Does high-dose benzodiazepine abuse really produce liver toxicity? Results from a series of 201 benzodiazepine monoabusers.

Expert Opin Drug Saf. 2018 Apr 06;:1-6

Authors: Lugoboni F, Mirijello A, Morbioli L, Arzenton E, Leone R, Faccini M, Casari R, De Cosmo S, Gasbarrini A, Addolorato G

Abstract
BACKGROUND: Several side-effects related to prolonged benzodiazepines (BZD) use have been reported. Given the primary role of liver in BZD metabolism, toxicity related to prolonged high-dose BZD use could be conceivable. No data are available on the long-term impact of high-dose BZD use on liver.
RESEARCH DESIGN AND METHODS: A total of 201 BZD mono-abusers admitted to an Addiction Unit for detoxification were evaluated. Liver enzymes were evaluated at admission, before starting any treatment. An elevation of more than five times the upper limit of normal range (ULN) in serum ALT or conjugated bilirubin, or a combined elevation of AST, alkaline phosphatase and total bilirubin, one of which exceeding >2 the ULN, was considered diagnostic for drug-induced liver injury.
RESULTS: None of the evaluated subjects showed significant alterations of liver enzymes. Those with the highest transaminase levels were showing high body mass index. Twenty patients (10%) showed elevated gamma-glutamyl-transferase. No alteration of alkaline phosphatase, nor bilirubin was found in any patient. The average dosage of BZD was 307 mg of diazepam-equivalents for 7 years.
CONCLUSIONS: Present data suggest that prolonged use of high-dose BZD, although very dangerous for several reasons, does not seem to produce a significant drug-induced liver injury.

PMID: 29621907 [PubMed - as supplied by publisher]

Managing Cancer Pain in Older Adults.

Cancer J. 2017 Jul/Aug;23(4):242-245

Authors: Guerard EJ, Cleary JF

Abstract
Managing cancer pain in older adults can be complex and challenging. Understanding the unique needs of older patients with cancer is important to safe and effective pain management. The goals of this review are to discuss the assessment of older adults with cancer-related pain, treatment of cancer pain, and adverse effects or potential risks from treatment that are unique to older patients. A detailed pain assessment and when possible utilizing the geriatric assessment are vital to developing a cancer pain management plan. The geriatric assessment can help clinicians uncover problems not routinely assessed in the standard oncologic evaluation. Opioid pain medications are safe and effective for older adults with cancer pain as long as these medications are closely monitored and titrated slowly. In addition to the well-known adverse effects of opioid medications, clinicians need to be aware of the unique risks in older adults, which could include delirium, polypharmacy, and falls.

PMID: 28731948 [PubMed - indexed for MEDLINE]

The Impact of Polypharmacy on Patient Outcomes in Older Adults With Cancer.

Cancer J. 2017 Jul/Aug;23(4):211-218

Authors: Nightingale G, Skonecki E, Boparai MK

Abstract
Polypharmacy is prevalent in older adults with cancer and may be advantageous for the management of certain chronic disease states, but uncertainty exists regarding potential hazards and consequences. Cancer-related therapy adds to the prevalence of polypharmacy, which can lead to compromised cancer management plans (i.e., postoperative complications, treatment delays, and/or premature treatment discontinuation). Polypharmacy has been identified as one of the domains commonly included in the Comprehensive Geriatric Assessment likely because of the potential influence on health outcomes. This review summarizes existing evidence regarding health outcomes associated with polypharmacy in older adults with cancer. Preliminary evidence demonstrated that relationships exist between polypharmacy and health outcomes including adverse drug events, falls, frailty, hospitalization, postoperative complications, and mortality. This research is limited by study confounders, inconsistent definitions for polypharmacy, heterogeneous cancer types and stages, and the complex relationship between medication regimens and outcomes. Additional studies are needed to enhance the accuracy and replicability of this research.

PMID: 28731943 [PubMed - indexed for MEDLINE]

Points to Consider in Designing and Conducting Juvenile Toxicology Studies.

Int J Toxicol. 2017 Jul/Aug;36(4):325-339

Authors: Kim NN, Parker RM, Weinbauer GF, Remick AK, Steinbach T

Abstract
In support of a clinical trial in the pediatric population, available nonclinical and clinical data provide input on the study design and safety monitoring considerations. When the existing data are lacking to support the safety of the planned pediatric clinical trial, a juvenile animal toxicity study is likely required. Usually a single relevant species, preferably a rodent, is chosen as the species of choice, while a nonrodent species can be appropriate when scientifically justified. Juvenile toxicology studies, in general, are complicated both conceptually and logistically. Development in young animals is a continuous process with different organs maturing at different rates and time. Structural and functional maturational differences have been shown to affect drug safety. Key points to consider in conducting a juvenile toxicology study include a comparative development of the organ systems, differences in the pharmacokinetics/absorption, distribution, metabolism, excretion (PK/ADME) profiles of the drug between young animal and child, and logistical requirement in the juvenile study design. The purpose of this publication is to note pertinent points to consider when designing and conducting juvenile toxicology studies and to aid in future modifications and enhancements of these studies to enable a superior predictability of safety of medicines in the pediatric population.

