Development and Validation of Algorithms to Identify Statin Intolerance in a US Administrative Database.

Value Health. 2016 Sep - Oct;19(6):852-860

Authors: Schulman KL, Lamerato LE, Dalal MR, Sung J, Jhaveri M, Koren A, Mallya UG, Foody JM

Abstract
OBJECTIVES: To develop and validate algorithms to define statin intolerance (SI) in an administrative database using electronic medical records (EMRs) as the reference comparison.
METHODS: One thousand adults with one or more qualifying changes in statin therapy and one or more previous diagnoses of hyperlipidemia, hypercholesterolemia, or mixed dyslipidemia were identified from the Henry Ford Health System administrative database. Data regarding statin utilization, comorbidities, and adverse effects were extracted from the administrative database and corresponding EMR. Patients were stratified by cardiovascular (CV) risk. SI was classified as absolute intolerance or titration intolerance on the basis of changes in statin utilization and/or the occurrence of adverse effects and laboratory testing for creatine kinase. Measures of concordance (Cohen's kappa [κ]) and accuracy (sensitivity, specificity, positive predictive value [PPV], and negative predictive value) were calculated for the administrative database algorithms.
RESULTS: Half of the sample population was white, 52.9% were women, mean age was 60.6 years, and 35.7% were at high CV risk. SI was identified in 11.5% and 14.0%, absolute intolerance in 2.2% and 3.1%, and titration intolerance in 9.7% and 11.8% of the patients in the EMR and the administrative database, respectively. The algorithm identifying any SI had substantial concordance (κ = 0.66) and good sensitivity (78.1%), but modest PPV (64.0%). The titration intolerance algorithm performed better (κ = 0.74; sensitivity 85.4%; PPV 70.1%) than the absolute intolerance algorithm (κ = 0.40; sensitivity 50%; PPV 35.5%) and performed best in the high CV-risk group (n = 353), with robust concordance (κ = 0.73) and good sensitivity (80.9%) and PPV (75.3%).
CONCLUSIONS: Conservative but comprehensive algorithms are available to identify SI in administrative databases for application in real-world research. These are the first validated algorithms for use in administrative databases available to decision makers.

PMID: 27712714 [PubMed - indexed for MEDLINE]

Measuring High-Risk Patients' Preferences for Pharmacogenetic Testing to Reduce Severe Adverse Drug Reaction: A Discrete Choice Experiment.

Value Health. 2016 Sep - Oct;19(6):767-775

Authors: Dong D, Ozdemir S, Mong Bee Y, Toh SA, Bilger M, Finkelstein E

Abstract
OBJECTIVES: To investigate patient preferences and willingness to pay (WTP) for a genetic test that can reduce the risk of life-threatening adverse drug reactions (ADRs). We hypothesize that test features (risk of developing the adverse reaction with and without testing, test cost, and treatment cost) and the choice context (physician recommendation and the most common choice made by peer patients) will influence choices.
METHODS: A discrete choice experiment was conducted in which 189 patients at high risk for gout were asked to choose between treatment options that varied along key attributes. A latent class logit model was used to analyze the choice data and test the hypotheses.
RESULTS: We identified two classes of patients: the risk-averse class and the cost-conscious class. The WTP to reduce the risk of life-threatening ADRs from 1 out of 600 to 1 out of 1 million was SGD1215 in the risk-averse class. In contrast, in the cost-conscious class, the WTP was insensitive to the extent of risk reduction. Overall, the predicted take-up rate for the test is 65% at a price of SGD400. If the test was recommended by a physician or was chosen by most of the patients, the take-up rate for the test would increase by 8.5 and 1.5 percentage points, respectively.
CONCLUSIONS: There is a potentially large demand for genetic tests that could reduce the risk of life-threatening ADRs. Physician recommendations and providing information on the choices of others are powerful influences on demand, even more so than moderate price reductions.

PMID: 27712704 [PubMed - indexed for MEDLINE]

Long-Acting Bronchodilator Initiation in COPD and the Risk of Adverse Cardiopulmonary Events: A Population-Based Comparative Safety Study.

