Tocilizumab in the treatment of patients with rheumatoid arthritis in real clinical practice: results of an Italian observational study.

Clin Exp Rheumatol. 2017 May 08;

Authors: Caporali R, Idolazzi L, Bombardieri S, Ferraccioli G, Gerli R, Govoni M, Matucci Cerinic M, Pomponio G, Salaffi F, Tirri R, Benaglio F, Bianchino L, Sarzi-Puttini P, TRUST study investigators.

Abstract
OBJECTIVES: To describe the effectiveness and safety of tocilizumab (TCZ), an interleukin-6 receptor inhibitor, in a cohort of patients with rheumatoid arthritis (RA) recruited in clinical practice.
METHODS: TRUST was an observational study in RA patients who started treatment with TCZ in the 6 months prior to site activation and were still on treatment at start of study; patients were followed up to 12 months after the first TCZ infusion.
RESULTS: 322 RA patients were enrolled in 59 Italian centres (mean age: 55.8 years; mean disease duration: 120.5 months; baseline DAS28: 5.3). After 6 months of TCZ treatment, patients achieving low disease activity (DAS28 ≤3.2; 57.52%) or disease remission (DAS28 <2.6; 38.05%) were 216 out of 226 patients with available DAS28 (p<0.001). No statistically significant differences were found in mean DAS28 and HAQ score changes from baseline (start of TCZ treatment) to study end between patients previously inadequately responding to disease-modifyinganti-rheumatic drugs (DMARD-IR) or to DMARDs plus tumour necrosis factor inhibitors (DMARD +TNFi-IR): both patient populations responded to TCZ. A statistically significant decrease in mean VAS Fatigue score (48.4 vs. 34.7; p=0.0025) at month 6 was observed. In patients treated with TCZ as monotherapy (32.61%), DAS28, VAS fatigue and HAQ scores decreased from baseline to any post-baseline time point. Overall, 62 patients (19.3%) prematurely discontinued TCZ treatment, 24 (7.5%) for safety reasons. Drug-related adverse events occurred in 92 patients (28.6%) (mostly 3 hypercholesterolaemia and leucopenia) and drug-related serious adverse events in 11 patients (3.4%).
CONCLUSIONS: This study confirms the good effectiveness and safety profile of TCZ in real life RA patient care.

PMID: 28516890 [PubMed - as supplied by publisher]

Topical non-steroidal anti-inflammatory drugs for analgesia in traumatic corneal abrasions.

Cochrane Database Syst Rev. 2017 May 18;5:CD009781

Authors: Wakai A, Lawrenson JG, Lawrenson AL, Wang Y, Brown MD, Quirke M, Ghandour O, McCormick R, Walsh CD, Amayem A, Lang E, Harrison N

Abstract
BACKGROUND: Traumatic corneal abrasions are relatively common and there is a lack of consensus about analgesia in their management. It is therefore important to document the clinical efficacy and safety profile of topical ophthalmic non-steroidal anti-inflammatory drugs (NSAIDs) in the management of traumatic corneal abrasions.
OBJECTIVES: To identify and evaluate all randomised controlled trials (RCTs) comparing the use of topical NSAIDs with placebo or any alternative analgesic interventions in adults with traumatic corneal abrasions (including corneal abrasions arising from foreign body removal), to reduce pain, and its effects on healing time.
SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2017, Issue 2), MEDLINE Ovid (1946 to 30 March 2017), Embase Ovid (1947 to 30 March 2017), LILACS (Latin American and Caribbean Health Sciences Literature Database) (1982 to 30 March 2017), OpenGrey (System for Information on Grey Literature in Europe) (www.opengrey.eu/); searched 30 March 2017, ZETOC (1993 to 30 March 2017), the ISRCTN registry (www.isrctn.com/editAdvancedSearch); searched 30 March 2017, ClinicalTrials.gov (www.clinicaltrials.gov); searched 30 March 2017 and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en); searched 30 March 2017. We did not use any date or language restrictions in the electronic searches for trials.We checked the reference lists of identified trials to search for further potentially relevant studies.
SELECTION CRITERIA: RCTs comparing topical NSAIDs to placebo or any alternative analgesic interventions in adults with traumatic corneal abrasions.
DATA COLLECTION AND ANALYSIS: Two review authors independently performed data extraction and assessed risks of bias in the included studies. We rated the certainty of the evidence using GRADE.
MAIN RESULTS: We included nine studies that met the inclusion criteria, reporting data on 637 participants.The studies took place in the UK, USA, Israel, Italy, France and Portugal. These studies compared five types of topical NSAIDs (0.1% indomethacin, 0.03% flurbiprofen, 0.5% ketorolac, 1% indomethacin, 0.1% diclofenac) to control (consisting of standard care and in four studies used placebo eye drops). Overall, the studies were at an unclear or high risk of bias (particularly selection and reporting bias). None of the included studies reported the primary outcome measures of this review, namely participant-reported pain intensity reduction of 30% or more or 50% or more at 24 hours. Four trials, that included data on 481 participants receiving NSAIDs or control (placebo/standard care), reported on the use of 'rescue' analgesia at 24 hours as a proxy measure of pain control. Topical NSAIDs were associated with a reduction in the need for oral analgesia compared with control (risk ratio (RR) 0.46, 95% confidence interval (CI) 0.34 to 0.61; low-certainty evidence). Approximately 4 out of 10 people in the control group used rescue analgesia at 24 hours. No data were available on the use of analgesia at 48 or 72 hours.One trial (28 participants) reported on the proportion of abrasions healed after 24 and 48 hours. These outcomes were similar in both arms of the trial. (at 24 hours RR 1.00 (0.81 to 1.23); at 48 hours RR 1.00 (0.88 to 1.14); low-certainty evidence). In the control group nine out of 10 abrasions were healed within 24 hours and all were healed by 48 hours. Complications of corneal abrasions were reported in 6 studies (609 participants) and were infrequently reported (4 complications, 1 in NSAID groups (recurrent corneal erosion) and 3 in control groups (2 recurrent corneal erosions and 1 corneal abscess), very low-certainty evidence). Possible drug-related adverse events (AEs) were reported in two trials (163 participants), with the number of adverse events low (4 AEs, 3 in NSAID group, including discomfort/photophobia on instillation, conjunctival hyperaemia and urticaria, and 1 in the control group, corneal abscess) very low-certainty evidence.
AUTHORS' CONCLUSIONS: The findings of the included studies do not provide strong evidence to support the use of topical NSAIDs in traumatic corneal abrasions. This is important, since NSAIDs are associated with a higher cost compared to oral analgesics. None of the trials addressed our primary outcome measure of participant-reported pain intensity reduction of 30% or more or 50% or more at 24 hours.

