lower Minnesota Living With Heart Failure Questionnaire (MLHFQ) scores (WMD: - 19.6; 95 % CI: - 23.6-- 15.7; p < 0.001) compared with patients in the rate control group. Overall, there were only ten procedure-related events and the procedure-related events rate was 4.9 % per procedure and 5.6 % per patient.
CONCLUSION: The present analysis suggests that catheter ablation of AF has benefits in terms of an improvement in LVEF, in functional capacity, and in quality of life compared with rate control in patients with systolic LV dysfunction, and the risk of complications related to procedures is acceptable.

PMID: 26598417 [PubMed - indexed for MEDLINE]

Prospective Assessment of Inpatient Boxed Warning Prescriber Adherence.

J Patient Saf. 2017 Mar;13(1):25-30

Authors: Kloet MA, Lohr BR, Smithburger PL, Seybert AL, Kane-Gill SL

Abstract
OBJECTIVE: To evaluate medication boxed warning nonadherence in the inpatient setting.
METHODS: This was a prospective cohort quality improvement project approved by our institution's Total Quality Council. General medicine and ICU patients 18 years and older were included if they were cared for by a prescriber-led multidisciplinary team that included a pharmacist. Patients were evaluated for medication orders with an actionable boxed warning; if boxed warning nonadherence occurred, the physician's reason was determined. Patients with boxed warning nonadherence were monitored for adverse drug reactions until discharge.
RESULTS: A total of 393 patients (224 general medicine and 169 ICU) were evaluated for nonadherence to 149 actionable boxed warnings. There were 293 drugs (175 general medicine and 118 ICU) with boxed warnings prescribed, and more than 50% of these were medications restarted from home. A total of 23 boxed warning nonadherences occurred in general medicine patients, and NSAIDs accounted for 81% of these events. ICU patients experienced 11 boxed warning nonadherences, with nearly 54% from anti-infectives and immunosuppressants. Antipsychotics were the most commonly ordered boxed warning medication class in ICU patients. Reasons for nonadherence included knowledge deficit and an acceptable risk-to-benefit ratio. Two adverse drug reactions occurred from boxed warning nonadherences, both because of a drug-drug interaction.
CONCLUSIONS: Boxed warning nonadherence is a concern in the inpatient setting, specifically with NSAID use in general medicine patients and antipsychotic use in ICU patients. More than half of boxed warning nonadherence occurred in medications restarted from home, which emphasizes the need for medication evaluation during transitions of care.

PMID: 24647270 [PubMed - indexed for MEDLINE]

Drugs for Children.

Clin Pharmacol Ther. 2017 Jun;101(6):704-706

Authors: Ito S

Abstract
The "Therapeutic Orphan" status of children is gradually improving, but our efforts to eliminate off-label/off-evidence use must be sustained for safer and more effective pediatric drug therapy. This is even more important in resource-scarce settings, because of the increasing child population in those regions. The juncture of pediatric pharmacology and global child health represents an emerging field of clinical pharmacology illuminating a crucial societal need on a global scale.

PMID: 28510298 [PubMed - indexed for MEDLINE]

Evaluation of the Safety of Drugs and Biological Products Used During Lactation: Workshop Summary.

Clin Pharmacol Ther. 2017 Jun;101(6):736-744

Authors: Wang J, Johnson T, Sahin L, Tassinari MS, Anderson PO, Baker TE, Bucci-Rechtweg C, Burckart GJ, Chambers CD, Hale TW, Johnson-Lyles D, Nelson RM, Nguyen C, Pica-Branco D, Ren Z, Sachs H, Sauberan J, Zajicek A, Ito S, Yao LP

Abstract
This report serves as a summary of a 2-day public workshop sponsored by the US Food and Drug Administration (FDA) to discuss the safety of drugs and biological products used during lactation. The aim of the workshop was to provide a forum to discuss the collection of data to inform the potential risks to breastfed infants with maternal use of medications during lactation. Discussions included the review of current approaches to collect data on medications used during lactation, and the considerations for future approaches to design and guide clinical lactation studies. This workshop is part of continuing efforts to raise the awareness of the public for women who choose to breastfeed their infants.

