First-in-human, phase I single-ascending-dose study of the safety, pharmacokinetics, and relative bioavailability of selatinib, a dual EGFR-ErbB2 inhibitor in healthy subjects.

Invest New Drugs. 2020 Jun 13;:

Authors: Wang MN, Kuang Y, Gong LY, Hua Y, Pei Q, Guo CX, Cao Y, Huang J, Yang GP

Abstract
We assessed the pharmacokinetics and safety of a single oral administration of selatinib to healthy Chinese subjects and evaluated the potential bioavailability advantage of selatinib relative to lapatinib. Healthy subjects aged 18-40 years were enrolled in this two-part study: Part 1, a single ascending dose (50-500 mg), randomized, double-blind, placebo-control study with 64 subjects; and Part 2, an open-label, positive control, randomized, three-treatment, three-period, three-sequence crossover design study, with 6 subjects administered a single 500-mg dose of selatinib tablets (A), selatinib suspension (B), or lapatinib tablets C) per cycle. In part 1, selatinib was well-tolerated up to the planned maximum dose of 500 mg; thus the maximum tolerated dose was not attained. Twenty-two adverse events were observed in 19 (36.5%) of the 52 subjects administered the test drug. The most common drug-related adverse event was diarrhea. The mean selatinib peak plasma concentration was 69.4-494 ng/mL, which was achieved in a median peak time of 3.5-4.5 h, with a mean elimination half-life between 13.8 and 15.8 h. In Part 2, A and B showed similar bioavailability. Plasma exposure to the active drug (selatinib plus the metabolite, lapatinib) after A intake was more than two-fold higher than that of the same dose of C. In the dose range of 50-500 mg, selatinib was safe and well-tolerated by healthy Chinese subjects, and it conformed with linear pharmacokinetics. Active exposure to selatinib was much greater than that to lapatinib, supporting its development as an adjuvant for anticancer treatment.

PMID: 32535812 [PubMed - as supplied by publisher]

High-dose methotrexate in ICU patients: a retrospective study.

Ann Intensive Care. 2020 Jun 13;10(1):81

Authors: Valade S, Mariotte E, Azoulay E, Darmon M

Abstract
BACKGROUND: High-dose methotrexate (HD-MTX) is commonly used in the treatment of solid tumors and hematological malignancies. Severe toxicities are frequent, leading to organ dysfunction and death. Risk-benefit ratio of using HD-MTX in critically ill patients is unknown. This study aims to describe MTX-induced toxicities and to assess outcome in ICU patients. We conducted a retrospective single-center study conducted in a university hospital ICU between January 2002 and December 2018. Consecutive patients treated by HD-MTX were included.
RESULTS: 33 patients (24 men and 9 women) aged 48 years [34-63], were included. B cell lymphoma had been diagnosed in 31 patients (Burkitt, n = 14; diffuse large B-cell lymphoma with CNS (central nervous system) involvement, n = 9; primary CNS lymphoma, n = 5) and T-cell lymphoma in two patients. Patients were mainly admitted for coma (n = 14; 42%) or acute kidney injury (n = 8; 24%). MTX was administered at a median dose of 6.1 g [5-14]. Fourteen patients had concomitant medication interacting with MTX. Median MTX clearance was 4 days [4-5]. Frequent MTX-related complication were mucositis (n = 21, 64%), diarrhea (n = 14, 44%) or hepatic failure (n = 15, 45%). During ICU stay, 11 patients experienced acute kidney injury (KDIGO stage 3 [2-3]). Two patients received carboxypeptidase and three underwent dialysis. Overall, 19 patients (57%) required mechanical ventilation, 10 (30%) vasopressors. Hospital mortality was 30% (n = 10). Cox model identified MTX concentration 24 h after administration higher than 4.6 µmol/L as associated with hospital mortality (HR 6.7; 95% CI 1.6-27.3).
CONCLUSIONS: To our knowledge, this is the first study assessing characteristics and outcome of critically ill patients receiving HD-MTX. MTX concentration at H24 was associated with hospital mortality. Despite underlying malignancy, ICU support of these patients was associated with a meaningful survival.

PMID: 32535662 [PubMed - as supplied by publisher]

Emerging role of immune checkpoint inhibitors and their relevance for the cardiovascular system.