PMID: 28516471 [PubMed - as supplied by publisher]

Quantitative prediction of drug side effects based on drug-related features.

Interdiscip Sci. 2017 May 17;:

Authors: Niu Y, Zhang W

Abstract
MOTIVATION: Unexpected side effects of drugs are great concern in the drug development, and the identification of side effects is an important task. Recently, machine learning methods are proposed to predict the presence or absence of interested side effects for drugs, but it is difficult to make the accurate prediction for all of them.
METHODS: In this paper, we transform side effect profiles of drugs as their quantitative scores, by summing up their side effects with weights. The quantitative scores may measure the dangers of drugs, and thus help to compare the risk of different drugs. Here, we attempt to predict quantitative scores of drugs, namely the quantitative prediction. Specifically, we explore a variety of drug-related features and evaluate their discriminative powers for the quantitative prediction. Then, we consider several feature combination strategies (direct combination, average scoring ensemble combination) to integrate three informative features: chemical substructures, targets, and treatment indications. Finally, the average scoring ensemble model which produces the better performances is used as the final quantitative prediction model.
RESULTS: Since weights for side effects are empirical values, we randomly generate different weights in the simulation experiments. The experimental results show that the quantitative method is robust to different weights, and produces satisfying results. Although other state-of-the-art methods cannot make the quantitative prediction directly, the prediction results can be transformed as the quantitative scores. By indirect comparison, the proposed method produces much better results than benchmark methods in the quantitative prediction. In conclusion, the proposed method is promising for the quantitative prediction of side effects, which may work cooperatively with existing state-of-the-art methods to reveal dangers of drugs.

PMID: 28516319 [PubMed - as supplied by publisher]

The current state of adverse event reporting in hemophilia.

Expert Rev Hematol. 2017 Feb;10(2):161-168

Authors: van Vulpen LF, Saccullo G, Iorio A, Makris M

Abstract
INTRODUCTION: Replacement of the missing clotting factor is the mainstay of hemophilia treatment. Whilst historically many hemophilia patients were infected with blood-borne viruses transmitted via plasma-derived products, nowadays the formation of alloantibodies against the missing clotting factor is the main adverse event of treatment. Areas covered: This paper provides an overview of the current national and international adverse event reporting systems, what these surveillance schemes taught us about side effects of the products presently in use, and elaborates on how to adapt these systems to the challenges we face with the changing treatment landscape. Expert commentary: Treatment of inherited bleeding disorders was accompanied by severe complications in the past, resulting in major morbidity and mortality. Current products are much safer, but still require monitoring via efficient safety surveillance systems. Adverse events are reported in national and international systems. With many new products entering the market, as well as non-factor replacement therapies, new safety issues may arise. It is important to identify potential adverse events early by making surveillance systems suitable to pick up unknown or unexpected effects, and to recognize and communicate patterns of adverse events rapidly.

