Incidence and Clinical Associations of Childhood Acute Pancreatitis.

Pediatrics. 2016 Sep;138(3):

Authors: Majbar AA, Cusick E, Johnson P, Lynn RM, Hunt LP, Shield JP

Abstract
OBJECTIVES: To establish the UK incidence and clinical associations of acute pancreatitis (AP) in children aged 0 to 14 years.
METHODS: Monthly surveillance of new cases of AP in children under 15 years of age through the British Pediatric Surveillance Unit conducted from April 2013 to April 2014 (inclusive) followed by 1-year administrative follow-up for all valid cases.
RESULTS: Ninety-four cases (48 boys) fulfilled the diagnostic criteria. The median age at diagnosis was 11.2 years (range 1.3-14.9). White children accounted for 61% of the cases compared with 28% from Asian and 5% from African ethnicities. Pakistani children accounted for 18 of 26 (69%) Asian patients and 19% of the total cohort. The incidence of AP in children in the United Kingdom was 0.78 per 100 000/year (95% confidence interval [CI] 0.62-0.96). The incidence in Pakistani children (4.55; 95% CI 2.60-7.39) was sevenfold greater than white children (0.63; 95% CI 0.47-0.83). Of the 94 cases, 35 (37%) were idiopathic; other associations were: drug therapy, 18 (19%); gallstones, 12 (13%); hereditary, 7 (7%); organic acidemias, 7 (7%); anatomic anomalies, 5 (5%); viral infections, 3 (3%); systemic diseases, 2 (2%); and trauma 1 (1%). The most common drug associations were asparaginase (28%), azathioprine (17%), and sodium valproate (17%).
CONCLUSIONS: Although still relatively uncommon in the United Kingdom, on average there is >1 case of childhood AP diagnosed every week. The associations of AP have changed significantly since the 1970-80s. Overrepresentation of Pakistani children is worthy of further investigation.

PMID: 27535145 [PubMed - indexed for MEDLINE]

Endomorphin analog analgesics with reduced abuse liability, respiratory depression, motor impairment, tolerance, and glial activation relative to morphine.

Neuropharmacology. 2016 Jun;105:215-27

Authors: Zadina JE, Nilges MR, Morgenweck J, Zhang X, Hackler L, Fasold MB

Abstract
Opioids acting at the mu opioid receptor (MOR) are the most effective analgesics, however adverse side effects severely limit their use. Of particular importance, abuse liability results in major medical, societal, and economic problems, respiratory depression is the cause of fatal overdoses, and tolerance complicates treatment and increases the risk of side effects. Motor and cognitive impairment are especially problematic for older adults. Despite the host of negative side effects, opioids such as morphine are commonly used for acute and chronic pain conditions. Separation of analgesia from unwanted effects has long been an unmet goal of opioid research. Novel MOR agonist structures may prove critical for greater success. Here we tested metabolically stable analogs of the endomorphins, endogenous opioids highly selective for the MOR. Compared to morphine, the analogs showed dramatically improved analgesia-to-side-effect ratios. At doses providing equal or greater antinociception than morphine in the rat, the analogs showed reduced a) respiratory depression, b) impairment of motor coordination, c) tolerance and hyperalgesia, d) glial p38/CGRP/P2X7 receptor signaling, and e) reward/abuse potential in both conditioned place preference and self-administration tests. Differential effects on glial activation indicate a mechanism for the relative lack of side effects by the analogs compared to morphine. The results suggest that endomorphin analogs described here could provide gold standard pain relief mediated by selective MOR activation, but with remarkably safer side effect profiles compared to opioids like morphine.

PMID: 26748051 [PubMed - indexed for MEDLINE]

Phase I dose-escalation study of the c-Met tyrosine kinase inhibitor SAR125844 in Asian patients with advanced solid tumors, including patients with MET-amplified gastric cancer.

Oncotarget. 2017 Jun 16;:

Authors: Shitara K, Kim TM, Yokota T, Goto M, Satoh T, Ahn JH, Kim HS, Assadourian S, Gomez C, Harnois M, Hamauchi S, Kudo T, Doi T, Bang YJ