Chest. 2017 Jan;151(1):60-67

Authors: Suissa S, Dell'Aniello S, Ernst P

Abstract
BACKGROUND: Long-acting bronchodilators, including long-acting beta2-agonists (LABA) and the anticholinergic tiotropium, are recommended as initial maintenance therapy in COPD. Studies to date have been limited in size and reported ambivalent results on the comparative risk of cardiovascular, cerebrovascular, and pulmonary adverse events between these two long-acting bronchodilators. Moreover, little information is available for the period when treatment is first initiated, a time when subjects may be especially at risk.
METHODS: We identified a cohort of new users of long-acting bronchodilators between 2002 and 2012, age 55 or older, from the United Kingdom's Clinical Practice Research Datalink. Patients initiating tiotropium were matched on high-dimensional propensity scores and prior inhaled corticosteroid use with patients initiating LABAs, and followed for 1 year for the occurrence of acute myocardial infarction, stroke, heart failure, arrhythmia, and pneumonia.
RESULTS: A total of 26,442 tiotropium initiators were matched to 26,442 LABA initiators, mainly single inhalers combined with inhaled corticosteroids. The hazard ratio of acute myocardial infarction associated with tiotropium initiation, relative to LABA initiation, was 1.10 (95% CI, 0.88-1.38), whereas for stroke it was 1.02 (95% CI, 0.78-1.34), for arrhythmia 0.81 (95% CI, 0.60-1.09), and heart failure 0.90 (95% CI, 0.79-1.02). The incidence of pneumonia was significantly less with tiotropium (hazard ratio, 0.81; 95% CI, 0.72-0.92).
CONCLUSION: COPD treatment initiation with tiotropium compared with LABA does not increase cardiovascular risk in the first year of treatment. The risk of pneumonia is higher with LABA, a likely effect of the inhaled corticosteroids present in many LABA inhalers used in real world clinical practice.

PMID: 27554300 [PubMed - indexed for MEDLINE]

A clustered randomized trial to IMProve treatment with AntiCoagulanTs in patients with Atrial Fibrillation (IMPACT-AF): design and rationale.

Am Heart J. 2016 Jun;176:107-13

Authors: Rao MP, Ciobanu AO, Lopes RD, Fox KA, Xian Y, Pokorney SD, Al-Khalidi HR, Jiang J, Kamath DY, Berwanger O, Xavier D, Bahit CM, Tajer C, Vinereanu D, Huo Y, Granger CB

Abstract
Atrial fibrillation (AF) is common, increasing as the population ages, and a major cause of embolic stroke. While oral anticoagulation (OAC) is highly effective at preventing stroke in patients with AF, it continues to be underused in eligible patients worldwide. The objective of this prospective, cluster randomized controlled trial (IMPACT-AF; ClinicalTrials.gov #NCT02082548) is to determine whether a comprehensive customized intervention will increase the rate and persistence of use of OAC in patients with AF. IMPACT-AF will be conducted in approximately 50 centers in 5 low- to middle-income countries. Before randomization, sites within countries will be paired to match in size, practice type and baseline rate of OAC use. Site pairs will be randomized to intervention versus control. In total, 40 to 70 patients with AF and at least 2 CHA2DS2-VASc risk factors will be enrolled at each site using a consecutive enrollment strategy, with the goal of capturing actual practice patterns. We aim for patients with a new diagnosis of AF to comprise at least 30% of the study cohort. Assuming an average baseline OAC use of 60% and a post-intervention use of 70% with a post-control rate of 60%, there will be roughly 94-98% power with 25 clusters per group (intracluster correlation coefficient of 0.02). While this trial focuses on improving treatment use and reducing preventable strokes, we also aim to better understand the reasons for OAC underuse. This will improve the intervention with the goal of creating educational recommendations to improve care for patients with AF.

PMID: 27264227 [PubMed - indexed for MEDLINE]

Protocol for analyses of adverse event data from randomized controlled trials of statin therapy.

Am Heart J. 2016 Jun;176:63-9

Authors: Cholesterol Treatment Trialists' (CTT) Collaboration

Abstract
The Cholesterol Treatment Trialists' (CTT) Collaboration was originally established to conduct individual participant data meta-analyses of major vascular events, cause-specific mortality, and site-specific cancers in large, long-term, randomized trials of statin therapy (and other cholesterol-modifying treatments). The results of the trials of statin therapy and their associated meta-analyses have shown that statins significantly reduce the risk of major vascular events without any increase in the risk of nonvascular causes of death or of site-specific cancer, but do produce small increases in the incidence of myopathy, diabetes, and, probably, hemorrhagic stroke. The CTT Collaboration has not previously sought data on other outcomes, and so a comprehensive meta-analysis of all adverse events recorded in each of the eligible trials has not been conducted. This protocol prospectively describes plans to extend the CTT meta-analysis data set so as to provide a more complete understanding of the nature and magnitude of any other effects of statin therapy.