PMID: 28013565 [PubMed - indexed for MEDLINE]

Short-term open-label chamomile (Matricaria chamomilla L.) therapy of moderate to severe generalized anxiety disorder.

Phytomedicine. 2016 Dec 15;23(14):1699-1705

Authors: Keefe JR, Mao JJ, Soeller I, Li QS, Amsterdam JD

Abstract
BACKGROUND: Conventional drug treatments for Generalized Anxiety Disorder (GAD) are often accompanied by substantial side effects, dependence, and/or withdrawal syndrome. A prior controlled study of oral chamomile (Matricaria chamomilla L.) extract showed significant efficacy versus placebo, and suggested that chamomile may have anxiolytic activity for individuals with GAD.
HYPOTHESIS: We hypothesized that treatment with chamomile extract would result in a significant reduction in GAD severity ratings, and would be associated with a favorable adverse event and tolerability profile.
STUDY DESIGN: We report on the open-label phase of a two-phase randomized controlled trial of chamomile versus placebo for relapse-prevention of recurrent GAD.
METHODS: Subjects with moderate to severe GAD received open-label treatment with pharmaceutical-grade chamomile extract 1500mg/day for up to 8 weeks. Primary outcomes were the frequency of clinical response and change in GAD-7 symptom scores by week 8. Secondary outcomes included the change over time on the Hamilton Rating Scale for Anxiety, the Beck Anxiety Inventory, and the Psychological General Well Being Index. Frequency of treatment-emergent adverse events and premature treatment discontinuation were also examined.
RESULTS: Of 179 subjects, 58.1% (95% CI: 50.9% to 65.5%) met criteria for response, while 15.6% prematurely discontinued treatment. Significant improvement over time was also observed on the GAD-7 rating (β=-8.4 [95% CI=-9.1 to -7.7]). A similar proportion of subjects demonstrated statistically significant and clinically meaningful reductions in secondary outcome ratings of anxiety and well-being. Adverse events occurred in 11.7% of subjects, although no serious adverse events occurred.
CONCLUSION: Chamomile extract produced a clinically meaningful reduction in GAD symptoms over 8 weeks, with a response rate comparable to those observed during conventional anxiolytic drug therapy and a favorable adverse event profile. Future comparative effectiveness trials between chamomile and conventional drugs may help determine the optimal risk/benefit of these therapies for patients suffering from GAD.

PMID: 27912871 [PubMed - indexed for MEDLINE]

A Computer Prescribing Order Entry-Clinical Decision Support system designed for neonatal care: results of the 'preselected prescription' concept at the bedside.

J Clin Pharm Ther. 2017 Feb;42(1):64-68

Authors: Gouyon B, Iacobelli S, Saliba E, Quantin C, Pignolet A, Jacqz-Aigrain E, Gouyon JB

Abstract
WHAT IS KNOWN: The neonatal intensive care units (NICUs) are at the highest risk of drug dose error of all hospital wards. NICUs also have the most complicated prescription modalities. The computerization of the prescription process is currently recommended to decrease the risk of preventable adverse drug effects (pADEs) in NICUs. However, Computer Prescribing Order Entry-Clinical Decision Support (C.P.O.E./C.D.S.) systems have been poorly studied in NICUs, and their technical compatibility with neonatal specificities has been limited.
OBJECTIVES: We set up a performance study of the preselected prescription of drugs for neonates, which limited the role of the prescriber to choosing the drugs and their indications.
METHODS: A single 29 bed neonatal ward used this neonatal C.P.O.E./C.D.S. system for all prescriptions of all hospitalized newborns over an 18-month period. The preselected prescription of drugs was based on the indication, gestational age, body weight and post-natal age. The therapeutic protocols were provided by a formulary reference (330 drugs) that had been specifically designed for newborns. The preselected prescription also gave complete information about preparation and administration of drugs by nurses. The prescriber was allowed to modify the preselected prescription but alarms provided warning when the prescription was outside the recommended range. The main clinical characteristics and all items of each line of prescription were stored in a data warehouse, thus enabling this study to take place.
RESULTS: Seven hundred and sixty successive newborns (from 24 to 42 weeks' gestation) were prescribed 52 392 lines of prescription corresponding to 65 drugs; About 30·4% of neonates had at least one out of licensed prescription; A prescription out of the recommended range for daily dose was recorded for 1·0% of all drug prescriptions. WHAT IS NEW?: The C.P.O.E./C.D.S. systems can currently provide a complete preselected prescription in NICUs according to dose rules, which are specific to newborns and also comply with local specificities (therapeutic protocols and formulation of drugs). The role of the prescriber is limited to the choice of drugs and their indications. The prescriber still retains the possibility of modifying each item of the prescription, with all other prescription items being calculated by the C.P.O.E. system. In these conditions, the prescribers rarely modified the preselected prescription and the rate of out of range prescription was low. A multicentric study is required to confirm and extend these observations.
CONCLUSIONS: This study showed the feasibility of preselected prescription in NICUs and a low rate of out of range prescriptions. The preselected prescription could play a key role in lowering the dose error rate in NICUs.