PMID: 28466670 [PubMed - indexed for MEDLINE]

Minocycline hepatotoxicity: Clinical characterization and identification of HLA-B∗35:02 as a risk factor.

J Hepatol. 2017 Jul;67(1):137-144

Authors: Urban TJ, Nicoletti P, Chalasani N, Serrano J, Stolz A, Daly AK, Aithal GP, Dillon J, Navarro V, Odin J, Barnhart H, Ostrov D, Long N, Cirulli ET, Watkins PB, Fontana RJ, Drug-Induced Liver Injury Network (DILIN), Pharmacogenetics of Drug-Induced Liver Injury group (DILIGEN), International Serious Adverse Events Consortium (iSAEC)

Abstract
BACKGROUND & AIMS: Minocycline hepatotoxicity can present with prominent autoimmune features in previously healthy individuals. The aim of this study was to identify genetic determinants of minocycline drug-induced liver injury (DILI) in a well-phenotyped cohort of patients.
METHODS: Caucasian patients with minocycline DILI underwent genome-wide genotyping and were compared to unexposed population controls. Human leukocyte antigen (HLA) binding of minocycline was assessed using AutoDock Vina.
RESULTS: Among the 25 cases, 80% were female, median age was 19years and median latency from drug start to DILI onset was 318days. At presentation, 76% had acute hepatocellular liver injury, median ALT 1,077U/L (range: 63 to 2,333), median bilirubin 4.5mg/dl (range: 0.2 to 16.7), and 90% had a +ANA. During follow-up, 50% were treated with corticosteroids and no participants died or required a liver transplant. A significant association was noted between HLA-B∗35:02 and risk for minocycline DILI; a 16% carrier frequency in DILI cases compared to 0.6% in population controls (odds ratio: 29.6, 95% CI: 7.8-89.8, p=2.5×10-8). Verification of HLA-B∗35:02 imputation was confirmed by sequence-based HLA typing. HLA-B∗35:02 carriers had similar presenting features and outcomes compared to non-carriers. In silico modeling studies support the hypothesis that direct binding of minocycline to this novel HLA risk allele might be an important initiating event in minocycline DILI.
CONCLUSION: HLA-B∗35:02 is a rare HLA allele that was more frequently identified in the 25 minocycline DILI cases compared to population controls. If confirmed in other cohorts, this HLA allele may prove to be a useful diagnostic marker of minocycline DILI.
LAY SUMMARY: Development of liver injury following prolonged use of minocycline for acne is a rare but potentially severe form of drug-induced liver injury. Our study demonstrates that individuals who are HLA-B∗35:02 carriers are at increased risk of developing minocycline related liver injury. These results may help doctors more rapidly and confidently diagnose affected patients and possibly reduce the risk of liver injury in individuals receiving minocycline going forward.

PMID: 28323125 [PubMed - indexed for MEDLINE]

Proper Management of Medications to Limit Errors: What the Oral Surgeon Should Know to Limit Medication Errors and Adverse Drug Events.

Oral Maxillofac Surg Clin North Am. 2017 May;29(2):141-149

Authors: Sarasin DS, Mauer JE

Abstract
Providing safe and effective ambulatory anesthesia is a key component in delivering optimal care to oral and maxillofacial patients. Unfortunately, medication errors and adverse drug events (ADEs) occur in offices, as they do in hospital operating rooms. Preparing and delivering medication seems simple. In reality, this is a complex process with multiple opportunities for drug errors leading to actual or potential ADEs. This article reviews medication errors and ADEs, introduces a medication safety paradigm for oral and maxillofacial surgery facilities, and provides practical safety initiatives that can be implemented to achieve the goal of optimal anesthesia patient care and safety.

PMID: 28259386 [PubMed - indexed for MEDLINE]

Daikenchuto for reducing postoperative ileus in patients undergoing elective abdominal surgery.