PMID: 27264221 [PubMed - indexed for MEDLINE]

Extended duration dual antiplatelet therapy in patients with myocardial infarction: A study-level meta-analysis of controlled randomized trials.

Am Heart J. 2016 Jun;176:36-43

Authors: Patti G, Cavallari I

Abstract
BACKGROUND: Whether dual antiplatelet therapy (DAPT) is beneficial beyond 1 year after myocardial infarction (MI) is not demonstrated; in particular, available studies may be individually underpowered for end points at low incidence, that is, major and fatal bleeding or mortality. We thus assessed the effectiveness and safety of prolonged DAPT after MI over the long term.
METHODS: We conducted a systematic search to identify randomized trials on the topic; 3 studies and 21,534 post-MI patients receiving placebo or aspirin plus P2Y12 inhibition for ≥2 years were included. Incidence of the following outcome measures was evaluated: major adverse cardiac events (MACE), major bleeding, fatal bleeding, and cardiovascular and noncardiovascular death.
RESULTS: Occurrence of MACE was lower in patients treated with prolonged DAPT: 6.3% vs 7.9% in those without prolonged DAPT (odds ratios 0.74, 95% CI 0.60-0.91, P = .005); in the former, there was also a significant 16% reduction in cardiovascular mortality. Increase in major bleeding with extended duration DAPT was not significant in the overall analysis (1.5% vs 1.0%; P = .10), but became significant in the analysis restricted to patients receiving ticagrelor or prasugrel as second antiplatelet agent (odds ratios 2.16, 95% CI 1.63-2.86); prolonged use of DAPT did not raise rates of fatal bleeding or noncardiovascular mortality.
CONCLUSION: Prolonged DAPT after MI reduces MACE and cardiovascular mortality over the long term; this was paralleled by higher risk of nonfatal major bleeding mainly with the newer, more potent P2Y12 antagonists. Tailoring duration of DAPT after MI on the comparative evaluation of both ischemic and bleeding risk is mandatory in this setting.

PMID: 27264218 [PubMed - indexed for MEDLINE]

Evaluation of Anemia.

Obstet Gynecol Clin North Am. 2016 Jun;43(2):247-64

Authors: Kujovich JL

Abstract
Anemia is a common problem in primary care. Classification based on mean cell volume narrows the differential diagnosis and directs testing. A marked macrocytosis is characteristic of vitamin B12 and folate deficiencies, certain medications, and primary bone marrow disorders. The three most common causes of microcytic anemia are iron deficiency, thalassemia trait, and anemia of inflammation. Additional laboratory testing is required for diagnosis. Determination of the rate of development of anemia and examination of a blood smear may provide diagnostic clues to guide more specialized testing. Diagnosis of iron, vitamin B12, or folate deficiency mandates determination of the underlying cause.

PMID: 27212091 [PubMed - indexed for MEDLINE]

Safety and tolerability of high-dose ulinastatin after 2-hour intravenous infusion in adult healthy Chinese volunteers: A randomized, double-blind, placebo-controlled, ascending-dose study.

PLoS One. 2017;12(5):e0177425

Authors: Chen Q, Hu C, Liu Y, Liu Y, Wang W, Zheng H, Rong L, Jia J, Sun S, Yu C, Liu YM

Abstract
Ulinastatin, is a broad-spectrum protease inhibitor purified from human urine, inhibits endogenous proteases such as trypsin, α-chymotrypsin, hyaluronidase, and plasmin. It is widely being used at increasingly higher doses for the treatment of acute or chronic pancreatitis, severe infection, and acute organ failure. We aimed to evaluate the safety and tolerability of high-dose ulinastatin in healthy volunteers in our single center, randomized, double-blind, placebo-controlled, single-dose escalation study. Fifty-one healthy Chinese subjects were enrolled in 9 dose cohorts (3×105 U, 6×105 U, 12×105 U, 20×105 U, 30×105 U, 45×105 U, 60×105 U, 70×105 U, or 80×105 U of ulinastatin) and randomized to UTI or matching placebo (n = 1). Each dose cohort was composed of 3-7 subjects. All subjects were required to have 2 h of intravenous infusion. Safety and tolerability were assessed throughout the study via monitoring of vital signs, physical examinations, clinical laboratory tests, 12-lead electrocardiograms, and interviews with the subjects about adverse events. Fifty-one subjects (35 men and 16 women) completed the study. A total of 13 AEs were reported by 10 subjects: 11 adverse events in the ulinastatin groups and 2 adverse events in the placebo group. Twelve of the adverse events were possibly related to the study drug. The most common drug-related adverse events included dizziness, pain at injection site, and a decrease in white blood cell count. All adverse events were of mild severity; none were serious. In conclusion, 2 hours of intravenous infusion of ulinastatin (3×105 to 80×105 U) was well tolerated by healthy Chinese subjects.