PMID: 27882560 [PubMed - indexed for MEDLINE]

Prevalence of drug-related problems associated with direct oral anticoagulants in hospitalized patients: a multicenter, cross-sectional study.

J Clin Pharm Ther. 2017 Feb;42(1):58-63

Authors: Viprey M, Jeannin R, Piriou V, Chevalier P, Michel C, Aulagner G, Berthiller J, Armoiry X

Abstract
WHAT IS KNOWN AND OBJECTIVE: The complex dose regimens of the direct-acting oral anticoagulants (DOAC) make their appropriate prescribing highly challenging. Inappropriate prescribing of the DOAC remains poorly addressed. We studied the patterns of DOAC prescription and estimated the prevalence of drug-related problems (DRPs) associated with their use.
METHODS: A cross-sectional study was conducted using data from medical records system of the Lyon teaching hospitals. DRPs, identified among patients who received a DOAC, between 1 January 2010 and 31 July 2013, were categorized according to the Pharmaceutical Care Network Europe Classification System. The prevalence of hospital stays with a DRP was estimated, and a subgroup analysis according to DOAC and their indication for use was provided. Clinical outcomes were not assessed.
RESULTS: Of the 4154 hospital stays with at least one DOAC administration [3412 patients; median age (range): 71 years (14-98), 57% female], 70·8% were excluded from the analysis mainly due to missing information for renal function and/or patient weight. Of the 1188 hospital stays that were screened, 100 DRPs were identified (prevalence 8·4%; 95% CI, 6·8-10·0). The highest prevalence was found among patients who received rivaroxaban for atrial fibrillation (14·6%; 95% CI, 10·7-18·5). A too low drug dose was the most frequent DRP (n = 56; 4·7%), followed by a too high drug dose (n = 37; 3·1%), contraindication (n = 5; 0·4%), and pharmacokinetic problem requiring dose adjustment (n = 2; 0·2%).
WHAT IS NEW AND CONCLUSION: Drug-related problems associated with the DOACs occur quite commonly among hospitalized patients. Although these DRPs were considered to be of minor severity, prescribing protocols to support better prescribing should be disseminated to reduce the risk to patients. Renal function and body weight data should be mandatory on prescriptions to allow cross-checking.

PMID: 27778374 [PubMed - indexed for MEDLINE]

Safety and efficacy of outpatient parenteral antibiotic therapy in an academic infectious disease clinic.

J Clin Pharm Ther. 2017 Feb;42(1):39-43

Authors: Suleyman G, Kenney R, Zervos MJ, Weinmann A

Abstract
WHAT IS KNOWN AND OBJECTIVE: Outpatient parenteral therapy (OPAT) has become a safe and effective modality for patients requiring intravenous or prolonged antimicrobial therapy since the 1970s. It is being increasingly utilized in various settings; however, studies evaluating the safety and efficacy of clinic-based OPAT are limited. Since 2012, patients being considered for OPAT have required an infectious disease (ID) consultation at our institution. Candidates receiving once-daily antimicrobials who were ineligible for home infusion or nursing home placement as determined by their insurance companies and those who preferred the clinic over nursing home or home infusion were referred to the ID clinic. This study assessed the safety and outcome of patients receiving OPAT in an academic inner-city ID clinic in Detroit, Michigan.
METHODS: This was a retrospective cross-sectional study of electronic medical records of patients, identified through clinic records, who received at least 2 days of OPAT from December 2012 to December 2015. Demographics, types of infections, antimicrobial regimen used, adverse events and outcome were evaluated.
RESULTS: A total of 122 cases were identified during the study period. Mean age was 62 years with 55% male; 102 (84%) of 122 patients had peripherally inserted central catheter (PICC). Fifty-five per cent of patients participated in the clinic-based OPAT programme for insurance reasons, and 43% preferred the clinic over nursing home or home infusion. The most common infections were bone and joint (36%), followed by skin and soft tissue (18%) and urinary tract infections (12%). Ertapenem (44%) and daptomycin (41%) alone or in combination were used most frequently with 40% of patients receiving at least 4 weeks of treatment. Thirteen patients (11%) experienced one or more adverse drug events on daptomycin and/or ertapenem; of these, nine (69%) patients were receiving daptomycin monotherapy. Gastrointestinal symptoms (29%), cramping and myalgias (29%) and asymptomatic creatine phosphokinase (CPK) elevation (24%) were the most common adverse events. Three (3%) of 102 patients had PICC-related complications. Fourteen (88%) of 16 patients with adverse events or PICC-related complications required changing or stopping antibiotics; two (2%) had infection-related readmission. Conversely, 113 (93%) of 122 patients who completed treatment were considered cured and none had treatment failure at the end of 30 days of treatment. No patients died as a result of treatment or infection-related complications.
WHAT IS NEW AND CONCLUSION: Outpatient parenteral therapy in our academic ID clinic was a safe and effective alternative to home infusion or skilled nursing facilities for patients requiring long-term antibiotics with few adverse events and complications.

