Pharmacovigilance evaluation of the relationship between impaired glucose metabolism and BCR-ABL inhibitor use by using an adverse drug event reporting database.

Cancer Med. 2018 Dec 18;:

Authors: Okada N, Niimura T, Zamami Y, Hamano H, Ishida S, Goda M, Takechi K, Chuma M, Imanishi M, Ishizawa K

Abstract
Breakpoint cluster region-Abelson murine leukemia (BCR-ABL) inhibitors markedly improve the prognosis of chronic myeloid leukemia. However, high treatment adherence is necessary for successful treatment with BCR-ABL inhibitors. Therefore, an adequate understanding of the adverse event profiles of BCR-ABL inhibitors is essential. Although many adverse events are observed in trials, an accurate identification of adverse events based only on clinical trial results is difficult because of strict entry criteria or limited follow-up durations. In particular, BCR-ABL inhibitor-induced impaired glucose metabolism remains controversial. Pharmacovigilance evaluations using spontaneous reporting systems are useful for analyzing drug-related adverse events in clinical settings. Therefore, we conducted signal detection analyses for BCR-ABL inhibitor-induced impaired glucose metabolism by using the FDA Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) database. Signals for an increased reporting rate of impaired glucose metabolism were detected only for nilotinib use, whereas these signals were not detected for other BCR-ABL inhibitors. Subgroup analyses showed a clearly increased nilotinib-associated reporting rate of impaired glucose metabolism in male and younger patients. Although FAERS- and JADER-based signal detection analyses cannot determine causality perfectly, our study suggests the effects on glucose metabolism are different between BCR-ABL inhibitors and provides useful information for the selection of appropriate BCR-ABL inhibitors.

PMID: 30561126 [PubMed - as supplied by publisher]

Inhibition of complement C1s improves severe hemolytic anemia in cold agglutinin disease: a first-in-human trial.

Blood. 2018 Dec 17;:

Authors: Jäger U, D'Sa S, Schörgenhofer C, Bartko J, Derhaschnig U, Sillaber C, Jilma-Stohlawetz P, Fillitz M, Schenk T, Patou G, Panicker S, Parry GC, Gilbert JC, Jilma B

Abstract
Cold agglutinin disease is a difficult-to-treat autoimmune hemolytic anemia in which immunoglobulin M antibodies bind to erythrocytes and fix complement, resulting in predominantly extravascular hemolysis. This trial tested the hypothesis that the anti-C1s antibody sutimlimab would ameliorate hemolytic anemia. Ten patients with cold agglutinin disease participated in the phase 1b component of a first-in-human trial. Patients received a test dose of 10 mg/kg sutimlimab followed by a full dose of 60 mg/kg 1-4 days later and 3 additional weekly doses of 60 mg/kg. All infusions were well tolerated without premedication. No drug-related serious adverse events were observed. Seven of 10 patients with cold agglutinin disease responded with a hemoglobin increase >2 g/dL. Sutimlimab rapidly increased hemoglobin levels by a median of 1.6 g/dL within the first week, and by a median of 3.9 g/dL (interquartile range, 1.3-4.5; 95% confidence interval, 2.1-4.5) within 6 weeks (P = 0.005). Sutimlimab rapidly abrogated extravascular hemolysis, normalizing bilirubin levels within 24 hours in most patients and normalizing haptoglobin levels in 4 patients within 1 week. Hemolytic anemia recurred when drug levels were cleared from the circulation 3-4 weeks after the last dose of sutimlimab. Re-exposure to sutimlimab in a named patient program recapitulated the control of hemolytic anemia. All 6 previously transfused patients became transfusion-free during treatment. In conclusion, sutimlimab was safe, well tolerated, and rapidly stopped C1s complement-mediated hemolysis in patients with cold agglutinin disease significantly increasing hemoglobin levels and precluding the need for transfusions. This trial was registered at https://clinicaltrials.gov/ as #NCT02502903.