Abstract
SAR125844 is a potent and selective inhibitor of the c-Met kinase receptor. This was an open-label, phase I, multicenter, dose-escalation, and dose-expansion trial of SAR125844 in Asian patients with solid tumors, a subgroup of whom had gastric cancer and MET amplification (NCT01657214). SAR125844 was administered by intravenous infusion (260-570 mg/m2) on days 1, 8, 15, and 22 of each 28-day cycle. Objectives were to determine the maximum tolerated dose (MTD) and to evaluate SAR125844 safety and pharmacokinetic profile. Antitumor activity was also assessed. Of 38 patients enrolled (median age 64.0 years), 22 had gastric cancer, including 14 with MET amplification. In the dose-escalation cohort (N = 19; unselected population, including three patients with MET-amplification [two with gastric cancer and one with lung cancer]), the MTD was not reached, and the recommended dose was established at 570 mg/m2. Most frequent treatment-emergent adverse events (AEs) were nausea (36.8%), vomiting (34.2%), decreased appetite (28.9%), and fatigue or asthenia, constipation, and abdominal pains (each 21.1%); none appeared to be dose-dependent. Grade ≥ 3 AEs were observed in 39.5% of patients and considered drug-related in 7.9%. SAR125844 exposure increased slightly more than expected by dose proportionality; dose had no significant effect on clearance. No objective responses were observed in the dose-escalation cohort, with seven patients (three gastric cancer, two colorectal cancer, one breast cancer, and one with cancer of unknown primary origin) having stable disease. Modest antitumor activity was observed at 570 mg/m2 in the dose-expansion cohort, comprising patients with MET-amplified tumors (N = 19). Two gastric cancer patients had partial responses, seven patients had stable disease (six gastric cancer and one kidney cancer), and 10 patients had progressive disease. Single-agent SAR125844 administered up to 570 mg/m2 has acceptable tolerability and modest antitumor activity in patients with MET-amplified gastric cancer.

PMID: 28636538 [PubMed - as supplied by publisher]

Sorafenib in Japanese Patients With Locally Advanced or Metastatic Medullary Thyroid Carcinoma and Anaplastic Thyroid Carcinoma.

Thyroid. 2017 Jun 21;:

Authors: Ito Y, Onoda N, Ito KI, Sugitani I, Takahashi S, Yamaguchi I, Kabu K, Tsukada K

Abstract
BACKGROUND: Therapeutic options for treating advanced or metastatic medullary thyroid carcinoma (MTC) and anaplastic thyroid carcinoma (ATC) are still limited in Japan even though vandetanib for MTC, and lenvatinib for MTC and ATC have been approved. Sorafenib is an oral multikinase inhibitor approved for the treatment of patients with radioactive iodine-refractory (RAI-R) differentiated thyroid cancer (DTC). We conducted an uncontrolled, open-label, multicenter, single-arm, phase 2 clinical study to evaluate the safety and efficacy of sorafenib in Japanese patients with MTC and ATC.
METHODS: Japanese patients with histologically confirmed ATC and locally advanced or metastatic MTC were enrolled from April to September 2014. The primary endpoint was to evaluate the safety of sorafenib. Treatment efficacy variables including progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and maximum reduction in tumor size were evaluated as secondary endpoints. Patients received sorafenib 400 mg orally twice daily on a continuous basis and then continued treatment until the occurrence of disease progression, unacceptable toxicity, or withdrawal of consent.
RESULTS: A total of 20 patients were screened and 18, including 8 with MTC and 10 with ATC, were enrolled. The most common drug-related adverse events were palmar-plantar erythrodysesthesia (72%), alopecia (56%), hypertension (56%), and diarrhea (44%). In the ATC patients, median PFS was 2.8 months (95% CI, 0.7-5.6), and median OS was 5.0 months (95% CI, 0.7-5.7); ORR and DCR were 0% and 40%, respectively. In the MTC population, neither median PFS nor OS had been reached at the time of this analysis; ORR was 25% and DCR was 75%.
CONCLUSIONS: The toxicities reported in this study were consistent with the known safety profile of sorafenib. Sorafenib seems to be effective in the treatment of advanced MTC but not ATC and could be a new treatment option for locally advanced or metastatic MTC and RAI-R DTC.

PMID: 28635560 [PubMed - as supplied by publisher]

No blank slates: Pre-existing schemas about pharmaceuticals predict memory for side effects.

Psychol Health. 2017 Apr;32(4):402-421

Authors: Heller MK, Chapman SC, Horne R

Abstract
OBJECTIVES: Attribution of symptoms as medication side effects is informed by pre-existing beliefs about medicines and perceptions of personal sensitivity to their effects (pharmaceutical schemas). We tested whether (1) pharmaceutical schemas were associated with memory (recall/recognition) for side effect information (2) memory explained the attribution of a common unrelated symptom as a side effect.
DESIGN: In this analogue study participants saw the patient leaflet of a fictitious asthma drug listing eight side effects.
MAIN OUTCOME MEASURES: We measured recall and recognition memory for side effects and used a vignette to test whether participants attributed an unlisted common symptom (headache) as a side effect.
RESULTS: Participants who perceived pharmaceuticals as more harmful in general recalled fewer side effects correctly (rCorrect Recall = -.273), were less able to differentiate between listed and unlisted side effects (rRecognition Sensitivity = -.256) and were more likely to attribute the unlisted headache symptom as a side effect (rside effect attribution = .381, ps < .01). The effect of harm beliefs on side effect attribution was partially mediated by correct recall of side effects.
CONCLUSION: Pharmaceutical schemas are associated with memory for side effect information. Memory may explain part of the association between pharmaceutical schemas and the attribution of unrelated symptoms as side effects.