PMID: 28493932 [PubMed - in process]

Effects of Low-Dose Recombinant Human Brain Natriuretic Peptide on Anterior Myocardial Infarction Complicated by Cardiogenic Shock.

Braz J Cardiovasc Surg. 2017 Mar-Apr;32(2):96-103

Authors: Pan Y, Lu Z, Hang J, Ma S, Ma J, Wei M

Abstract
INTRODUCTION:: The mortality due to cardiogenic shock complicating acute myocardial infarction (AMI) is high even in patients with early revascularization. Infusion of low dose recombinant human brain natriuretic peptide (rhBNP) at the time of AMI is well tolerated and could improve cardiac function.
OBJECTIVE:: The objective of this study was to evaluate the hemodynamic effects of rhBNP in AMI patients revascularized by emergency percutaneous coronary intervention (PCI) who developed cardiogenic shock.
METHODS:: A total of 48 patients with acute ST segment elevation myocardial infarction (STEMI) complicated by cardiogenic shock and whose hemodynamic status was improved following emergency PCI were enrolled. Patients were randomly assigned to rhBNP (n=25) and control (n=23) groups. In addition to standard therapy, study group individuals received rhBNP by continuous infusion at 0.005 µg kg-1 min-1 for 72 hours.
RESULTS:: Baseline characteristics, medications, and peak of cardiac troponin I (cTnI) were similar between both groups. rhBNP treatment resulted in consistently improved pulmonary capillary wedge pressure (PCWP) compared to the control group. Respectively, 7 and 9 patients died in experimental and control groups. No drug-related serious adverse events occurred in either group.
CONCLUSION:: When added to standard care in stable patients with cardiogenic shock complicating anterior STEMI, low dose rhBNP improves PCWP and is well tolerated.

PMID: 28492790 [PubMed - in process]

The Role of Amantadine Withdrawal in 3 Cases of Treatment-Refractory Altered Mental Status.

J Psychiatr Pract. 2017 May;23(3):191-199

Authors: Fryml LD, Williams KR, Pelic CG, Fox J, Sahlem G, Robert S, Revuelta GJ, Short EB

Abstract
Amantadine, which was originally developed as an antiviral medication, functions as a dopamine agonist in the central nervous system and consequently is utilized in the treatment of Parkinson disease, drug-induced extrapyramidal reactions, and neuroleptic malignant syndrome. For reasons that are not entirely understood, abrupt changes in amantadine dosage can produce a severe withdrawal syndrome. Existing medical literature describes case reports of amantadine withdrawal leading to delirium, which at times has progressed to neuroleptic malignant syndrome. Amantadine withdrawal may be under-recognized by mental health clinicians, which has the potential to lead to protracted hospital courses and suboptimal outcomes. The goal of this case series is to highlight the role of amantadine withdrawal in the cases of 3 medically complex patients with altered mental status. In the first case, the cognitive side effects of electroconvulsive therapy masked acute amantadine withdrawal in a 64-year-old man with Parkinson disease. In the second case, a 75-year-old depressed patient developed a catatonic delirium when amantadine was discontinued. Finally, a refractory case of neuroleptic malignant syndrome in a 57-year-old patient with schizoaffective disorder rapidly resolved with the reintroduction of outpatient amantadine. These cases highlight several learning objectives regarding amantadine withdrawal syndrome: First, it may be concealed by co-occurring causes of delirium in medically complex patients. Second, its symptoms are likely to be related to a cortical and limbic dopamine shortage, which may be reversed with electroconvulsive therapy or reintroduction of amantadine. Third, its clinical presentation may occur on a spectrum and may include features suggestive of delirium, catatonia, or neuroleptic malignant syndrome.

PMID: 28492457 [PubMed - in process]

Safety & tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma.