Cochrane Database Syst Rev. 2018 Apr 05;4:CD012271

Authors: Hoshino N, Takada T, Hida K, Hasegawa S, Furukawa TA, Sakai Y

Abstract
BACKGROUND: Postoperative ileus is a major complication for persons undergoing abdominal surgery. Daikenchuto, a Japanese traditional medicine (Kampo), is a drug that may reduce postoperative ileus.
OBJECTIVES: To assess the efficacy and safety of Daikenchuto for reducing prolonged postoperative ileus in persons undergoing elective abdominal surgery.
SEARCH METHODS: We searched the following databases on 3 July 2017: CENTRAL, MEDLINE, Embase, ICHUSHI, WHO (World Health Organization) International Clinical Trials Registry Platform (ICTRP), EU Crinical Trials registry (EU-CTR), UMIN Clinical Trials Registry (UMIN-CTR), ClinicalTrials.gov, The Japan Society for Oriental Medicine (JSOM), American Society of Clinical Oncology (ASCO), Society of American Gastrointestinal and Endscopic Surgeons (SAGES). We set no limitations on language or date of publication.
SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing Daikenchuto with any control condition in adults, 18 years of age or older, undergoing elective abdominal surgery.
DATA COLLECTION AND ANALYSIS: We applied standard methodological procedures expected by Cochrane. Two review authors independently reviewed the articles identified by literature searches, extracted data, and assessed risk of bias of the included studies using the Cochrane software Review Manager 5.
MAIN RESULTS: We included seven RCTs with a total of 1202 participants. Overall, we judged the risk of bias as low in four studies and high in three studies. We are uncertain whether Daikenchuto reduced time to first flatus (mean difference (MD) -11.32 hours, 95% confidence interval (CI) -17.45 to -5.19; two RCTs, 83 participants; very low-quality evidence), or time to first bowel movement (MD -9.44 hours, 95% CI -22.22 to 3.35; four RCTs, 500 participants; very low-quality evidence) following surgery. There was little or no difference in time to resumption of regular solid food following surgery (MD 3.64 hours, 95% CI -24.45 to 31.74; two RCTs, 258 participants; low-quality evidence). There were no adverse events in either arm of the five RCTs that reported on drug-related adverse events (risk difference (RD) 0.00, 95% CI -0.02 to 0.02, 568 participants, low-quality evidence). We are uncertain of the effect of Daikenchuto on patient satisfaction (MD 0.09, 95% CI -0.19 to 0.37; one RCT, 81 participants; very low-quality of evidence). There was little or no difference in the incidence of any re-interventions for postoperative ileus before leaving hospital (risk ratio (RR) 0.99, 95% CI 0.06 to 15.62; one RCT, 207 participants; moderate-quality evidence), or length of hospital stay (MD -0.49 days, 95% CI -1.21 to 0.22; three RCTs, 292 participants; low-quality evidence).
AUTHORS' CONCLUSIONS: Evidence from current literature was unclear whether Daikenchuto reduced postoperative ileus in patients undergoing elective abdominal surgery, due to the small number of participants in the meta-analyses. Very low-quality evidence means we are uncertain whether Daikenchuto improved postoperative flatus or bowel movement. Further well-designed and adequately powered studies are needed to assess the efficacy of Daikenchuto.

PMID: 29619778 [PubMed - as supplied by publisher]

Type B adverse drug reactions reported by an immunoallergology department.

Pharm Pract (Granada). 2018 Jan-Mar;16(1):1070

Authors: Costa MJ, Herdeiro MT, Polónia JJ, Ribeiro-Vaz I, Botelho C, Castro E, Cernadas J

Abstract
Objective: Characterization of the adverse drug reactions (ADR) reported by the immunoallergology department (IAD), Centro Hospitalar de São João (Porto), to the Northern Pharmacovigilance Centre (NPC).
Methods: An observational, descriptive and retrospective study was conducted, based in a spontaneous report system. Participants were all the patients from the IAD, with suspected ADR, reported to NPC by specialists after the study was completed.
Results: Studied population had a median age of 41 years, with the predominance of the female gender (73.2%). Allergic rhinitis and asthma were the most frequent comorbidities. All studied ADR were type B, 89.6% were serious, 86.4% unexpected and 2.6% associated with drugs that presented less than 2 years in the market. The most represented drug classes were the non-steroidal anti-inflammatory drugs (NSAIDs) (52.6%) and antibiotics (25.2%). Skin symptoms represented 61.2% of the reported complaints. About 52.9% of these ADR occurred in less than one hour after intake. The most frequent ADR treatment at the time of the reaction was drug interruption (86.2%), followed by the prescription of anti-histamines (42.2%).
Conclusions: Reported ADR to NPC by the Drug Alert Unit were mainly serious, unexpected, associated with NSAIDs and antibiotics and related with marketing authorization medicines older than two years. These results could be very useful to develop strategies to prevent the clinical and economic consequences of ADR.