PMID: 28219295 [PubMed - indexed for MEDLINE]

A Study of Acute Poisoning Cases Admitted to the University Hospital Emergency Department in Tabriz, Iran.

Drug Res (Stuttg). 2017 Mar;67(3):183-188

Authors: Oraie M, Hosseini MJ, Islambulchilar M, Hosseini SH, Ahadi-Barzoki M, Sadr H, Yaghoubi H

Abstract
Chemical substances have an important threat due to extensive use in medicine, agriculture, industry and environment. In this retrospective study, etiological and demographic characteristics of acute poisoning cases admitted to a hospital in Iran were investigated. We compared these data with those reported from other parts of the country and the international experiences to evaluate any difference if exists. 7 052 poisoned cases admitted to the hospital from April 2006 to March 2013, by data collected from the medical record in poison center section. According to our results there is a predominance of male patients and the majority of the poisoned patients were between 20-30 years old. Drug poisoning was the most common cause of poisonings. The most frequently involved drugs were benzodiazepines and antidepressants. The seasonal distribution of our study showed a peak in summer. To prevent acute poisonings, the social education about the risk assessment of central nervous system-acting drugs and reduction of the exposure period of people to pesticides are recommended. This study suggested a proper educational program for the public and primary care units. Our results provide useful information for preventive strategies.

PMID: 28073114 [PubMed - indexed for MEDLINE]

Disclosure of Adverse Events in Pediatrics.

Pediatrics. 2016 Dec;138(6):

Authors: COMMITTEE ON MEDICAL LIABILITY AND RISK MANAGEMENT, COUNCIL ON QUALITY IMPROVEMENT AND PATIENT SAFETY

Abstract
Despite increasing attention to issues of patient safety, preventable adverse events (AEs) continue to occur, causing direct and consequential injuries to patients, families, and health care providers. Pediatricians generally agree that there is an ethical obligation to inform patients and families about preventable AEs and medical errors. Nonetheless, barriers, such as fear of liability, interfere with disclosure regarding preventable AEs. Changes to the legal system, improved communications skills, and carefully developed disclosure policies and programs can improve the quality and frequency of appropriate AE disclosure communications.

PMID: 27940747 [PubMed - indexed for MEDLINE]

Systematic Review and Meta-Analysis of Randomised Trials to Ascertain Fatal Gastrointestinal Bleeding Events Attributable to Preventive Low-Dose Aspirin: No Evidence of Increased Risk.

PLoS One. 2016;11(11):e0166166

Authors: Elwood PC, Morgan G, Galante J, Chia JW, Dolwani S, Graziano JM, Kelson M, Lanas A, Longley M, Phillips CJ, Pickering J, Roberts SE, Soon SS, Steward W, Morris D, Weightman AL

Abstract
BACKGROUND: Aspirin has been shown to lower the incidence and the mortality of vascular disease and cancer but its wider adoption appears to be seriously impeded by concerns about gastrointestinal (GI) bleeding. Unlike heart attacks, stroke and cancer, GI bleeding is an acute event, usually followed by complete recovery. We propose therefore that a more appropriate evaluation of the risk-benefit balance would be based on fatal adverse events, rather than on the incidence of bleeding. We therefore present a literature search and meta-analysis to ascertain fatal events attributable to low-dose aspirin.
METHODS: In a systematic literature review we identified reports of randomised controlled trials of aspirin in which both total GI bleeding events and bleeds that led to death had been reported. Principal investigators of studies in which fatal events had not been adequately described were contacted via email and asked for further details. A meta-analyses was then performed to estimate the risk of fatal gastrointestinal bleeding attributable to low-dose aspirin.
RESULTS: Eleven randomised trials were identified in the literature search. In these the relative risk (RR) of 'major' incident GI bleeding in subjects who had been randomised to low-dose aspirin was 1.55 (95% CI 1.33, 1.83), and the risk of a bleed attributable to aspirin being fatal was 0.45 (95% CI 0.25, 0.80). In all the subjects randomised to aspirin, compared with those randomised not to receive aspirin, there was no significant increase in the risk of a fatal bleed (RR 0.77; 95% CI 0.41, 1.43).
CONCLUSIONS: The majority of the adverse events caused by aspirin are GI bleeds, and there appears to be no valid evidence that the overall frequency of fatal GI bleeds is increased by aspirin. The substantive risk for prophylactic aspirin is therefore cerebral haemorrhage which can be fatal or severely disabling, with an estimated risk of one death and one disabling stroke for every 1,000 people taking aspirin for ten years. These adverse effects of aspirin should be weighed against the reductions in vascular disease and cancer.