Blood. 2017 May 10;:

Authors: Zinzani PL, Ribrag V, Moskowitz CH, Michot JM, Kuruvilla J, Balakumaran A, Zhang Y, Chlosta S, Shipp MA, Armand P

Abstract
Treatment options for relapsed/refractory primary mediastinal large B-cell lymphoma (rrPMBCL) are limited and prognosis is generally poor (overall response rate [ORR] 0-25%; 2-year overall survival 15%). PMBCL frequently involves PD-1 ligand overexpression, potentially making PMBCL particularly susceptible to PD-1 blockade. We evaluated safety and antitumor activity of pembrolizumab, an anti-PD-1 antibody, in rrPMBCL as part of the KEYNOTE-013 multicohort Phase 1b trial. At time of data cutoff, 18 patients (median age 30; median 3 prior lines of therapy) had been enrolled and treated, of whom 17 were included in the efficacy analyses. Eleven patients (61%) experienced drug-related adverse events, mostly grade 1-2; none discontinued treatment due to adverse events. ORR was 41% (7/17); 6 additional patients (35%) had stable disease. Of patients evaluable by imaging, 13/16 (81%) had decreases in target lesions. With a median follow-up of 11.3 months, median duration of response was not reached. Two patients reached the maximum 2-year treatment duration and remain in remission. Median overall survival was not reached for treated patients overall; all responders were still alive at data cutoff. These results in heavily pretreated rrPMBCL patients demonstrate that PD-1 blockade with pembrolizumab has a manageable safety profile and promising antitumor activity. (Registered to www.clinicaltrials.gov as NCT01953692).

PMID: 28490569 [PubMed - as supplied by publisher]

A First-in-Human, Phase I, Dose-Escalation Study of TAK-117, a Selective PI3Kα Isoform Inhibitor, in Patients with Advanced Solid Malignancies.

Clin Cancer Res. 2017 May 10;:

Authors: Juric D, de Bono JS, LoRusso PM, Nemunaitis J, Heath EI, Kwak EL, Macarulla Mercadé T, Geuna E, Jose de Miguel-Luken M, Patel C, Kuida K, Sankoh S, Westin EH, Zohren F, Shou Y, Tabernero J

Abstract
Purpose: To evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of TAK-117 (MLN1117/INK1117), an investigational PI3K&alpha;-selective inhibitor, in patients with advanced solid tumors. <p>Experimental Design: Seventy-one patients received oral TAK-117 once daily (QD, 100-300 mg [n = 24]), or 3 days per week (Mon-Wed-Fri [MWF], 200-1200 mg [n = 27]; Mon-Tue-Wed [MTuW], 200-900 mg [n = 20]), in 21-day cycles. Dose escalation proceeded via a 3+3 design.</p> <p>Results: TAK-117 QD dosing was associated with dose-limiting grade ≥3 alanine/aspartate aminotransferase (ALT/AST) elevations, resulting in a narrow range of tolerable doses (100-150 mg QD). With MWF/MTuW dosing, no dose-limiting ALT/AST elevations occurred until the MTD of 900 mg; total weekly dose was 2.6-fold that of 150 mg QD. Drug-related grade ≥3 adverse events occurred in 25%/22%/35% (including hyperglycemia in 0%/7%/15%) of QD/MWF/MTuW patients. TAK-117 (100-1200 mg) exhibited moderately fast oral absorption, a generally dose-proportional increase in exposure, and plasma half-life of ~11 hours. Total weekly exposures with 900 mg MWF/MTuW dosing were ~four times greater than with 150 mg QD. Skin pS6 expression was suppressed at ≥200 mg. There were 3/1/0 partial responses (QD/MWF/MTuW) and 5/7/5 patients had stable disease lasting ≥3 months (all PIK3CA mutated).</p> <p>Conclusion: Intermittent dosing of TAK-117 had an acceptable safety profile and enabled higher doses and total weekly exposures versus QD dosing. While the potential for TAK-117 as single-agent therapy appears limited, further evaluation in combination approaches for advanced solid tumors is warranted.

PMID: 28490463 [PubMed - as supplied by publisher]

Is the Prophylactic Use of Hepatoprotectants Necessary in Anti-Tuberculosis Treatment?