PMID: 30559259 [PubMed - as supplied by publisher]

Long-term safety and efficacy of deferasirox in patients with myelodysplastic syndrome, aplastic anemia and other rare anemia in Taiwan.

Hematology. 2019 Dec;24(1):247-254

Authors: Ko BS, Chang MC, Chiou TJ, Chang TK, Chen YC, Lin SF, Chang CS, Lu YC, Yeh SP, Chen TY, Hwang WS

Abstract
OBJECTIVE: Patients with myelodysplastic syndromes (MDS), aplastic anemia (AA) or other rare anemia require chronic blood transfusions which can lead to iron overload and subsequent excess iron-mediated complications. Intensive iron chelation with deferasirox could remove excess iron and can alleviate these events; however, the long-term safety and efficacy in Chinese population are not clearly characterized. This study examined the long-term efficacy and safety of deferasirox in a real-world setting in Taiwan.
METHODS: This observational, non-interventional, single-arm, multi-center, phase IV study was designed to collect the safety and clinical information about patients who were treated with deferasirox according to investigator's judgment and in accordance with the general clinical practice.
RESULTS: From 2009 to 2011, patients with MDS (N = 38), AA (N = 23), and other rare anemias (N = 18) were enrolled. The mean deferasirox exposure was 17.7 ± 4.02 mg/kg/day. The most common drug-related AEs were skin disorders (32.9%) and gastrointestinal disorders (30.4%), while grade 3-4 AEs were rare (5.1%). In the overall patient population, deferasirox effectively decreased serum ferritin levels at 1 year (P = 0.0154) and 3 years (P = 0.0424) from the baseline. Upon the use of deferasirox, 32.9% patients showed erythroid response and 16.7% patients had platelet response.
CONCLUSIONS: For patients with MDS, AA, and other rare anemias, the AEs observed in this 3-year surveillance study with deferasirox were mostly mild or moderate. In addition, the hematological response rate was higher than that in the EPIC study, which primarily enrolled Caucasian patients.

PMID: 30558522 [PubMed - in process]

Emerging technologies for food and drug safety.

Regul Toxicol Pharmacol. 2018 Oct;98:115-128

Authors: Slikker W, de Souza Lima TA, Archella D, de Silva JB, Barton-Maclaren T, Bo L, Buvinich D, Chaudhry Q, Chuan P, Deluyker H, Domselaar G, Freitas M, Hardy B, Eichler HG, Hugas M, Lee K, Liao CD, Loo LH, Okuda H, Orisakwe OE, Patri A, Sactitono C, Shi L, Silva P, Sistare F, Thakkar S, Tong W, Valdez ML, Whelan M, Zhao-Wong A

Abstract
Emerging technologies are playing a major role in the generation of new approaches to assess the safety of both foods and drugs. However, the integration of emerging technologies in the regulatory decision-making process requires rigorous assessment and consensus amongst international partners and research communities. To that end, the Global Coalition for Regulatory Science Research (GCRSR) in partnership with the Brazilian Health Surveillance Agency (ANVISA) hosted the seventh Global Summit on Regulatory Science (GSRS17) in Brasilia, Brazil on September 18-20, 2017 to discuss the role of new approaches in regulatory science with a specific emphasis on applications in food and medical product safety. The global regulatory landscape concerning the application of new technologies was assessed in several countries worldwide. Challenges and issues were discussed in the context of developing an international consensus for objective criteria in the development, application and review of emerging technologies. The need for advanced approaches to allow for faster, less expensive and more predictive methodologies was elaborated. In addition, the strengths and weaknesses of each new approach was discussed. And finally, the need for standards and reproducible approaches was reviewed to enhance the application of the emerging technologies to improve food and drug safety. The overarching goal of GSRS17 was to provide a venue where regulators and researchers meet to develop collaborations addressing the most pressing scientific challenges and facilitate the adoption of novel technical innovations to advance the field of regulatory science.

PMID: 30048704 [PubMed - indexed for MEDLINE]

Non-toxic and non teratogenic extract of Thuja orientalis L. inhibited angiogenesis in zebra fish and suppressed the growth of human lung cancer cell line.