PMID: 27747899 [PubMed - indexed for MEDLINE]

Transporters affecting biochemical test results: Creatinine-drug interactions.

Clin Pharmacol Ther. 2016 Nov;100(5):437-440

Authors: Chu X, Bleasby K, Chan GH, Nunes I, Evers R

Abstract
Creatinine is eliminated by the kidneys through a combination of glomerular filtration and active transport. Drug-induced increases in serum creatinine (SCr) and/or reduced creatinine renal clearance are used as a marker for acute kidney injury. However, inhibition of active transport of creatinine can result in reversible and, therefore, benign increases in SCr levels. Herein, the transporters involved in creatinine clearance are discussed, in addition to limitations of using creatinine as a biomarker for kidney damage.

PMID: 27509262 [PubMed - indexed for MEDLINE]

Statin Intolerance: A Literature Review and Management Strategies.

Prog Cardiovasc Dis. 2016 Sep - Oct;59(2):153-164

Authors: Saxon DR, Eckel RH

Abstract
Statin intolerance is a commonly encountered clinical problem for which useful management strategies exist. Although many patients report statin-related muscle symptoms, studies indicate that the majority of these patients can tolerate a statin upon re-challenge. Alternative statin dosing strategies are an effective way to modify and reintroduce statin therapy for patients reporting adverse symptoms. Correction of vitamin D deficiency and hypothyroidism may improve statin tolerability in some patients. CoQ10 supplementation has been found to be of no benefit for statin-related muscle symptoms in most recent clinical trials. PCSK9 inhibitors are a new therapeutic option that if confirmed as safe and effective by outcomes trials may be of substantial benefit to select patients at high ASCVD risk who are unable to achieve adequate low-density lipoprotein cholesterol (LDL-C) lowering on maximally tolerated statin therapy. Other available medications to lower LDL-C in statin intolerant patients include ezetimibe, bile acid sequestrants, niacin, and fibrates.

PMID: 27497504 [PubMed - indexed for MEDLINE]

Successful Comparison of US Food and Drug Administration Sentinel Analysis Tools to Traditional Approaches in Quantifying a Known Drug-Adverse Event Association.

Clin Pharmacol Ther. 2016 Nov;100(5):558-564

Authors: Gagne JJ, Han X, Hennessy S, Leonard CE, Chrischilles EA, Carnahan RM, Wang SV, Fuller C, Iyer A, Katcoff H, Woodworth TS, Archdeacon P, Meyer TE, Schneeweiss S, Toh S

Abstract
The US Food and Drug Administration's Sentinel system has developed the capability to conduct active safety surveillance of marketed medical products in a large network of electronic healthcare databases. We assessed the extent to which the newly developed, semiautomated Sentinel Propensity Score Matching (PSM) tool could produce the same results as a customized protocol-driven assessment, which found an adjusted hazard ratio (HR) of 3.04 (95% confidence interval [CI], 2.81-3.27) comparing angioedema in patients initiating angiotensin-converting enzyme (ACE) inhibitors vs. beta-blockers. Using data from 13 Data Partners between 1 January 2008, and 30 September 2013, the PSM tool identified 2,211,215 eligible ACE inhibitor and 1,673,682 eligible beta-blocker initiators. The tool produced an HR of 3.14 (95% CI, 2.86-3.44). This comparison provides initial evidence that Sentinel analytic tools can produce findings similar to those produced by a highly customized protocol-driven assessment.

PMID: 27416001 [PubMed - indexed for MEDLINE]

Bivalirudin versus heparin in non-ST and ST-segment elevation myocardial infarction-a registry-based randomized clinical trial in the SWEDEHEART registry (the VALIDATE-SWEDEHEART trial).

Am Heart J. 2016 May;175:36-46

Authors: Erlinge D, Koul S, Eriksson P, Scherstén F, Omerovic E, Linder R, Östlund OP, Wallentin L, Fröbert O, James S