PMID: 27846246 [PubMed - indexed for MEDLINE]

Eliciting the child's voice in adverse event reporting in oncology trials: Cognitive interview findings from the Pediatric Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events initiative.

Pediatr Blood Cancer. 2017 Mar;64(3):

Authors: Reeve BB, McFatrich M, Pinheiro LC, Weaver MS, Sung L, Withycombe JS, Baker JN, Mack JW, Waldron MK, Gibson D, Tomlinson D, Freyer DR, Mowbray C, Jacobs S, Palma D, Martens CE, Gold SH, Jackson KD, Hinds PS

Abstract
BACKGROUND: Adverse event (AE) reporting in oncology trials is required, but current practice does not directly integrate the child's voice. The Pediatric Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) is being developed to assess symptomatic AEs via child/adolescent self-report or proxy-report. This qualitative study evaluates the child's/adolescent's understanding and ability to provide valid responses to the PRO-CTCAE to inform questionnaire refinements and confirm content validity.
PROCEDURE: From seven pediatric research hospitals, children/adolescents ages 7-15 years who were diagnosed with cancer and receiving treatment were eligible, along with their parent-proxies. The Pediatric PRO-CTCAE includes 130 questions that assess 62 symptomatic AEs capturing symptom frequency, severity, interference, or presence. Cognitive interviews with retrospective probing were completed with children in the age groups of 7-8, 9-12, and 13-15 years. The children/adolescents and proxies were interviewed independently.
RESULTS: Two rounds of interviews involved 81 children and adolescents and 74 parent-proxies. Fifteen of the 62 AE terms were revised after Round 1, including refinements to the questions assessing symptom severity. Most participants rated the PRO-CTCAE AE items as "very easy" or "somewhat easy" and were able to read, understand, and provide valid responses to questions. A few AE items assessing rare events were challenging to understand.
CONCLUSIONS: The Pediatric and Proxy PRO-CTCAE performed well among children and adolescents and their proxies, supporting its content validity. Data from PRO-CTCAE may improve symptomatic AE reporting in clinical trials and enhance the quality of care that children receive.

PMID: 27650708 [PubMed - indexed for MEDLINE]

Effect-enhancing and toxicity-reducing activity of usnic acid in ascitic tumor-bearing mice treated with bleomycin.

Int Immunopharmacol. 2017 May;46:146-155

Authors: Su ZQ, Liu YH, Guo HZ, Sun CY, Xie JH, Li YC, Chen JN, Lai XP, Su ZR, Chen HM

Abstract
Usnic acid (UA) can be found in certain lichen species. Growing evidence suggests that UA possesses antitumoral, antioxidative and anti-inflammatory activities. Bleomycin (BLM) is widely used in the treatment of malignant ascites, however, it unexpectedly causes pulmonary fibrosis (PF). Researches show that excessive inflammatory response and oxidative stress in lung tissue is conspicuous causes of BLM-induced PF. Here we investigated mechanism underlying the effect-enhancing and toxicity-reducing activity of UA on H22-bearing mice treated with BLM. UA combined with BLM was significantly more effective than BLM alone in inhibiting the tumor growth, arresting the cell cycle at G0/G1 phase, and promoting the cleaved caspase-3 and cleaved caspase-8 activities to induce cancer cellular apoptosis. The mechanism may be associated with the transcriptional regulation of p53/p21/Cyclin pathway. Furthermore, UA effectively moderated the histopathological changes, reduced the content of MDA, HYP, TNF-α, IL-1β, IL-6 and TGF-β1, and increased the level of SOD when combined with BLM in lung tissues of H22-bearing mice, which was believed to be related to the inhibition on the protein level of p-Smad2/3 and enhancement of Smad7 expression. These findings suggested that UA might be a potential effect-enhancing and toxicity-reducing candidate for BLM in the treatment of malignant ascites.

PMID: 28284148 [PubMed - indexed for MEDLINE]

Off-Label Prescribing and Polypharmacy: Minimizing the Risks.