Chemotherapy. 2017 May 11;62(5):269-278

Authors: Xu L, Zhang F, Xu C, Liu KG, Wu W, Tian YX

Abstract
BACKGROUND: Liver injury is one of the serious side effects of anti-tuberculosis (TB) drugs. It is controversial whether hepatoprotectant prophylaxis is efficient and safe in anti-TB treatment, so we aimed to assess the efficacy and safety of hepatoprotectant prophylaxis in patients who had received anti-TB treatment.
METHODS: PubMed, the Cochrane library, Embase, Ovid, Springer link, Wiley, Elsevier, Web of Science, and the Karger Online Journal were systematically searched prior to April 2016 for articles related to hepatoprotectant prophylaxis in the treatment of TB. A meta-analysis was conducted to estimate the effect of hepatoprotective agents on liver function and adverse events (AEs) in patients who had received anti-TB drugs. The primary outcomes were changes in alanine transaminase (ALT) and aspartate transaminase (AST) levels. The other outcomes were drug-induced liver injury (DILI) and AEs.
RESULTS: In our review, 6 trials that involved 1,227 patients were included. Our analysis indicated that hepatoprotective agents exerted protective effects on liver function in patients who had received anti-TB drugs (weighted mean difference, WMD = -7.81, 95% CI [-12.26, -3.37], p = 0.0006 [ALT]; WMD = -7.07, 95% CI [-11.43, -2.72], p = 0.001 [AST]) in any age group. However, in the subgroup analysis of treatment duration, the use of hepatoprotective agents was not associated with significant changes in ALT and AST levels after 2 weeks of treatment and exhibited a positive effect on liver function after 4 weeks of treatment. Moreover, the use of hepatoprotectants significantly decreased the number of DILI cases (risk ratio, RR 0.50, 95% CI [0.34-0.73], p = 0.0004). However, the use of hepatoprotectants led to similar AEs in the control groups (RR 1.07, 95% CI [0.82-1.39], p = 0.62).
CONCLUSIONS: The use of hepatoprotective drugs may prevent liver injury in patients who are receiving anti-TB drugs without any significant AEs 4 weeks after the initiation of hepatoprotective medication.

PMID: 28490012 [PubMed - as supplied by publisher]

Octreotide-Associated Neutropenia.

Pharmacotherapy. 2017 May 10;:

Authors: Tse SS, Kish T

Abstract
Drug-induced neutropenia and agranulocytosis are rare adverse events but can be fatal. Neutropenia can be induced by a myriad of drugs from almost every pharmacologic class. Octreotide is a somatostatin analogue that has been used to treat variceal bleeding, acromegaly, and severe diarrhea associated with metastatic tumors, and to reduce symptoms in the setting of malignant bowel obstruction and pseudo-obstruction. The most common adverse effects associated with octreotide include pain at the injection site and gastrointestinal effects such as loose stools, cramping, and nausea; neutropenia is not currently listed as an adverse effect of the drug. We describe the case of an 87-year-old man who developed neutropenia immediately after administration of one dose of subcutaneous octreotide. He presented to the hospital with a history of constipation and straining for 3 days. He was admitted, and laxatives, suppositories, and enemas were administered over the next 3 days to induce a bowel movement; however, they were ineffective. Bowel obstruction secondary to a mass was confirmed by computed tomography; the mass was eventually diagnosed as colon cancer. Octreotide 100 mcg subcutaneously every 8 hours was started for the obstruction on the evening of hospital day 4. After the patient had received three doses of octreotide, his white blood cell count (WBC) had decreased from 4.1 x 10(3) /mm(3) (neutrophils 75.4%, absolute neutrophil count [ANC] 3.1 x 10(3) /mm(3) ) on admission to 1.6 x 10(3) /mm(3) (neutrophils 62%, ANC 0.99 x 10(3) /mm(3) ) on day 5. Given the temporal relationship of octreotide and neutropenia as well as the lack of a reasonable alternative cause, it was suspected that octreotide was the most likely culprit of the patient's neutropenia. Octreotide was subsequently discontinued, and his WBC increased to 4.9 x 10(3) /mm(3) (neutrophils 66.3%, ANC 3.2 x 10(3) /mm(3) ) the next day. The remainder of the patient's hospitalization was not significant for any further hematologic abnormalities. His WBC and ANC (WBC 6.7 x 10(3) /mm(3) , neutrophils 83.2%, ANC 5.6 x 10(3) /mm(3) ) remained stable 30 days after the incident. Use of the Naranjo Adverse Drug Reaction Probability Scale indicated a probable relationship (score of 5) between the patient's development of neutropenia and octreotide therapy. To our knowledge, this report highlights the first case of octreotide-associated neutropenia. Although the frequency of drug-induced neutropenia remains rare outside of cytotoxic chemotherapy, the importance of recognizing this adverse effect cannot be understated given the mortality risks for neutropenic patients. This article is protected by copyright. All rights reserved.