Abstract
BACKGROUND: The optimal anticoagulant for patients with acute coronary syndrome treated with percutaneous coronary intervention (PCI) has not been validated in current practice of radial approach and pretreatment with potent P2Y12 inhibitors. Several studies have indicated increased bleeding rate and, in some instances, even increased mortality by the routine use of heparin and glycoprotein IIb/IIIa inhibitors compared to bivalirudin. Direct comparison of bivalirudin versus heparin alone has yielded contradictory results depending on study designs.
METHODS/DESIGN: The VALIDATE-SWEDEHEART trial is a multicenter, prospective, randomized, registry-based, controlled, and open-label clinical trial in patients with ST-segment elevation myocardial infarction (STEMI) or non-STEMI undergoing PCI pretreated with ticagrelor, prasugrel, or cangrelor. We hypothesize that bivalirudin is superior to heparin alone in reducing death, myocardial infarction, and major bleeding events at 180 days (primary end point). The trial will enroll 3,000 patients with STEMI and 3,000 patients with non-STEMI undergoing PCI. The trial will use a hybrid registry-based randomized clinical trial design where inclusion, randomization, and baseline data collection are performed using The Swedish Web-system for Enhancement and Development of Evidence-based care in Heart disease Evaluated According to Recommended Therapies registry. The primary composite end point (death, myocardial infarction, or major bleeding events at 180 days) will be identified through active screening after 7 and 180 days and adjudicated by a blinded central end point committee. Secondary end points and long-term outcomes will be recorded from national registries.
CONCLUSION: The VALIDATE-SWEDEHEART trial is founded on a nationwide clinical registry and uses a hybrid registry-based randomized clinical trial (RRCT) design methodology to evaluate efficacy and safety of bivalirudin as compared to heparin alone for acute coronary syndrome, in a large population receiving contemporary recommended therapies including predominantly radial invasive approach and pretreatment with potent P2Y12 inhibitors.

PMID: 27179722 [PubMed - indexed for MEDLINE]

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Use of Epinephrine in Patients with Drug-Induced Anaphylaxis: An Analysis of the Beijing Pharmacovigilance Database.

Int Arch Allergy Immunol. 2017 May 16;173(1):51-60

Authors: Wang T, Ma X, Xing Y, Sun S, Zhang H, Stürmer T, Wang B, Li X, Tang H, Jiao L, Zhai S

Abstract
BACKGROUND: Few studies assessing the use of epinephrine in drug-induced anaphylaxis (DIA) in the hospital setting are available. We utilized the Beijing Pharmacovigilance Database (BPD) to evaluate the appropriateness of epinephrine for DIA management.
METHODS: DIA cases collected in the BPD from January 2004 to December 2014 were adjudicated and analyzed for demographics, causative drugs, clinical signs, outcomes, initial treatment, route, dosing, and cardiovascular adverse events (CAE) of epinephrine.
RESULTS: DIA was primarily caused by antibiotics (38.4%), radiocontrast agents (11.9%), traditional Chinese medicine injections (10.9%), and chemotherapeutic drugs (10.3%). Only 708 (59.5%) patients received epinephrine treatment. Patients who received epinephrine were more likely to experience wheezing (p < 0.001) and respiratory arrest (p < 0.001). Among 518 patients with a complete record of the epinephrine administration route, the percentage of patients receiving it by intramuscular (IM) injection, subcutaneous (SC) injection, intravenous (IV) bolus injection, or IV continuous infusion was 16.9, 31.5, 43.5, and 8.1%, respectively. Among the 427 patients with a record of both the administration route and the dosing, an overdose was more likely with IV bolus (94.1%) in contrast to IM injection (56.6%; p < 0.001) or SC injection (43.7%; p < 0.001). Among the patients analyzed for CAE (n = 349), 17 patients accounted for 19 CAE, and 13 (76.5%) of these patients were overdosed with epinephrine.
CONCLUSION: Underuse, inappropriate IV bolus use, and overdosing were the 3 major problems with epinephrine use in DIA in China. Educational training for health care professionals on the appropriate use of epinephrine in managing anaphylactic reactions is suggested.

PMID: 28505618 [PubMed - as supplied by publisher]

Olanzapine for chemotherapy-induced nausea and vomiting: systematic review and meta-analysis.

Pharm Pract (Granada). 2017 Jan-Mar;15(1):877

Authors: Chelkeba L, Gidey K, Mamo A, Yohannes B, Matso T, Melaku T

Abstract
BACKGROUND: Chemotherapy induced nausea and vomiting (CINV) remains the most distressing event in patients receiving highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC).
OBJECTIVE: Therefore, this meta-analysis was conducted to evaluate the efficacy of olanzapine containing regimen in preventing acute, delayed and overall phases of CINV.
METHODS: PubMed, EBSCO, and Cochrane central register of controlled trials electronic databases were searched to identify RCTs that compared the effects of olanzapine with non-olanzapine regimen in preventing CINV. Randomized clinical trials (RCTs) that compared olanzapine containing regimen with non-olanzapine regimen were included. The primary outcomes were the percentage of patients achieving no vomiting or no nausea in acute, delayed and overall phases.
RESULTS: 13 RCTs that enrolled 1686 participants were included in this meta-analysis. 852 patients were assigned to olanzapine and 834 patients were assigned to non-olanzapine regimen (other standard antiemetic regimen). The percentages of no emesis achieved were 87.5%, 76.2%, 73.6% in olanzapine versus 76.7%, 61.8%, and 56.4% in non-olanzapine regimen in acute, delayed and overall phases, respectively. The percentages of no nausea were 82%, 64.3%, 61.6% in olanzapine group versus 71.3%, 41.8%, and 40.6% in non-olanzapine group in acute, delayed and overall phases, respectively. In general, olanzapine containing regimen achieved statistical superiority to non-olanzapine regimen in no vomiting endpoint in acute phase (OR 2.16; 95%CI 1.60 to 2.91, p<0.00001; I-square=5%; p=0.40), delayed phase (OR 2.28; 95%CI 1.1.46 to 3.54, p=0.0003; I-square=65%; p=0.001) and overall phase (OR 2.48; 95%CI 1.59 to 3.86, p<0.0001; I-square=69%; p< 0.0001).
CONCLUSION: The current meta-analysis showed that olanzapine was statistically and clinically superior to non-olanzapine regimen in preventing CINV in most domains of the parameters.