J Psychosoc Nurs Ment Health Serv. 2017 Feb 01;55(2):17-22

Authors: Leahy LG

Abstract
Off-label prescribing and polypharmacy are commonplace in today's health care environment. Patients are treated with multiple medications obtained through multiple providers, and all too frequently, there is no collaboration amongst professionals. Nurses can address these issues by educating themselves and their patients regarding medication indications and uses, side effects, risks, and benefits. By exploring a patient's medication reconciliation, including over-the-counter agents, and identifying the U.S. Food and Drug Administration-approved indications, as well as potential off-label uses and overlapping side effects of the medications prescribed, nurses can facilitate collaboration among prescribers to reduce polypharmacy, minimize medication side effects, and alleviate drug-drug interactions, while improving patient outcomes and quality of life. [Journal of Psychosocial Nursing and Mental Health Services, 55(2), 17-22.].

PMID: 28218925 [PubMed - indexed for MEDLINE]

Supporting clinical rules engine in the adjustment of medication (SCREAM): protocol of a multicentre, prospective, randomised study.

BMC Geriatr. 2017 Jan 26;17(1):35

Authors: Mestres Gonzalvo C, de Wit HA, van Oijen BP, Hurkens KP, Janknegt R, Schols JM, Mulder WJ, Verhey FR, Winkens B, van der Kuy PM

Abstract
BACKGROUND: In the nursing home population, it is estimated that 1 in every 3 patients is polymedicated and given their considerable frailty, these patients are especially prone to adverse drug reactions. Clinical pharmacist-led medication reviews are considered successful interventions to improve medication safety in the inpatient setting. Due to the limited available evidence concerning the benefits of medication reviews performed in the nursing home setting, we propose a study aiming to demonstrate a positive effect that a clinical decision support system, as a health care intervention, may have on the target population. The primary objective of this study is to reduce the number of patients with at least one event when using the clinical decision support system compared to the regular care. These events consist of hospital referrals, delirium, falls, and/or deaths.
METHOD/DESIGN: This study is a multicentre, prospective, randomised study with a cluster group design. The randomisation will be per main nursing home physician and stratified per ward (somatic and psychogeriatric). In the intervention group the clinical decision support system will be used to screen medication list, laboratory values and medical history in order to obtain potential clinical relevant remarks. The remarks will be sent to the main physician and feedback will be provided whether the advice was followed or not. In the control group regular care will be applied.
DISCUSSION: We strongly believe that by using a clinical decision support system, medication reviews are performed in a standardised way which leads to comparable results between patients. In addition, using a clinical decision support system eliminates the time factor to perform medication reviews as the major problems related to medication, laboratory values, indications and/or established patient characteristics will be directly available. In this way, and in order to make the medication review process complete, consultation within healthcare professionals and/or the patient itself will be time effective and the medication surveillance could be performed around the clock.
TRIAL REGISTRATION: The Netherlands National Trial Register NTR5165 . Registered 2nd April 2015.

PMID: 28125977 [PubMed - indexed for MEDLINE]

Evolution After Anti-TNF Discontinuation in Patients With Inflammatory Bowel Disease: A Multicenter Long-Term Follow-Up Study.

Am J Gastroenterol. 2017 Jan;112(1):120-131

Authors: Casanova MJ, Chaparro M, García-Sánchez V, Nantes O, Leo E, Rojas-Feria M, Jauregui-Amezaga A, García-López S, Huguet JM, Arguelles-Arias F, Aicart M, Marín-Jiménez I, Gómez-García M, Muñoz F, Esteve M, Bujanda L, Cortés X, Tosca J, Pineda JR, Mañosa M, Llaó J, Guardiola J, Pérez-Martínez I, Muñoz C, González-Lama Y, Hinojosa J, Vázquez JM, Martinez-Montiel MP, Rodríguez GE, Pajares R, García-Sepulcre MF, Hernández-Martínez A, Pérez-Calle JL, Beltrán B, Busquets D, Ramos L, Bermejo F, Barrio J, Barreiro-de Acosta M, Roncedo O, Calvet X, Hervías D, Gomollón F, Domínguez-Antonaya M, Alcaín G, Sicilia B, Dueñas C, Gutiérrez A, Lorente-Poyatos R, Domínguez M, Khorrami S, Muñoz C, Taxonera C, Rodríguez-Pérez A, Ponferrada A, Van Domselaar M, Arias-Rivera ML, Merino O, Castro E, Marrero JM, Martín-Arranz M, Botella B, Fernández-Salazar L, Monfort D, Opio V, García-Herola A, Menacho M, Ramírez-de la Piscina P, Ceballos D, Almela P, Navarro-Llavat M, Robles-Alonso V, Vega-López AB, Moraleja I, Novella MT, Castaño-Milla C, Sánchez-Torres A, Benítez JM, Rodríguez C, Castro L, Garrido E, Domènech E, García-Planella E, Gisbert JP