PMID: 29619134 [PubMed]

Cost-effectiveness of cladribine tablets, alemtuzumab and natalizumab in the treatment of relapsing-remitting multiple sclerosis with high disease activity in England.

J Med Econ. 2018 Apr 05;:1-23

Authors: Hettle R, Harty G, Wong SL

Abstract
AIMS: Cladribine tablets is the first oral short-course treatment approved for highly active relapsing multiple sclerosis (MS). The Association of British Neurologists guidelines currently recommend two infusion therapies, alemtuzumab and natalizumab, to treat high disease activity relapsing remitting MS (HDA-RRMS). This analysis assessed the cost-effectiveness of cladribine tablets in HDA-RRMS compared with alemtuzumab and natalizumab, from the perspective of the National Health Service (NHS) in England.
MATERIALS AND METHODS: A cohort-based Markov model with 11 health states (10 Expanded Disability Status Scale [EDSS] plus death) was developed. Transition matrices from the British Columbia registry were used to model the natural history of EDSS. Treatment effect on EDSS was modelled using hazard ratios for 6-month confirmed disability progression from an indirect treatment comparison (ITC). Relapses and drug-related adverse events were modelled via annualized relapse rates and event probabilities, with associated costs and quality-adjusted life year (QALY) losses. Utilities were derived from trials and the literature, and costs from NHS and literature sources. Uncertainty was assessed via probabilistic and deterministic sensitivity analyses.
RESULTS: Cladribine tablets was dominant (i.e., less costly and more effective) versus alemtuzumab and natalizumab in pairwise comparisons, and the dominant strategy in fully incremental analyses. Incremental cost was driven largely by drug acquisition and administration costs, and incremental QALY gain largely by differences in delayed EDSS progression. Cladribine tablets had a 93% probability of being cost-effective at a threshold of GBP 30,000 per QALY gained, and remained dominant across the scenario analyses tested. The greatest influence on results was the treatment effect on disability progression derived from the ITC.
LIMITATIONS: Uncertainty over the efficacy of DMT beyond trial durations. In line with other comparative effectiveness analyses, the network meta-analysis informing this cost-effectiveness analysis was associated with a degree of uncertainty. No treatment switching analyses were undertaken.
CONCLUSIONS: Cladribine tablets are a cost-effective alternative to alemtuzumab and natalizumab in the treatment of HDA-RRMS from the perspective of the NHS in England.

PMID: 29618273 [PubMed - as supplied by publisher]

Drug evaluation studies in neonates: how to overcome the current limitations.

Expert Rev Clin Pharmacol. 2018 Apr;11(4):387-396

Authors: Allegaert K, Smits A, van den Anker JN

Abstract
INTRODUCTION: Regulatory initiatives have stimulated drug research in infants, but the potential impact of drugs to improve health outcome in neonates remains underexplored. Areas covered: In this review, we focus on current limitations in drug evaluation studies and how to overcome these. The low volume of studies has additional weaknesses such as single center studies, non-commercial sponsorship, overrepresentation of high postulated risk reductions, and underrepresentation of therapeutic exploratory studies. Master protocols and selection criteria for neonatal centers to participate in studies are useful to improve logistics related to performance. Limitations also relate to inaccurate assessment of drug effects (efficacy/safety). This is because of poor symptom recognition, case definitions, and suboptimal data on adverse drug reactions (ADRs) epidemiology. To overcome these limitations, it is necessary to develop core outcome sets, reference values, and specific ADR tools. The limitations identified and approaches suggested to improve drug evaluation are illustrated using neonatal abstinence syndrome as an example. Expert commentary: We anticipate to see an evolving neonatal clinical pharmacology discipline driven by neonatal pathophysiology and knowledge. Multidisciplinary collaborative efforts between health care providers, academia, pharmaceutical industry, advocacy groups and regulatory agencies are crucial to improve the impact of drug evaluation studies in neonates.

PMID: 29421929 [PubMed - indexed for MEDLINE]

[The clinical analysis of frontline nilotinib vs imatinib therapies for newly diagnosed chronic myeloid leukemia in chronic phase].