PMID: 28503222 [PubMed - in process]

Collecting and Reporting Safety Data and Monitoring Trial Conduct In Pragmatic Trials.

J Clin Epidemiol. 2017 May 11;:

Authors: Irving E, van den Bor R, Welsing P, Walsh V, Alfonso-Cristancho R, Harvey C, Garman N, Grobbee DE, GetReal Work Package 3

Abstract
Pragmatic trials offer the opportunity to obtain real-life data on the relative effectiveness and safety of a treatment before or after market authorisation. This is the penultimate paper in a series of eight, describing the impact of design choices on the practical implementation of pragmatic trials. This paper focuses on the practical challenges of collecting and reporting safety data and of monitoring trial conduct while maintaining routine clinical care practice. Current ICH guidance recommends that, all serious adverse events (SAEs) and all drug-related events must be reported in an interventional trial. In line with current guidance, we propose a risk based approach to the collection of non-drug related non-serious AEs, and even serious events not related to treatment based on the risk profile of the medicine/class in the patient population of interest. Different options available to support the collection and reporting of safety data whilst minimizing study-related follow-up visits are discussed. A risk-based approach to monitoring trial conduct is also discussed, highlighting the difference in the balance of risks likely to occur in a pragmatic trial compared to traditional clinical trials, and the careful consideration that must be given to the mitigation and management of these risks in order to maintain routine care.

PMID: 28502812 [PubMed - as supplied by publisher]

Long-term seizure, quality of life, depression, and verbal memory outcomes in a controlled, mesial temporal lobe epilepsy surgical series using Portuguese-validated instruments.

World Neurosurg. 2017 May 11;:

Authors: Dias L, Angelis G, Teixeira W, Casulari L

Abstract
OBJECTIVE: We aimed to evaluate long-term surgical outcomes in patients treated for mesial temporal lobe epilepsy (MTLE) compared to a similar group of patients that underwent a preoperative evaluation.
METHODS: Patient interviews were conducted by an independent neuropsychologist and included a socio-demographic questionnaire and validated versions of the Beck Depression Inventory-II (BDI-II), Adverse Events Profile (AEP), Quality of Life in Epilepsy-31 (QOLIE-31), and Rey Auditory Verbal Learning Test (RAVLT).
RESULTS: Seventy-one patients who underwent surgery and 20 who underwent MTLE preoperative evaluations were interviewed. After an 81-month mean postoperative follow-up, 44% of the surgical patients achieved complete seizure relief according to Engel's classification and 68% according to ILAE's. The surgical group had a significantly lower prevalence of depression (p = 0.002) and drug-related adverse effects (p = 0.002). Improvement on unemployment (p = 0.02) was achieved but not on driving or education. Delayed verbal memory recall was impaired in 76% of the surgical and 65% of the control cases (p = 0.32). Regarding the QOLIE-31, the operated patients scored higher in their total score (M = 75.44 vs. M = 60.08, p < 0.001) and in all but the cognitive functioning domain irrespective of the follow-up length. Seizure control, Beck's depression score, and AEP severity explained 73% of the variance in the surgical group QOL.
CONCLUSION: Our study found that, while surgical treatment was effective, its impact on social indicators was modest. Moreover, the self-reported QOL relied not only on seizure control but also on depressive symptoms and AED burden.

PMID: 28502691 [PubMed - as supplied by publisher]

The standardized functional observational battery: Its intrinsic value remains in the instrument of measure: The rat.