Abstract
OBJECTIVES: The aims of this study were to assess the risk of relapse after discontinuation of anti-tumor necrosis factor (anti-TNF) drugs in patients with inflammatory bowel disease (IBD), to identify the factors associated with relapse, and to evaluate the overcome after retreatment with the same anti-TNF in those who relapsed.
METHODS: This was a retrospective, observational, multicenter study. IBD patients who had been treated with anti-TNFs and in whom these drugs were discontinued after clinical remission was achieved were included.
RESULTS: A total of 1,055 patients were included. The incidence rate of relapse was 19% and 17% per patient-year in Crohn's disease and ulcerative colitis patients, respectively. In both Crohn's disease and ulcerative colitis patients in deep remission, the incidence rate of relapse was 19% per patient-year. The treatment with adalimumab vs. infliximab (hazard ratio (HR)=1.29; 95% confidence interval (CI)=1.01-1.66), elective discontinuation of anti-TNFs (HR=1.90; 95% CI=1.07-3.37) or discontinuation because of adverse events (HR=2.33; 95% CI=1.27-2.02) vs. a top-down strategy, colonic localization (HR=1.51; 95% CI=1.13-2.02) vs. ileal, and stricturing behavior (HR=1.5; 95% CI=1.09-2.05) vs. inflammatory were associated with a higher risk of relapse in Crohn's disease patients, whereas treatment with immunomodulators after discontinuation (HR=0.67; 95% CI=0.51-0.87) and age (HR=0.98; 95% CI=0.97-0.99) were protective factors. None of the factors were predictive in ulcerative colitis patients. Retreatment of relapse with the same anti-TNF was effective (80% responded) and safe.
CONCLUSIONS: The incidence rate of inflammatory bowel disease relapse after anti-TNF discontinuation is relevant. Some predictive factors of relapse after anti-TNF withdrawal have been identified. Retreatment with the same anti-TNF drug was effective and safe.

PMID: 27958281 [PubMed - indexed for MEDLINE]

Drug-induced progressive multifocal leukoencephalopathy: a case/noncase study in the French pharmacovigilance database.

Fundam Clin Pharmacol. 2017 Apr;31(2):237-244

Authors: Colin O, Favrelière S, Quillet A, Neau JP, Houeto JL, Lafay-Chebassier C, Pérault-Pochat MC, French Pharmacovigilance Network

Abstract
Progressive multifocal leukoencephalopathy (PML) is an often fatal demyelinating disease of the central nervous system. As effective treatment is unavailable, identification of all drugs that could be associated with PML is essential. The objective of this study was to investigate the putative association of reports of PML and drugs. We used the case/noncase method in the French PharmacoVigilance database (FPVD). Cases were reports of PML in the FPVD between January 2008 and December 2015. Noncases were all other reports during the same period. To assess the association between PML and drug intake, we calculated an adverse drug report odds ratio (ROR) with its 95% confidence interval. We have studied the delay of onset of PML for each drug concerned. Among the 101 cases of PML, 39 drugs were mentioned as suspect. The main therapeutic classes suspected with significant ROR were antineoplastic agents (n = 85), immunosuppressants (n = 67), and corticosteroids. A latent interval from the time of drug initiation to the development of PML is established: the median time to onset was 365 days (123-1095 days). The onset of PML is highly variable and differs among drug classes [from 1 to 96 months (IQR: 39.0-126)]. An association between PML and some immunosuppressant drugs was found as expected, but also with antineoplastic agents and glucocorticoids. An important delay of PML onset after stopping treatment is suspected and should alert prescribers. Prescribers but also patients should be informed about the potential associations with all these drugs. Monitoring could be necessary for many drugs to early detect PML.

PMID: 27736027 [PubMed - indexed for MEDLINE]

Using Rich Data on Comorbidities in Case-Control Study Design with Electronic Health Record Data Improves Control of Confounding in the Detection of Adverse Drug Reactions.