Zhonghua Nei Ke Za Zhi. 2017 Nov 01;56(11):810-815

Authors: Yin H, Chen LF, Cui JK, Xiong YY, You Y, Zou P, Li WM

Abstract
Objective: To compare the clinical efficacy and safety of nilotinib and imatinib as frontline therapy in newly diagnosed patients with chronic myeloid leukemia in chronic phase(CML-CP). Methods: Until December 31st 2016, 18 patients using nilotinib and 83 using imatinib were recruited in our study. The efficacy and safety of two groups were evaluated. Results: A total of 101 patients with CML-CP included 18 receiving nilotinib and 83 imatinib. The optimal response rates at 3, 6, 12 and 18 months in nilotinib and imatinib group were 88.9% (16/18) vs 57.3% (47/82) (P=0.012), 82.4% (14/17) vs 55.7% (44/79) (P=0.041), 9/12 vs 63.9% (39/61) (P=0.460), 6/9 vs 68.9% (31/45) (P=0.896) respectively. The optimal response rates by 3 months in low sokal risk group on nilotinib and imatinib were 9/9 vs 76.5%(26/34) (P=0.107), in intermediate and high sokal risk group were 7/8 vs 45.2%(14/31) (P=0.032). At the end of follow-up, the rate of major molecular response (MMR) in nilotinib group was 72.2%, which was higher than 56.6% in imatinib group (P=0.021). The rate of complete cytogenetic response (CCyR) in nilotinib group was 100%, which was higher than 71.1% in imatinib group (P = 0.002). Progression free survival (PFS) rates in nilotinib and imatinib groups were 94.4% and 98.8% (P=0.019) respectively; whereas event free survival (EFS) rates were 88.9% and 48.2% (P=0.045). The incidence of drug related adverse reactions in nilotinib and imatinib was similar with only minor proportion of grade 3/4 adverse reactions. Conclusions: Nilotinib achieves a deeper molecular response in a shorter time than imatinib in newly diagnosed patients with CML-CP, especially in patients with high risk outcome. Good safety is obtained in both groups so as to ensure a long-term administration and improving prognosis.

PMID: 29136709 [PubMed - indexed for MEDLINE]

Potential Drug-Drug and Herb-Drug Interactions in Patients With Cancer: A Prospective Study of Medication Surveillance.

J Oncol Pract. 2017 Jul;13(7):e613-e622

Authors: Ramos-Esquivel A, Víquez-Jaikel Á, Fernández C

Abstract
PURPOSE: Patients with cancer frequently use herbal supplements and concomitant medications along with antineoplastic agents. These patients are at high risk of herb-drug interactions (HDIs) and drug-drug interactions (DDIs). We aimed to determine clinically relevant DDIs and HDIs leading to pharmaceutical intervention.
METHODS: Patients starting a new anticancer therapy were asked to complete a questionnaire to identify concomitant use of any over-the-counter drug or herbal supplement. Potential DDIs and HDIs were identified using two different databases. If a potentially clinically relevant DDI was recognized by the clinical pharmacist, a notification was sent to the prescribing oncologist, who decided whether to carry out a suggested intervention. Regression analyses were performed to identify variables associated with clinically relevant DDIs.
RESULTS: A total of 149 patients were included in this study, with 36 potentially clinically relevant DDIs identified in 26 patients (17.4%; 95% CI, 11.3% to 23.5%), all of them leading to therapy modifications. In total, four patients (2.7%; 95% CI, 0.1% to 5.3%) had experienced clinical consequences from DDIs at the time of pharmacist notification. Additionally, 84 patients (56.4%; 95% CI, 48.4% to 64.4%) reported using concurrent herbal supplements, and 122 possible HDIs were detected. Concomitant use of two or more drugs was independently associated with high risk of a clinically significant DDI (odds ratio, 2.53; 95% CI, 1.08 to 5.91; P = .03).
CONCLUSION: Potentially clinically relevant DDIs and possible HDIs were frequently detected in this prospective study. A multidisciplinary approach is required to identify and avoid potentially harmful combinations with anticancer therapy.

PMID: 28628392 [PubMed - indexed for MEDLINE]

Informativeness of patient initial reports of adverse drug reactions. Can it be improved by a pharmacovigilance centre?

Eur J Clin Pharmacol. 2017 Aug;73(8):1009-1018

Authors: Kheloufi F, Default A, Rouby F, Laugier-Castellan D, Boyer M, Rodrigues B, Ponte-Astoul J, Jean-Pastor MJ, Blin O, Micallef J

Abstract
PURPOSE: Little is known about the informativeness of initial patient reports before they are reviewed by a pharmacovigilance centre (PVC). We aim to describe the patterns of patient adverse drug reaction (ADR) reporting in France and estimate the contribution of a review by a PVC assessor on the informativeness of these reports.
METHODS: A retrospective study was conducted on patient reports between July 2011 and July 2015. Informativeness of 16 key elements of information (including drug start and end date, duration of treatment, time to onset and duration of the ADR, outcome, medical history and concomitant medication) was assessed in initial reports before and after review by a pharmacovigilance assessor.
RESULTS: Overall, 240 reports concerning 522 ADR and involving 278 drugs were reported over this 4-year period. Mean number of available key elements of information in initial reports was increased from 11/16 to 15/16 after review of reports by the PVC. Time to onset and duration of the ADR were respectively available in only 51 and 58% of the reports before review compared to 83 and 90% after review. Medical history and concomitant medication were missing in 75% of the initial reports compared to less than 30% of the reports after review. Contacting the reporter enabled an increase of informativeness of most elements of information for more than 90% of the reports.
CONCLUSION: Patient reports often need to be completed on key elements of information that are required to assess reports. Both upstream education of patients and downstream intervention of a pharmacovigilance assessor to complete missing information could help to enhance the informativeness of such reports.