J Pharmacol Toxicol Methods. 2016 Nov - Dec;82:90-108

Authors: Gauvin DV, Yoder JD, Holdsworth DL, Harter ML, May JR, Cotey N, Dalton JA, Baird TJ

Abstract
The International Conference on Harmonisation's (ICH) Tripartite Guideline on Safety Pharmacology Studies for Human Pharmaceuticals has adopted the requirement that each new test substance must be tested for effects on the central nervous system prior to "first dose in man". This assessment is required to measure, at a minimum, the effects of the substance on general motor activity, behavioral changes, coordination, sensory/motor reflex responses, and body temperatures. To achieve this goal, ICH S7A recommends a neurobehavioral assessment (usually a functional observational battery (FOB) or modified Irwin test), which is generally undertaken in the rat. There seems to be a growing lack of consensus on the value of the FOB to determine CNS safety. This review highlights the importance of the time, effort and cost of training technicians to familiarize with their instrument of measure, so that each observer is better able to identify and document very subtle changes in behavior that will serve to increase the reliability and validity of these assays with respect to CNS safety assessments.

PMID: 27534836 [PubMed - indexed for MEDLINE]

Safety and Tolerability of Intravenous Valproic Acid in Healthy Subjects: A Phase I Dose-Escalation Trial.

Clin Pharmacokinet. 2017 May 11;:

Authors: Georgoff PE, Nikolian VC, Bonham T, Pai MP, Tafatia C, Halaweish I, To K, Watcharotone K, Parameswaran A, Luo R, Sun D, Alam HB

Abstract
BACKGROUND: Valproic acid, a histone deacetylase inhibitor, has beneficial effects in the setting of cancer, neurologic diseases, and traumatic injuries. In animal models of traumatic injury, a single dose of valproic acid has been shown to reduce mortality. The purpose of this trial was to determine the maximum tolerated single dose of intravenous valproic acid in healthy humans.
METHODS: A double-blinded, placebo-controlled, dose-escalation trial design was used to identify dose-limiting toxicities in healthy subjects who received a single dose of intravenous valproic acid. Patients were monitored for adverse events and data were collected for pharmacokinetic, pharmacodynamic, and safety profiling of valproic acid.
RESULTS: Fifty-nine healthy subjects (mean 30 ± 12 years) were enrolled. Forty-four subjects received valproic acid in doses from 15 to 150 mg/kg. The most common adverse events were hypoacusis (n = 19), chills (n = 18), and headache (n = 16). The maximum tolerated dose was 140 mg/kg. Dose-limiting toxicities included headache and nausea lasting longer than 12 h. No drug-related abnormalities were seen in other safety measures including laboratory tests, hemodynamic parameters, cardiac rhythm monitoring, and cognitive testing. A two-compartment model was predictive of valproic acid concentration-time profiles, with a strong correlation (R (2) = 0.56) observed between the number of reported adverse events and the dose level.
CONCLUSIONS: The maximum tolerated dose of intravenous valproic acid in healthy subjects is 140 mg/kg. This is significantly higher than the previously established maximum tolerated dose of 60-75 mg/kg. Next, the safety and tolerability of high-dose valproic acid will be tested in trauma patients in hemorrhagic shock. ClinicalTrials.gov Identifier: NCT01951560.

PMID: 28497259 [PubMed - as supplied by publisher]

Unusual side effect from a luteinizing hormone-releasing hormone agonist, leuprorelin, in the treatment of prostate cancer: a case report.

J Med Case Rep. 2016 Nov 11;10(1):323

Authors: Chang JI, Bucci J

Abstract
BACKGROUND: The treatment options for high-risk prostate cancer are either radical prostatectomy or radiotherapy/brachytherapy depending on the patients' prognosis. In older men with multiple comorbidities, radiotherapy with androgen deprivation therapy is an attractive option. Common side effects of androgen deprivation therapy include hot flushes, tiredness, increased risk of fractures, increased risk of metabolic disorders, coronary heart disease, and psychological effects. This case highlights the potential side effect of lipodystrophy secondary to leuprolide acetate injections. To the best of our knowledge, this is the first reported case of such an instance.
CASE PRESENTATION: In this case report, we describe a 70-year-old white man with prostate-specific antigen of 1.8 ng/mL, clinical stage T2bN0M0, Gleason 4+5=9 prostate cancer who developed an unusual side effect from leuprolide acetate as part of his androgen deprivation therapy. Approximately 2 months after the initial 3-monthly injection of leuprolide acetate (Eligard 22.5 mg) our patient developed abnormal lipid deposition particularly in his deltoid and abdominal region. His upper limb mobility gradually became compromised due to the size of these abnormal fat depositions. He had liposuction to correct this lipodystrophy and had a good functional outcome and cosmesis from the procedure.
CONCLUSIONS: To the best of our knowledge, this is the first reported case of lipodystrophy secondary to leuprolide acetate injections. Leuprolide acetate in commonly used as one of the gonadotrophin-releasing hormone agonists and thus we should be mindful of the potential effect of producing lipodystrophy, especially in patients with cirrhosis, and to watch for any signs and symptoms as appropriate. The implication of this potential side effect poses difficult management strategies for such patients, and second-line alternatives such as chemotherapy may need to be considered.

PMID: 27836000 [PubMed - indexed for MEDLINE]