PMID: 28488730 [PubMed - as supplied by publisher]

[Ventricular tachyarrhythmia as a side effect of pharmacotherapy].

Herzschrittmacherther Elektrophysiol. 2017 May 09;:

Authors: Demming T, Bonnemeier H

Abstract
Ventricular tachyarrhythmia is a severe and life-threatening potential side effect of pharmacotherapy. Substances with proarrhythmic potential belong to various groups of medication. Apart from antiarrhythmic agents, especially antibiotics and psychiatric drugs are worth mentioning owing to their broad application. Interaction with cardiac potassium channels is the most important reason for drug-induced ventricular tachyarrhythmia. Over 20 years of research in animal models and clinical studies have uncovered the underlying mechanisms. Findings in this field of research have also made a contribution to the understanding of genetic long QT syndromes. Clinical concerns that take drug interactions into account have been neglected due to the mechanistic research approach. For daily clinical practice, combination therapy of several potentially arrhythmogenic drugs is of predominant concern especially in situations when the therapeutic regime is changing such as admission to the hospital, admission to an intensive care unit or consultation of a new specialist. Especially in these situations, considerations about the arrhythmogenic potential of additionally administered drugs should be paid explicit attention. Additional concern should be paid to the fact that several proarrhythmogenic agents are metabolized over single pathways and are therefore prone to drug interactions that can severely raise the drug concentration and as a result arrhythmogenic potential.

PMID: 28488108 [PubMed - as supplied by publisher]

Signal Detection of Imipenem Compared to Other Drugs from Korea Adverse Event Reporting System Database.

Yonsei Med J. 2017 May;58(3):564-569

Authors: Park K, Soukavong M, Kim J, Kwon KE, Jin XM, Lee J, Yang BR, Park BJ

Abstract
PURPOSE: To detect signals of adverse drug events after imipenem treatment using the Korea Institute of Drug Safety & Risk Management-Korea adverse event reporting system database (KIDS-KD).
MATERIALS AND METHODS: We performed data mining using KIDS-KD, which was constructed using spontaneously reported adverse event (AE) reports between December 1988 and June 2014. We detected signals calculated the proportional reporting ratio, reporting odds ratio, and information component of imipenem. We defined a signal as any AE that satisfied all three indices. The signals were compared with drug labels of nine countries.
RESULTS: There were 807582 spontaneous AEs reports in the KIDS-KD. Among those, the number of antibiotics related AEs was 192510; 3382 reports were associated with imipenem. The most common imipenem-associated AE was the drug eruption; 353 times. We calculated the signal by comparing with all other antibiotics and drugs; 58 and 53 signals satisfied the three methods. We compared the drug labelling information of nine countries, including the USA, the UK, Japan, Italy, Switzerland, Germany, France, Canada, and South Korea, and discovered that the following signals were currently not included in drug labels: hypokalemia, cardiac arrest, cardiac failure, Parkinson's syndrome, myocardial infarction, and prostate enlargement. Hypokalemia was an additional signal compared with all other antibiotics, and the other signals were not different compared with all other antibiotics and all other drugs.
CONCLUSION: We detected new signals that were not listed on the drug labels of nine countries. However, further pharmacoepidemiologic research is needed to evaluate the causality of these signals.

PMID: 28332362 [PubMed - indexed for MEDLINE]

Influence of ABCB1 polymorphisms and serum concentrations on venlafaxine response in patients with major depressive disorder.

Nord J Psychiatry. 2017 Apr;71(3):230-237

Authors: Ozbey G, Celikel FC, Cumurcu BE, Kan D, Yucel B, Hasbek E, Percin F, Guzey IC, Uluoglu C

Abstract
BACKGROUND: The pharmacokinetics and the pharmacodynamics of antidepressants show large inter-individual variations which result in unpredictable clinical responses.
AIM: The aim of the study was to examine the effect of ABCB1 polymorphisms and the serum concentrations on the efficacy and tolerability of venlafaxine in patients with major depressive disorder (MDD).
METHODS: Fifty-two outpatients who met the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) criteria for MDD were recruited for the study. The severity of depression was assessed using the 17-item Hamilton Rating Scale for Depression scale (HDRS17) and tolerability was assessed based on a query regarding side-effects for 6 weeks. The ABCB1 C3435T/A and G2677T/A polymorphisms were genotyped by PCR/RFLP and steady-state serum venlafaxine concentrations were measured by high-performance liquid chromatography.
RESULTS: Patients with the TT genotype for the C3435T and the TT/TA genotype for the G2677T/A polymorphism showed significantly higher frequencies in venlafaxine-induced akathisia. This relationship was not observed for efficacy. As regards serum venlafaxine concentrations, patient groups showed no significant differences in efficacy and tolerability.
CONCLUSION: The results suggest that individuals with the TT-TT/TA genotypes for the C3435T-G2677T/A polymorphisms of ABCB1 may be pre-disposed to a risk of akathisia.