PMID: 28391408 [PubMed - indexed for MEDLINE]

A case report of nifedipine-induced hepatitis with jaundice.

BMC Res Notes. 2018 Apr 03;11(1):228

Authors: Yusuf D, Christy J, Owen D, Ho M, Li D, Fishman MJ

Abstract
BACKGROUND: Nifedipine is a generic, well-known and commonly-prescribed dihydropyridine calcium channel blocker used in the treatment of hypertension and Prinzmetal's angina. A known but very rare and serious adverse effect of nifedipine is clinically-apparent hepatitis which can take months to resolve.
CASE PRESENTATION: Here we present a case of nifedipine-induced hepatitis in a 78-year-old Caucasian female with no prior history of liver or autoimmune disease. We discuss our investigative and management approach, and present a review of prior cases. We offer an approach for patients who present with signs of acute liver injury with jaundice and high elevations in serum transaminases.
CONCLUSION: Not much is known about nifedipine-induced hepatitis due to its rare occurrence. Its prevalence is unknown. The disease appears to afflict older men and women. It can present acutely (within days) or subacutely (within 4-8 weeks after medication start) and in an idiosyncratic manner. Chronic or latent cases have also been described, some diagnosed as late as 3 years after medication start. Common symptoms include jaundice, nausea, chills, rigors, diaphoresis, fatigue, and abdominal pain. Laboratory investigations often reveal profound elevations in AST, ALT, GGT, and conjugated bilirubin. Peripheral blood smear may demonstrate eosinophilia. Histology from liver biopsy typically demonstrates infiltration of immune cells, cholestasis, and a picture of steatohepatitis. Treatment involves immediate discontinuation of the drug with supportive care. Thus far, all published instances of nifedipine-induced hepatitis were self-limiting without mortality due to fulminant liver failure. However, this disease can take months to resolve. There is no randomized evidence for other treatments such as corticosteroids.

PMID: 29615102 [PubMed - in process]

Workers' medication as occupational risk at construction site with formworks.

Work. 2017;57(3):389-395

Authors: López-Arquillos A, Rubio-Romero JC, López-Arquillos C

Abstract
BACKGROUND: Accidents in the construction sector are a cause for concern. The influence of many different factors in construction accidents have been studied (age, company size, length of service, deviation, drugs or alcohol consumption, etc.) but the influence of medicinal substances in specific construction activities has not been evaluated until now.
OBJECTIVE: The aim of the research presented here is to identify the effect of different medicinal substances on the occupational risk levels of construction activities with formworks.
METHODS: An expert panel was selected in order to quantify the individual risk of each medication for each individual construction activity.
RESULTS: Results showed that narcotics, antipsychotics, and hypnotics had the highest risk values, and the use of cranes and cutting materials were considered the most dangerous activities for a medicated worker.
CONCLUSIONS: Data obtained in this research can help reduce the negative effects of the substances studied on the occupational safety of construction workers. A better knowledge of the risk levels according to the current capabilities of workers under the effects of medication is a powerful tool in planning safer construction activities.

PMID: 28800352 [PubMed - indexed for MEDLINE]

Epidemic Use of Benzodiazepines among Older Adults in Israel: Epidemiology and Leverage Points for Improvement.