Biomed Pharmacother. 2018 Oct;106:699-706

Authors: R EB, Jesubatham PD, V M BG, S V, S S

Abstract
Lung cancer is a malignant tumour with minimal survival rate and the current treatments are not showing complete remission of tumour and have many side effects. Thus a natural herbal medicine with good anti-cancer properties is highly demanded. Thuja orientalis L. is a traditionally used medicine to cure cough, bronchitis, excessive menstruation, asthma, skin infection and premature baldness. In addition, recent studies have revealed that it has anti-proliferative and anti-cancer activity. Angiogenesis is the main reason for the propagation and metastasis of cancers. We therefore intended to study the effects of the leaf extract of Thuja orientalis L. on angiogenesis as well as lung cancer cell growth. We have tested the anti-angiogenesis efficiency by alkaline phosphatase assay and also analysed the in vivo toxicity and teratogenic effects of various concentration of Thuja orientalis L. extract by establishing an in vivo zebra fish (Danio rerio), a promising model for cancer research which share genetic structure similarity to that of human beings. Also we demonstrated an anti-cancer effect of leaf extract from Thuja orientalis L. on human lung cancer cell line (A549) by MTT and trypan blue assay. The results revealed that the Thuja orientalis L. extract is efficient in repressing lung tumour cell growth significantly (p ≤ 0.01) in all treatments (2.4 mg/ml to 0.3 mg/ml) except 0.15 mg/ml compared to the control. The in vivo toxicity assay has proven that it is non-toxic at concentrations 0.6 mg/ml, 0.3 mg/ml and 0.15 mg/ml in zebrafish. The teratogenic assays revealed the therapeutic index (TI) as 0.808 with 0.7029 mg/ml as LC50 concentration at 24 h which is within the desirable value (below 1) for drug administration. Noticeable inhibition of angiogenesis also was observed in treatment with 2.4 mg/ml to 0.3 mg/ml. Overall we found that Thuja orientalis L. plant leaf extract exhibits better anti-cancer properties as we have validated by in vitro and in vivo analysis.

PMID: 29990861 [PubMed - indexed for MEDLINE]

Management of Common Side Effects of Apremilast.

J Cutan Med Surg. 2018 Jul/Aug;22(4):415-421

Authors: Langley A, Beecker J

Abstract
Apremilast is a relatively new therapy for the treatment of moderate to severe plaque psoriasis in adults. While this medication is considered safe with a very low risk of serious side effects, a few common (≥5% of patients) mild to moderate side effects have been reported, including diarrhea, nausea, headache, and nasopharyngitis. Not addressing these symptoms may lead to medication nonadherence and unnecessary discontinuation of therapy. These side effects are often easily managed with interventions available to the practicing dermatologist, and in only rare instances will these side effects require dose adjustment or discontinuation of therapy. The purpose of this article is to review common side effects of apremilast at its approved dose of 30 mg orally twice daily (BID) and to provide clear, simple recommendations for their management in dermatological practice.

PMID: 29290125 [PubMed - indexed for MEDLINE]

Fentanyl buccal tablet for breakthrough cancer pain in clinical practice: results of the non-interventional prospective study ErkentNIS.