PMID: 28510297 [PubMed - indexed for MEDLINE]

Adverse Drug Reactions in Children: The Double-Edged Sword of Therapeutics.

Clin Pharmacol Ther. 2017 Jun;101(6):725-735

Authors: Elzagallaai AA, Greff M, Rieder MJ

Abstract
Adverse drug reactions (ADRs) represent a major health problem worldwide, with high morbidity and mortality rates. ADRs are classified into Type A (augmented) and Type B (bizarre) ADRs, with the former group being more common and the latter less common but often severe and clinically more problematic due to their unpredictable nature and occurrence at any dose. Pediatric populations are especially vulnerable to ADRs due to the lack of data for this age group from the drug development process and because of the wide use of off-label and unlicensed use of drugs. Children are more prone to specific types of ADRs because of the level of maturity of body systems involved in absorption, metabolism, transportation, and elimination of drugs. This state-of-the-art review provides an overview of definitions, classifications, epidemiology, and pathophysiology of ADRs and discusses the available evidence for related risk factors and causes of ADRs in the pediatric population.

PMID: 28295234 [PubMed - indexed for MEDLINE]

Impulse control disorders and levodopa-induced dyskinesias in Parkinson's disease: an update.

Lancet Neurol. 2017 Mar;16(3):238-250

Authors: Voon V, Napier TC, Frank MJ, Sgambato-Faure V, Grace AA, Rodriguez-Oroz M, Obeso J, Bezard E, Fernagut PO

Abstract
Dopaminergic medications used in the treatment of patients with Parkinson's disease are associated with motor and non-motor behavioural side-effects, such as dyskinesias and impulse control disorders also known as behavioural addictions. Levodopa-induced dyskinesias occur in up to 80% of patients with Parkinson's after a few years of chronic treatment. Impulse control disorders, including gambling disorder, binge eating disorder, compulsive sexual behaviour, and compulsive shopping occur in about 17% of patients with Parkinson's disease on dopamine agonists. These behaviours reflect the interactions of the dopaminergic medications with the individual's susceptibility, and the underlying neurobiology of Parkinson's disease. Parkinsonian rodent models show enhanced reinforcing effects of chronic dopaminergic medication, and a potential role for individual susceptibility. In patients with Parkinson's disease and impulse control disorders, impairments are observed across subtypes of decisional impulsivity, possibly reflecting uncertainty and the relative balance of rewards and losses. Impairments appear to be more specific to decisional than motor impulsivity, which might reflect differences in ventral and dorsal striatal engagement. Emerging evidence suggests impulse control disorder subtypes have dissociable correlates, which indicate that individual susceptibility predisposes towards the expression of different behavioural subtypes and neurobiological substrates. Therapeutic interventions to treat patients with Parkinson's disease and impulse control disorders have shown efficacy in randomised controlled trials. Large-scale studies are warranted to identify individual risk factors and novel therapeutic targets for these diseases. Mechanisms underlying impulse control disorders and dyskinesias could provide crucial insights into other behavioural symptoms in Parkinson's disease and addictions in the general population.

PMID: 28229895 [PubMed - indexed for MEDLINE]

Essential Medicines for Children.

Clin Pharmacol Ther. 2017 Jun;101(6):718-720

Authors: Hoppu K

Abstract
The World Health Organization (WHO) defines Essential Medicines as those that satisfy the priority healthcare needs of the population. The right to essential medicines has been considered an important component of the right to health. In the name of equity, children should also have access to appropriate, available, affordable, and quality essential medicines they need, but children's essential medicines are too often missing.

PMID: 28182281 [PubMed - indexed for MEDLINE]