PLoS One. 2016;11(10):e0164304

Authors: Backenroth D, Chase H, Friedman C, Wei Y

Abstract
Recent research has suggested that the case-control study design, unlike the self-controlled study design, performs poorly in controlling confounding in the detection of adverse drug reactions (ADRs) from administrative claims and electronic health record (EHR) data, resulting in biased estimates of the causal effects of drugs on health outcomes of interest (HOI) and inaccurate confidence intervals. Here we show that using rich data on comorbidities and automatic variable selection strategies for selecting confounders can better control confounding within a case-control study design and provide a more solid basis for inference regarding the causal effects of drugs on HOIs. Four HOIs are examined: acute kidney injury, acute liver injury, acute myocardial infarction and gastrointestinal ulcer hospitalization. For each of these HOIs we use a previously published reference set of positive and negative control drugs to evaluate the performance of our methods. Our methods have AUCs that are often substantially higher than the AUCs of a baseline method that only uses demographic characteristics for confounding control. Our methods also give confidence intervals for causal effect parameters that cover the expected no effect value substantially more often than this baseline method. The case-control study design, unlike the self-controlled study design, can be used in the fairly typical setting of EHR databases without longitudinal information on patients. With our variable selection method, these databases can be more effectively used for the detection of ADRs.

PMID: 27716785 [PubMed - indexed for MEDLINE]

Short-term recovery of chemotherapy-induced peripheral neuropathy after treatment for pediatric non-CNS cancer.

Pediatr Blood Cancer. 2017 Jan;64(1):180-187

Authors: Gilchrist LS, Tanner LR, Ness KK

Abstract
PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent side effect of pediatric cancer treatment. The presentation of CIPN, trajectory and completeness of recovery over the first 6 months postchemotherapy, and the influence of patient and treatment characteristics on recovery are described.
PATIENTS AND METHODS: Sixty-seven children and adolescents treated for non-CNS cancers were evaluated for CIPN using the pediatric modified total neuropathy score (ped-mTNS) while on treatment and 3 and 6 months postchemotherapy. Differences between diagnostic groups and treatment type were evaluated as well as change in scores over time. Risk factors for on-treatment and persistent CIPN at 6 months were identified.
RESULTS: Overall, ped-mTNSs were in the abnormal range for 86.5% during treatment and scores decreased over time (initial 9.3 ± 0.6, 6 months 4.3 ± 0.4; F = 38.14, P < 0.001). By 6 months posttreatment, mean scores and percentage of children with abnormal scores were reduced to 2.4 ± 0.3 and 11.5%, respectively, in the ALL group, but remained higher at 5.7 ± 0.7 and 57%, respectively, for lymphoma, and 5.2 ± 1.0 and 60%, respectively, for other solid tumors. At 6 months posttreatment, light touch deficits and foot strength deficits remained in 19.4 and 59.7%, respectively, compared with only 4.9 and 9.8% of the control population. Subjects who were older at exposure, female, or who received etoposide in addition to vincristine were at higher risk for on-treatment CIPN. On-treatment sensory abnormalities were associated with increased risk of persistent CIPN.
CONCLUSION: While CIPN improves in most pediatric patients, significant numbers, especially those treated for lymphoma or other solid tumors, have remaining neuropathic signs and symptoms 6 months posttreatment.

PMID: 27567009 [PubMed - indexed for MEDLINE]

[Cardiovascular risk of androgen deprivation therapy for treatment of hormone-dependent prostate cancer : Differences between GnRH antagonists and GnRH agonists].

Herz. 2016 Dec;41(8):697-705

Authors: Tschöpe C, Kherad B, Spillmann F, Schneider CA, Pieske B, Krackhardt F

Abstract
BACKGROUND: Several studies have indicated that reduction of testosterone levels in patients with prostate cancer undergoing androgen deprivation therapy (ADT) with gonadotropin-releasing hormone (GnRH) agonists can be associated with an increased risk of cardiovascular events. The GnRH antagonists have a different mode of action compared with GnRH agonists and may be preferred in ADT for patients with cardiovascular disease.
OBJECTIVE: This review article discusses potential mechanisms underlying the development of cardiovascular events associated with ADT when using GnRH agonists and explains the differences in mode of action between GnRH agonists and GnRH antagonists. Additionally, relevant studies are presented and practical recommendations for the clinical practice are provided.
MATERIAL AND METHODS: A literature search was performed. Full publications and abstracts published in the last 10 years up to September 2015 were considered to be eligible.
RESULTS: The GnRH antagonists were associated with a decreased risk of cardiovascular events compared with GnRH agonists in prostate cancer patients undergoing ADT and particularly in patients with cardiovascular risk factors or a history of cardiovascular disease. This decrease may be due to the different mode of action of GnRH antagonists compared with GnRH agonists.
CONCLUSION: Prostate cancer patients with either cardiovascular disease or an increased risk of experiencing a cardiovascular event undergoing ADT should be preferentially treated with GnRH antagonists.

PMID: 27083586 [PubMed - indexed for MEDLINE]

Pharmacokinetic study of bortezomib administered intravenously in Taiwanese patients with multiple myeloma.