Support Care Cancer. 2018 02;26(2):491-497

Authors: Masel EK, Landthaler R, Gneist M, Watzke HH

Abstract
PURPOSE: Several patients with advanced cancer suffer from breakthrough cancer pain (BTcP). BTcP is pain exacerbation despite opioid baseline therapy. Fentanyl buccal tablet (FBT) is a rapid-onset opioid for the treatment of BTcP. The aim of this study is to document the feasibility of FBT in patients with BTcP.
METHODS: The study was performed in 64 centers. Basic pain score was rated on a numeric rating scale (NRS) before and after treatment. BTcP episodes, baseline opioid therapy, and FBT dose were rated as well as individual dose titration, findings on tolerability, patient satisfaction, and safety of the drug.
RESULTS: Two hundred sixty-three patients were available for analysis. Patients rated a basic pain score of 6 (range 2-10) points on an NRS and described an average of 2 to 5 BTcP episodes per day. After titration of FBT, BTcP control was achieved within 5 min in 36%, within 10 min in 68%, and within 15 min in 95%. Basic pain score decreased to a mean NRS of 4 and BTcP episodes decreased to < 1 to 3 episodes per day. BTcP control, onset of action of FBT, potency of FBT, tolerability of FBT, and safety of FBT were rated as excellent or good by 89 to 99% of the patients. Adverse drug reactions were registered in 3%.
CONCLUSIONS: Treatment with FBT led to rapid pain relief and reductions in the number of BTcP episodes and patient satisfaction was rated as excellent or good.

PMID: 28849261 [PubMed - indexed for MEDLINE]

Tolerability of Opioid Analgesia for Chronic Pain: A Network Meta-Analysis.

Sci Rep. 2017 05 17;7(1):1995

Authors: Meng Z, Yu J, Acuff M, Luo C, Wang S, Yu L, Huang R

Abstract
Aim of this study was to study the tolerability of opioid analgesia by performing a network meta-analysis (NMA) of randomized-controlled trials (RCTs) which investigated effectiveness of opioids for the management of chronic pain. Research articles reporting outcomes of RCT/s comparing 2 or more opioid analgesics for the management of chronic pain were obtained by database search. Bayesian NMAs were performed to combine direct comparisons between treatments with that of indirect simulated evidence. Study endpoints were: incidence of adverse events, incidence of constipation, trial withdrawal rate, and patient satisfaction with treatment. Outcomes were also compared with conventional meta-analyses. Thirty-two studies investigating 10 opioid drugs fulfilled the eligibility criteria. Tapentadol treatment was top-ranking owing to lower incidence of overall adverse events, constipation, and least trial withdrawal rate. Tapentadol was followed by oxycodone-naloxone combination in providing better tolerability and less trial withdrawal rate. Patient satisfaction was found to be higher with oxycodone-naloxone followed by fentanyl and tapentadol. These results were in agreement with those achieved with conventional meta-analyses. Tapentadol and oxycodone-naloxone are found to exhibit better tolerability characteristics in comparison with other opioid drugs for the management of chronic pain and are associated with low trial withdrawal rate and better patient satisfaction.

PMID: 28515426 [PubMed - indexed for MEDLINE]

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A Computerized Scoring System to Improve Assessment of Heparin-induced Thrombocytopenia Risk.

J Thromb Haemost. 2018 Dec 14;:

Authors: Gallo T, Curry SC, Padilla-Jones A, Heise CW, Ramos KS, Woosley RL, Raschke RA

Abstract
BACKGROUND: Heparin induced thrombocytopenia (HIT) is an immune-mediated adverse drug event associated with life-threatening thrombotic complications. The four T's (4Ts) score is widely used to estimate the risk for HIT and guide diagnostic testing, but it is not easily amenable to computerized clinical decision support (CDS) implementation.
OBJECTIVES: Our main objective was to develop a HIT computerized risk (HIT-CR) scoring system that provides platelet count surveillance for timing and degree of thrombocytopenia to identify those for whom diagnostic testing should be considered. Our secondary objective was to evaluate clinical management and subsequent outcomes in those identified to be at risk for HIT.
METHODS: We retrospectively analyzed data from a stratified sample of 150 inpatients treated with heparin to compare the performance of the HIT-CR scoring system to a clinically calculated 4Ts score. We took a 4Ts score ≥4 as the gold standard to determine if HIT diagnostic testing should be performed.
RESULTS: The best cutoff point of the HIT-CR score was a score of 3 which yielded 85% raw agreement with the 4Ts score and a kappa of 0.69 (95% CI: 0.57 to 0.81). Ninety percent of patients with 4Ts score ≥4 failed to undergo conventionally recommended diagnostic testing; 38% of these experienced persistent, unexplained thrombocytopenia, and 4% suffered life-threatening thrombotic complications suggestive of undiagnosed HIT.
CONCLUSION: The HIT-CR scoring system is practical for computerized CDS, agrees well with the 4Ts score, and should be prospectively evaluated for its ability to identify patients who should be tested for HIT. This article is protected by copyright. All rights reserved.