J Gen Intern Med. 2017 Aug;32(8):891-899

Authors: Steinman MA, Low M, Balicer RD, Shadmi E

Abstract
BACKGROUND: Benzodiazepines and benzodiazepine-receptor agonists (BDZRAs, often known as "Z-drugs") are commonly used in older adults despite well-documented harms.
OBJECTIVE: To evaluate patterns of benzodiazepine and BDZRA use in Israel, focusing on potential leverage points where quality improvement initiatives might effectively curtail new use or the transition from intermittent to chronic use.
DESIGN AND PARTICIPANTS: We used national electronic medical data to assess a 10% random sample of adults receiving care in Clalit Health Services, which serves half of Israel's population. The sample included 267,221 adults, of whom 56,808 (21%) were age 65 and older.
MAIN MEASURES: Medication use from 2013 to 2015 was ascertained using pharmacy dispensing data.
RESULTS: In 2014, 7% of adults age 21-64 and 32% of adults age 65 and older received at least one benzodiazepine/BDZRA, including 49% of adults age 85 and older (P < 0.001). The majority of older users (59%) were long-term users of the drugs, and 21% of older adults who were short-term users in 2014 transitioned to medium- or long-term use in 2015. Older Arab Israelis were much less likely to receive benzodiazepine/BDZRAs than older Jewish Israelis (adjusted OR 0.28, 95% 0.25-0.31), but within each community there was no major variation in prescribing rates across clinics. Depression diagnosis was associated with particularly high rates of benzodiazepine/BDZRA use: 17% of older adults with depression received a benzodiazepine/BDZRA but no antidepressant, and 42% received both. Recent hospitalization increased the risk of new benzodiazepine/BDZRA use (adjusted OR 1.41, 95% CI 1.01-1.96), but the absolute risk increase was only 3%.
CONCLUSIONS: Benzodiazepines/BDZRAs are used at exceptionally high rates by older Israeli adults, especially the oldest old. Important leverage points for quality improvement efforts include curtailing the transition from short-term to long-term use, reducing use in older adults with depression, and identifying reasons that explain large differences in benzodiazepine/BDZRA prescribing between different ethnic groups.

PMID: 28470549 [PubMed - indexed for MEDLINE]

Multifaceted interventions for improving spontaneous reporting of adverse drug reactions in a general hospital in China.

BMC Pharmacol Toxicol. 2017 Jun 26;18(1):49

Authors: Fang H, Lin X, Zhang J, Hong Z, Sugiyama K, Nozaki T, Sameshima T, Kobayashi S, Namba H, Asakawa T

Abstract
BACKGROUND: The present study investigates changes in spontaneous reporting (SR) compliance and ADR patterns following adoption of a new hospital SR system, and multiple interventions designed for its improvement use under modified drug administration guidelines.
METHODS: In total, 1389 ADR cases were reviewed. Cases were divided into two groups, cases from period 1 (n = 557, from January 2006 to June 2011) under the old SR system and cases in period 2 (n = 832, from July 2011 to December 2016) under the new SR system with multiple interventions to improve physician SR compliance. General information, drug information, and clinical manifestations were investigated and compared between periods.
RESULTS: Interventions for improved clinician training, education on knowledge, attitudes, and practices (KAP), and economic incentives substantially improved SR adherence. We also found that changing drug usage patterns (based on the new drug administration guidelines) greatly influenced ADR occurrence and type.
CONCLUSIONS: We found the SR compliance can be improved by multifaceted interventions. Drug usage patterns also influence ADR occurrence, so programs tailored for rational use are essential. These results could lead to further improvements in the SR system for ADRs in China, and provide guidance for establishing better methods of pharmacovigilance.

PMID: 28651624 [PubMed - indexed for MEDLINE]

How do smoking cessation medicines compare with respect to their neuropsychiatric safety? A protocol for a systematic review, network meta-analysis and cost-effectiveness analysis.

BMJ Open. 2017 Jun 17;7(6):e015414

Authors: Thomas KH, Caldwell D, Dalili MN, Gunnell D, Munafò MR, Stevenson M, Welton NJ

Abstract
INTRODUCTION: Cigarette smoking is one of the leading causes of early death in the UK and worldwide. Public health guidance recommends the use of varenicline, bupropion and nicotine replacement therapy (NRT) as smoking cessation aids in the UK. Additionally, the first electronic cigarette has been licensed for use as a smoking cessation medicine. However, there are ongoing concerns about the safety of these medicines. We present a protocol for a systematic review and network meta-analysis (NMA) to determine how these smoking cessation medicines compare to each other with respect to their neuropsychiatric safety in adult smokers. Secondary aims include updating the evidence regarding the effectiveness and cardiovascular safety of these medicines for use in a cost-effectiveness analysis.
METHODS AND ANALYSIS: We will include randomised controlled trials and observational studies with control groups comparing monotherapy with varenicline, bupropion, NRT or electronic cigarette and combination therapies to each other, placebo or usual care. The primary composite safety outcome will be serious adverse events, defined as events that resulted in death, were life threatening, required hospitalisation or resulted in significant disability or congenital/birth defect. The preferred effectiveness outcome will be sustained smoking cessation defined as abstinence for a minimum of 6 months as determined by biochemical validation. We will include trials identified by previous reviews and search relevant databases for newly published trials as well as contacting study authors to identify unpublished information. We will conduct fixed-effect and random-effect meta-analyses for each pairwise comparison of treatments and outcome; where these estimates differ, we will consider reasons for heterogeneity, quantified using the between-study variance (τ2). For each outcome, we will construct a NMA in a Bayesian framework which will be compared with the pair-wise results, allowing us to rank treatments. The effectiveness estimates from the NMA will be entered into a probabilistic economic model.
ETHICS AND DISSEMINATION: Ethics approval is not required for this evidence synthesis study as it involves analysis of secondary data from randomised controlled trials and observational studies. The review will make an important contribution to the knowledge base around the effectiveness, safety and cost-effectiveness of smoking cessation medicines. Results will be disseminated to the general public, healthcare practitioners and clinicians, academics, industry and policy makers.
PROSPERO REGISTRATION NUMBER: CRD42016041302.