PMID: 28079463 [PubMed - indexed for MEDLINE]

The Relationship Between Early Haloperidol Response and Associated Extrapyramidal Side Effects.

J Clin Psychopharmacol. 2017 Feb;37(1):8-12

Authors: Rasmussen SA, Rosebush PI, Mazurek MF

Abstract
BACKGROUND: Early response to antipsychotic medication within 2 weeks of initiating treatment can predict psychiatric outcomes. However, it is unclear whether early response is also predictive of extrapyramidal side effects (EPSs) associated with antipsychotic medications.
METHODS: In this study, we investigated 136 consecutive antipsychotic-naive, first-episode psychosis patients naturalistically treated with haloperidol. Patients were assessed at baseline and weekly after treatment initiation using the Brief Psychiatric Rating Scale, Hamilton Depression Rating Scale, and Hamilton Anxiety Rating Scale. Dystonia, parkinsonism, akathisia, and dyskinesia were also assessed weekly using standardized rating scales. Regression analyses were used to determine whether early response at week 2 of treatment predicted the incidence of EPS at any point during hospitalization. A secondary analysis was conducted to determine whether early response continued to predict EPS in patients who experienced no EPS within the first 2 weeks of treatment.
RESULTS: The analyses demonstrated that greater Brief Psychiatric Rating Scale percent improvement at week 2 predicted a decreased risk of EPSs (P = 0.004), even in patients who did not show any EPSs within the first 2 weeks of treatment (P = 0.005). For specific EPS, early response predicted decreased incidences of parkinsonism (P = 0.028) and dyskinesia (P = 0.025), but not akathisia or dystonia. Hamilton Depression Rating Scale and Hamilton Anxiety Rating Scale improvement at week 2 did not predict EPSs. In addition, EPSs were not predicted by the maximum antipsychotic dose received during hospitalization.
CONCLUSIONS: These results indicate that early antipsychotic response is valuable not only for predicting psychiatric outcomes, but also for predicting the risk of EPSs.

PMID: 28027109 [PubMed - indexed for MEDLINE]

Adverse Effects of Electroconvulsive Therapy.

Psychiatr Clin North Am. 2016 09;39(3):513-30

Authors: Andrade C, Arumugham SS, Thirthalli J

Abstract
Electroconvulsive therapy (ECT) is an effective treatment commonly used for depression and other major psychiatric disorders. We discuss potential adverse effects (AEs) associated with ECT and strategies for their prevention and management. Common acute AEs include headache, nausea, myalgia, and confusion; these are self-limiting and are managed symptomatically. Serious but uncommon AEs include cardiovascular, pulmonary, and cerebrovascular events; these may be minimized with screening for risk factors and by physiologic monitoring. Although most cognitive AEs of ECT are short-lasting, troublesome retrograde amnesia may rarely persist. Modifications of and improvements in treatment techniques minimize cognitive and other AEs.

PMID: 27514303 [PubMed - indexed for MEDLINE]

Core Concepts Involving Adverse Psychotropic Drug Effects: Assessment, Implications, and Management.

Psychiatr Clin North Am. 2016 09;39(3):375-89

Authors: Goldberg JF, Ernst CL

Abstract
Adverse effects from psychiatric drugs can profoundly influence treatment adherence and outcomes. Good care involves addressing adverse effects no differently than any other component of treatment. Knowledge about adverse effect assessment and management fosters a proper context that helps clinicians not sacrifice a drug's potential therapeutic benefits because of greater concerns about its tolerability. This article provides an overview of basic concepts related to the assessment and management of suspected adverse effects from psychotropic drugs. Key points are discussed regarding clinical, pharmacogenetic, pharmacokinetic, and pharmacodynamic risk factors for treatment-emergent adverse effects, alongside recommendations for their systematic assessment.

PMID: 27514295 [PubMed - indexed for MEDLINE]