PMID: 30552743 [PubMed - as supplied by publisher]

Impact of medication therapy management on pharmacotherapy safety in an intensive care unit.

Int J Clin Pharm. 2018 Dec 15;:

Authors: Martins RR, Silva LT, Lopes FM

Abstract
Background Drug-related problems are mostly preventable or predictable circumstances that may impact on health outcomes. Clinical pharmacy activities such as medication therapy management can identify and solve these problems, with potential to improve medication safety and effectiveness. Objective To evaluate ability of medication therapy management service to detect drug-related problems and prevent adverse drug events. This study also aimed to assess the risk factors for drugrelated problem occurrence. Setting Medical intensive care unit of a public tertiary hospital in Brazil. Methods Patients were evaluated by a clinical pharmacist, who provided medication therapy management service. Detected drug-related problems were categorized according to the Pharmaceutical Care Network Europe methodology and analyzed in multinomial regression to identify risk factors. Main outcome measure Potential risk factors for drug-related problem occurrence. Results The proposed medication therapy management service allowed detection of 170 drug-related problems that had potential to reach patients causing harm and other 50 unavoidable adverse events. Drug-related problems identified were more often associated with antibacterial use, caused by improper combinations or inadequate drug dosage. These problems required interventions that were accepted by the multidisciplinary team, resulting in more than 85% adherence and total problem solving. Main risk factors identified were previous diagnosis of kidney injury (OR = 8.38), use of midazolam (OR = 7.96), furosemide (OR = 5.87) and vancomycin (OR = 4.82). Conclusion Medication therapy management proved to be an effective method not only for drug-related problem detection, but also for adverse drug event prevention, contributing to improve patient safety.

PMID: 30552623 [PubMed - as supplied by publisher]

Treatment of chronic hepatitis C virus infection in Rwanda with ledipasvir-sofosbuvir (SHARED): a single-arm trial.

Lancet Gastroenterol Hepatol. 2018 Dec 10;:

Authors: Gupta N, Mbituyumuremyi A, Kabahizi J, Ntaganda F, Muvunyi CM, Shumbusho F, Musabeyezu E, Mukabatsinda C, Ntirenganya C, Van Nuil JI, Kateera F, Camus G, Damascene MJ, Nsanzimana S, Mukherjee J, Grant PM