Hematol Oncol. 2017 Jun 19;:

Authors: Huang SY, Chang CS, Liu TC, Wang PN, Yeh SP, Ho CL, Kuo MC, Lin HY, de Jong J, Chen JY, Yang YW

Abstract
This phase 4, single-arm, non-randomized, open-label, post approval commitment study evaluated the pharmacokinetics and safety of bortezomib in Taiwanese patients with multiple myeloma. Patients (≥20 years) with measurable secretory multiple myeloma (serum monoclonal IgG ≥10, IgA/IgE ≥5, IgD ≥0.5 g/L, IgM present [regardless of level], and urine M protein of ≥200 mg/24 h) received intravenous bortezomib 1.3 mg/m(2) , twice weekly for 2 weeks, followed by a 10-day resting phase (days 12 to 21). Pharmacokinetics and safety were assessed at pre-specified time points. All enrolled patients (n = 18, men: 11; women: 7) completed the study. Mean (SD) Cmax (maximum observed plasma concentration) on day 11 was 266 (77.5) ng/mL, approximately 60% higher compared with non-Asian patients receiving a similar bortezomib regimen but with overlapping ranges. Because of the protracted terminal phase, half-life (t1/2 ), area under the plasma concentration-time curve from time 0 to infinity (AUC∞ ), volume of distribution (Vz ), and systemic clearance were not assessable. All patients experienced treatment-emergent adverse events (TEAEs); 78% were drug-related. Most commonly reported TEAEs were thrombocytopenia (n = 11 [61%]), neutropenia (n = 9 [50%]), leukopenia (n = 6 [33%]), and diarrhoea (n = 6 [33%]); the most common serious adverse event was pneumonia (n = 2 [11%]). One patient had a dose reduction due to a TEAE of thrombocytopenia. Overall, bortezomib exposure (AUC) in Taiwanese patients (AUClast [SD]: 230 [147] ng·h/mL) with twice weekly intravenous administration was comparable with non-Asian population (AUClast [SD]: 241 [82] ng·h/mL). Bortezomib treatment was associated with manageable toxicity profile and did not limit the continuity of therapy.

PMID: 28626947 [PubMed - as supplied by publisher]

Clomiphene for the treatment of male infertility: a case report of mood change.

Curr Drug Saf. 2017 Jun 15;:

Authors: Aussedat M, Jean-Louis J, Djahangirian O, Brochet MS

Abstract
BACKGROUND: Clomiphene is normally used in women with ovulatory dysfunction. In men, it is used off label in some cases of infertility. Psychological adverse effects are reported in women but very few in men.
CASE: A 34 year-old man treated with clomiphene for oligoteratospermia presented anxiety, decreased appetite, and depressed mood making him unable to function properly at work, five days after initiation of therapy. Symptoms required reduction followed by discontinuation of treatment four days later because of absence of improvement. Following cessation, the patient noted a gradual then a complete resolution approximately one week later. The patient did not have any psychiatric or other medical condition neither drug nor substance abuse that could explain this clinical presentation. The Naranjo's score was used to prove the clomiphene's imputability.
CONCLUSION: Health care providers should advise patients of the risk of psychological adverse effects when initiating treatment with clomiphene and should provide a close monitoring of mood change, especially during the initial weeks.

PMID: 28625145 [PubMed - as supplied by publisher]

[Icelanders' beliefs about medicines. Use of BMQ].

Laeknabladid. 2017 Februar;103(2):67-72

Authors: Vilhelmsdottir H, Johannsson M

Abstract
OBJECTIVE: To study beliefs held by the general public in Iceland about medicines.
METHODS: The Beliefs about Medicines Questionnaire was used to explore Icelanders' beliefs about medicines. A sample of 1500 Icelandic citizens, aged 18-75, obtained from the Social Science Research Insti-tute was given The Beliefs about Medicines Questionnaire.
RESULTS: The response rate was 61.6%. Most Icelanders have positive beliefs about their medication as well as general trust. Those who suffer from chronic diseases are more positive towards medicines than others and less inclined to view them as excessively used and harmful. Higher level of education predicts more positive beliefs towards medication - and vice versa. Gender and age do not seem to affect such beliefs.
CONCLUSION: Gaining a better understanding of people´s beliefs about medicines and what determines these beliefs can be of considerable value in the search for ways to improve therapy and adherence, espe-cially for those suffering from chronic diseases. Promoting education for the general public about medicines might result in less mis-understanding among patients and subsequently better grounded -beliefs and more adequate therapeutic adherence. Key words: beliefs, medicines, Icelanders, BMQ, survey. Correspondence: Hlif Vilhelmsdottir, hlif84@gmail.com.

PMID: 28489012 [PubMed - indexed for MEDLINE]