PMID: 28624760 [PubMed - indexed for MEDLINE]

Data-driven prediction of adverse drug reactions induced by drug-drug interactions.

BMC Pharmacol Toxicol. 2017 Jun 08;18(1):44

Authors: Liu R, AbdulHameed MDM, Kumar K, Yu X, Wallqvist A, Reifman J

Abstract
BACKGROUND: The expanded use of multiple drugs has increased the occurrence of adverse drug reactions (ADRs) induced by drug-drug interactions (DDIs). However, such reactions are typically not observed in clinical drug-development studies because most of them focus on single-drug therapies. ADR reporting systems collect information on adverse health effects caused by both single drugs and DDIs. A major challenge is to unambiguously identify the effects caused by DDIs and to attribute them to specific drug interactions. A computational method that provides prospective predictions of potential DDI-induced ADRs will help to identify and mitigate these adverse health effects.
METHOD: We hypothesize that drug-protein interactions can be used as independent variables in predicting ADRs. We constructed drug pair-protein interaction profiles for ~800 drugs using drug-protein interaction information in the public domain. We then constructed statistical models to score drug pairs for their potential to induce ADRs based on drug pair-protein interaction profiles.
RESULTS: We used extensive clinical database information to construct categorical prediction models for drug pairs that are likely to induce ADRs via synergistic DDIs and showed that model performance deteriorated only slightly, with a moderate amount of false positives and false negatives in the training samples, as evaluated by our cross-validation analysis. The cross validation calculations showed an average prediction accuracy of 89% across 1,096 ADR models that captured the deleterious effects of synergistic DDIs. Because the models rely on drug-protein interactions, we made predictions for pairwise combinations of 764 drugs that are currently on the market and for which drug-protein interaction information is available. These predictions are publicly accessible at http://avoid-db.bhsai.org . We used the predictive models to analyze broader aspects of DDI-induced ADRs, showing that ~10% of all combinations have the potential to induce ADRs via DDIs. This allowed us to identify potential DDI-induced ADRs not yet clinically reported. The ability of the models to quantify adverse effects between drug classes also suggests that we may be able to select drug combinations that minimize the risk of ADRs.
CONCLUSION: Almost all information on DDI-induced ADRs is generated after drug approval. This situation poses significant health risks for vulnerable patient populations with comorbidities. To help mitigate the risks, we developed a robust probabilistic approach to prospectively predict DDI-induced ADRs. Based on this approach, we developed prediction models for 1,096 ADRs and used them to predict the propensity of all pairwise combinations of nearly 800 drugs to be associated with these ADRs via DDIs. We made the predictions publicly available via internet access.

PMID: 28595649 [PubMed - indexed for MEDLINE]

Repeated "Day 1" FOB testing in ICH S7A safety assessment protocols: The influence of within- and between-session learning.

J Pharmacol Toxicol Methods. 2017 May - Jun;85:61-72

Authors: Gauvin DV, Zimmermann ZJ, Dalton JA, Baird TJ

Abstract
A large number of CNS safety assessment studies using the standard Functional Observational Battery (FOB) are conducted each year at Contract Research Organizations throughout the globe. Study design characteristics are as varied as the Sponsors for whom they are contracted. Gender inclusion, sample sizes, and timing of the FOBs are generally negotiated during protocol development. The ICH S7A guidelines describe a dose-effect study design for CNS safety assessment to be conducted prior to the first dose administration in man. Additionally, some Sponsors attempt to use the CNS safety FOB to establish both time- and dose-related acute behavioral effects of their compound in this single critical safety study. In this review, we highlight the confounding influences of multiple postdose FOBs (Day 1) versus the more standard, single FOB scheduled near systemic Cmax of the compound. Within- and between-session learning, combined with changes in vigilance/alertness/fatigue in both the animals and raters, can limit the generalizability of the FOB to accurately assess CNS effects under the current guidelines. Rationale is provided as to the tenuous nature of conducting simultaneous time- and dose-effect behavioral assessments as part of the core safety pharmacology programs.

PMID: 28216425 [PubMed - indexed for MEDLINE]