Abstract
BACKGROUND: Limited treatment data are available for hepatitis C virus (HCV) in sub-Saharan Africa, especially for genotype 4. Our objective was to establish the safety and efficacy of ledipasvir-sofosbuvir for chronic HCV genotype 1 or 4 infection in adults in Rwanda.
METHODS: We did a single-arm trial to evaluate the safety and efficacy of ledipasvir-sofosbuvir in Rwandan adults with chronic HCV infection at a single study site (Rwanda Military Hospital, Kigali, Rwanda). We enrolled individuals aged 18 years or older with HCV genotype 1 or 4 infection and a plasma HCV RNA concentration of more than 1000 IU/mL at screening. All participants were given ledipasvir (90 mg) and sofosbuvir (400 mg) in a single combination tablet once daily for 12 weeks. We established HCV genotype using an Abbott platform, and HCV subtype with PCR amplification. The primary endpoint was the proportion of participants with a sustained virological response 12 weeks after therapy (SVR12). All patients enrolled in the study were included in the primary endpoint analyses. This study is registered with ClinicalTrials.gov, number NCT02964091.
FINDINGS: 300 participants were enrolled between Feb 6, 2017, and Sept 18, 2017, and the follow-up period was completed on March 1, 2018. On genotyping, 248 (83%) participants were reported as having genotype 4, four (1%) genotype 1, and 48 (16%) both genotype 1 and genotype 4. Subsequent viral sequencing showed all participants actually had genotype 4 infection with subtype 4k (134 [45%]), subtype 4r (48 [16%]), subtype 4q (42 [14%]), and subtype 4v (24 [8%]) predominating. Overall, 261 (87%, 95% CI 83-91) participants achieved SVR12. In participants with genotype 4r, SVR12 was observed in 27 (56%, 95% CI 41-71) participants versus 234 (93%, 90-96) individuals with other subtypes. There were no drug-related treatment discontinuations due to ledipasvir-sofosbuvir. The most common adverse events were hypertension (97 [32%]), headache (78 [26%]), dizziness (61 [20%]), and fatigue (56 [19%]). There were six serious adverse events; none were assessed to be due to the study drug. 296 participants had data for pill counts at week 4 and 8; 271 (92%) had 100% adherence and only one (<1%) had an adherence of less than 90%.
INTERPRETATION: This is the first large-scale prospective study reporting direct-acting antiviral outcomes in sub-Saharan Africa. The high adherence and treatment success without intensive support measures or highly specialised clinical providers, and lack of treatment discontinuations due to adverse events support the feasibility of HCV treatment decentralisation and scale-up in sub-Saharan Africa. Genotype 4r is uniquely expressed in this region and associated with high rates of treatment failure, suggesting a need for rigorous test-of-cure in clinical practice and consideration of the use of newer pangenotypic direct-acting antiviral regimens in this region.
FUNDING: Gilead Sciences.

PMID: 30552056 [PubMed - as supplied by publisher]

Association of good oncological response to therapy with the development of rheumatic immune-related adverse events following PD-1 inhibitor therapy.

Int J Rheum Dis. 2018 Nov 22;:

Authors: Liew DFL, Leung JLY, Liu B, Cebon J, Frauman AG, Buchanan RRC

Abstract
AIM: To investigate whether any patient or treatment characteristics are associated with the development of rheumatic immune-related adverse events (irAEs) following programmed cell death protein 1 (PD-1) inhibitor therapy for cancer.
METHOD: This was a retrospective chart review of all patients who were dispensed nivolumab or pembrolizumab at a single center before 1 January, 2017, with follow-up until 1 July, 2017. Patients with any diagnosis of a non-cutaneous irAE were identified, regardless of severity, and rheumatic irAEs were characterized.
RESULTS: Of 244 episodes of therapy, a non-cutaneous irAE occurred in 72 (29.5%). Rheumatic irAEs were diagnosed in 19 episodes of therapy (7.8%), with 12 de novo diagnoses (5.1% of episodes without a pre-existing autoimmune rheumatic disease) and 7 exacerbations of existing disease. Review by a rheumatologist occurred in only 11 of these. Rheumatic irAEs were more common in patients with a good oncological response to therapy (relative risk [RR] 11.16), those being treated for melanoma (RR 2.94) and those who developed another non-cutaneous irAE (RR 2.64).
CONCLUSION: Rheumatic irAEs are relatively common with PD-1 inhibitor therapy, and appear to be associated with a good oncological response to therapy. Many rheumatic irAEs were not referred to rheumatological services. Prospective systematic investigation would be of benefit to explore these characteristics.

PMID: 30549256 [PubMed - as supplied by publisher]

Comment on "Assessment of the Utility of Social Media for Broad-Ranging Statistical Signal Detection in Pharmacovigilance: Results from the WEB-RADR Project".

Drug Saf. 2018 12;41(12):1371-1373

Authors: Bousquet C, Audeh B, Bellet F, Lillo-Le Louët A

Abstract

PMID: 30341678 [PubMed - indexed for MEDLINE]

Dose-dependent transcriptomic responses of zebrafish eleutheroembryos to Bisphenol A.

Environ Pollut. 2018 Dec;243(Pt B):988-997

Authors: Martínez R, Esteve-Codina A, Herrero-Nogareda L, Ortiz-Villanueva E, Barata C, Tauler R, Raldúa D, Piña B, Navarro-Martín L

Abstract
Despite the abundant literature on the adverse effects of Bisphenol A (BPA) as endocrine disruptor, its toxicity mechanisms are still poorly understood. We present here a study of its effects on the zebrafish eleutheroembryo transcriptome at concentrations ranging from 0.1 to 4 mg L-1, this latter representing the lowest observed effect concentration (LOEC) found in our study at three different macroscopical endpoints (survival, hatching and swim bladder inflation). Multivariate data analysis methods identified both monotonic and bi-phasic patterns of dose-dependent responses. Functional analyses of genes affected by BPA exposure suggest an interaction of BPA with different signaling pathways, being the estrogenic and retinoid receptors two likely targets. In addition, we identified an apparently unrelated inhibitory effect on, among others, visual function genes. We interpret our data as the result of a sum of underlying, independent molecular mechanisms occurring simultaneously at the exposed animals, well below the macroscopic LOEC, but related to at least some of the observed morphological alterations, particularly in eye size and yolk sac resorption. Our data supports the idea that the physiological effects of BPA cannot be only explained by its rather weak interaction with the estrogen receptor, and that multivariate analyses are required to analyze the effects of toxicants like BPA, which interact with different cellular targets producing complex phenotypes.

PMID: 30248606 [PubMed - indexed for MEDLINE]

Side effects of corticosteroids in patients with advanced cancer: a systematic review.

Support Care Cancer. 2018 Dec;26(12):3979-3983

Authors: Hatano Y, Matsuoka H, Lam L, Currow DC

Abstract
PURPOSE: Corticosteroids are commonly used in palliative care settings, but are associated with several side effects. Although adverse events (AEs) are highly distressing for patients, few data are available from prospective studies to look at incidence or predictors of such harms. The aim of this study is to identify AE reporting among studies of patients with advanced cancer receiving corticosteroids for any reason.
METHODS: A systematic review was conducted using the following data sources: PubMed, Medline, SCOPUS, Cochrane reviews, and CINAHL. Randomized controlled trials (RCTs) with patients with advanced cancer assessing the effect of corticosteroids were included. Consecutive cohort observational studies of corticosteroid toxicities in cancer patients were also included.
RESULTS: Twenty-seven RCTs and 12 consecutive cohort observational studies were identified. The most frequently reported primary outcome of RCTs was nausea and vomiting (8/27). Dexamethasone was prescribed in almost half of RCTs (13/27). In consecutive cohort studies, the primary outcomes were a wide variety of symptoms. Dexamethasone was also the most common glucocorticoid used (7/12). In terms of quality of AE reporting, two RCTs and one consecutive cohort study used a validated AE assessment tool in their studies.
CONCLUSIONS: Side effects of corticosteroids in advanced cancer patients were poorly reported with few data using validated tools. Researchers should be aware of the guideline of AE reporting to provide the best evidence of risk-benefit balance. Developing specific consensus guidelines about AE reporting in studies of glucocorticoids in studies of people with advanced cancer would be useful.

PMID: 29980905 [PubMed - indexed for MEDLINE]

Prognostic significance of tumor budding in cutaneous squamous cell carcinoma.

J Am Acad Dermatol. 2018 07;79(1):e5

Authors: Kanitakis J, Karayannopoulou G

PMID: 29908823 [PubMed - indexed for MEDLINE]

A predictive index of biomarkers for ictogenesis from tier I safety pharmacology testing that may warrant tier II EEG studies.

J Pharmacol Toxicol Methods. 2018 Nov - Dec;94(Pt 1):50-63

Authors: Gauvin DV, Zimmermann ZJ, Yoder J, Harter M, Holdsworth D, Kilgus Q, May J, Dalton J, Baird TJ

Abstract
Three significant contributions to the field of safety pharmacology were recently published detailing the use of electroencephalography (EEG) by telemetry in a critical role in the successful evaluation of a compound during drug development (1] Authier, Delatte, Kallman, Stevens & Markgraf; JPTM 2016; 81:274-285; 2] Accardi, Pugsley, Forster, Troncy, Huang & Authier; JPTM; 81: 47-59; 3] Bassett, Troncy, Pouliot, Paquette, Ascaha, & Authier; JPTM 2016; 70: 230-240). These authors present a convincing case for monitoring neocortical biopotential waveforms (EEG, ECoG, etc) during preclinical toxicology studies as an opportunity for early identification of a central nervous system (CNS) risk during Investigational New Drug (IND) Enabling Studies. This review is about "ictogenesis" not "epileptogenesis". It is intended to characterize overt behavioral and physiological changes suggestive of drug-induced neurotoxicity/ictogenesis in experimental animals during Tier 1 safety pharmacology testing, prior to first dose administration in man. It is the presence of these predictive or comorbid biomarkers expressed during the requisite conduct of daily clinical or cage side observations, and in early ICH S7A Tier I CNS, pulmonary and cardiovascular safety study designs that should initiate an early conversation regarding Tier II inclusion of EEG monitoring. We conclude that there is no single definitive clinical marker for seizure liability but plasma exposures might add to set proper safety margins when clinical convulsions are observed. Even the observation of a study-related full tonic-clonic convulsion does not establish solid ground to require the financial and temporal investment of a full EEG study under the current regulatory standards.
PREFATORY NOTE: For purposes of this review, we have adopted the FDA term "sponsor" as it refers to any person who takes the responsibility for and initiates a nonclinical investigations of new molecular entities; FDA uses the term "sponsor" primarily in relation to investigational new drug application submissions.

PMID: 29751085 [PubMed - indexed for MEDLINE]

Anesthesia Case of the Month.

J Am Vet Med Assoc. 2017 06 01;250(11):1246-1249

Authors: Wendt-Hornickle E, Goudie-DeAngelis E, Baldo C

PMID: 28509637 [PubMed - indexed for MEDLINE]

Assessment of Incidence and Character of Neurologic/ Neuropsychiatric Complications in a Group of Patients with Malignant Melanoma Treated with Adjuvant High Dose Interferon.

Klin Onkol. 2018;31(5):361-365

Authors: Jarmila P, Jiří G, Jindřich K, Peter P, Iva P, Petronela T, Věra J, Adam P, Šárka L, Filip

Abstract
BACKGROUND: Authors describe the incidence and character of neurologic and neuropsychiatric complications - particularly depression and parkinsonism - during adjuvant treatment of malignant melanoma (MM) with high dose interferon (HDI). Among the most frequently observed side effects are fatigue, hematotoxicity, and hepatotoxicity. Most research has been directed at depression and parkinsonism because of the lack of literature concerning these complications. Interferon induced parkinsonism has only been described rarely and only in case reports.
PATIENTS AND METHODS: Twenty-nine patients with MM, treated from January 2010 to January 2014 with adjuvant high dose interferon alfa-2b intravenous (HDI 20MIU/sqm for 5 days per week during the first 4 weeks, and then maintenance subcutaneous 10MIU/sqm up to a total time of 1 year) were retrospectively evaluated and the incidence and character of neurologic and neuropsychiatric complications were determined.
RESULTS: Significant neurologic and neuropsychiatric complications were observed in 3 of the 29 patients. Dose modifications were required in 2 cases. One case developed parkinsonism and treatment had to be stopped after 10 applications of intravenous interferon.
CONCLUSION: High dose interferon can cause depression and parkinsonism. Prophylaxis with antidepressant medication can keep the incidence of depression as low as 10% or lower. Development of parkinsonism during HDI is rare. According to available reports, this is the first description of parkinsonism development related to HDI in MM. Key words malignant melanoma - high dose interferon - neurologic and neuropsychiatric complication - drug-induced depression - drug-induced  parkinsonism The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 7. 4. 2018 Accepted: 16. 8. 2018.

PMID: 30541322 [PubMed - in process]