Herz. 2020 Jun 12;:

Authors: Michel L, Totzeck M, Lehmann L, Finke D

Abstract
Immune checkpoint inhibitor (ICI) therapy induces an immune response against cancer cells. Immune checkpoint inhibitor therapy has tremendously improved the prognosis for a large number of cancers, but is associated with considerable immune-related adverse events (irAEs). Cardiovascular complications from ICI therapy occur in a modest proportion of patients, but show the highest lethality rates of all ICI-related complications. While ICI-related myocarditis is the most dangerous complication, its clinical manifestation varies, e.g., asymptomatic reduction of left ventricular function, isolated increase in cardiac troponins, and arrhythmias. This review delineates current data on cardiovascular complications of ICI therapy. The effects of ICI therapy on the cardiovascular system are classified in the context of preclinical data on the biochemical and immunological function of the immune checkpoint signaling pathways in the heart and the vascular system. Incidence, suspected pathomechanisms, typical symptoms, as well as recommended diagnostics are summarized. Current therapy recommendations for ICI-related cardiotoxicity are outlined and innovative new approaches with high potential for improving outcome in ICI-related myocarditis are delineated. A better understanding of cardiovascular complications is essential for the best possible oncocardiology care of the growing number of patients undergoing ICI therapy.

PMID: 32533218 [PubMed - as supplied by publisher]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2020/06/13

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Amoxicillin-Induced Aseptic Meningitis.

Eur J Case Rep Intern Med. 2020;7(6):001543

Authors: Sousa D, Raimundo P

Abstract
Amoxicillin is a semi-synthetic beta-lactam antibiotic that belongs to the penicillin family. It is the most prescribed antibiotic in the world. It has few side effects, even though hypersensitivity reactions may occur, with potential life-threatening effects. The authors present the case of a 63-year-old male admitted to the emergency department with a 2-week history of fever and occipital headache. The symptoms began after he started antibiotic prophylaxis with amoxicillin for a dental procedure. Cerebrospinal fluid analysis was suggestive of aseptic meningitis and the patient improved quickly after discontinuation of the drug. The patient's previous medical history highlighted a similar episode after he had started taking amoxicillin as part of a scheme for the treatment of a Helicobacter pylori infection. Aseptic meningitis is an extremely rare adverse reaction of amoxicillin, with only 16 cases reported in the literature.
LEARNING POINTS: Aseptic meningitis is a rare side effect of amoxicillin.It is a diagnosis of exclusion and establishing a chronological relationship between the administration of amoxicillin and the onset of clinical symptoms is a key element for the diagnosis.The physiopathology is not well defined, but the consensus is that it is most probably the result of an immunologic hypersensitivity reaction.

PMID: 32523916 [PubMed]

Epidemiology of balance disorders in primary care.

Acta Otorrinolaringol Esp. 2020 Jun 07;:

Authors: Domínguez-Durán E, Mármol-Szombathy I, Palmero-Olmo E, Nogales-Nieves A, López-Urbano MJ, Palomo-Sánchez A, Alarcón-Balanza F, Ruiz-de Arcos M, Bullón-Fernández B, Valle-Martín F, Mora-Quintero A, Poyatos-Poyatos B, Manjón-Collado MT, Sánchez-Gómez S

Abstract
BACKGROUND AND OBJECTIVE: In our country, there are no series of patients that have described the incidence of the different diseases which cause balance disorders (BD) in primary care. The objective of this study is to calculate the incidence of each disease to propose specific training measures.
MATERIALS AND METHOD: Prospective cross-sectional study. Patient data of five primary care physicians in five different primary care centres in our hospital area were collected. All patients who attended consultations for any type of vertigo, imbalance or dizziness over one year as the main reason for consultation were recruited. Using a diagnostic-therapeutic algorithm, patients were diagnosed and treated in primary care or referred for study in hospital care.
RESULTS: The population studied was 7,896 people. An annual incidence of BD of 2.2% was detected. Of the cases, 56.1% could be diagnosed and treated in primary care. Of the patients, 53.8% were diagnosed with some type of positional vertigo; the next three most frequent diagnoses were vestibular migraine, central nervous system ischaemia and medication side effects. These four groups accounted for 87.9% of the population.
CONCLUSIONS: The incidence of BD in primary care requires an approach that includes training in the diagnosis and treatment of benign paroxysmal positional vertigo, headache, cardiovascular risk factors and pharmacology. It is not necessary to prescribe vestibular suppressants in most patients.

PMID: 32522341 [PubMed - as supplied by publisher]

Calcitonin Gene-Related Peptide (CGRP) Antagonists and Their Use in Migraines.

J Pain Palliat Care Pharmacother. 2020 Mar;34(1):22-31

Authors: Henson B, Hollingsworth H, Nevois E, Herndon C

Abstract
Migraine is highly prevalent and associated with a large socio-economic burden in the United States. Current preventive medications have variable efficacy and their use is often limited by intolerable side effects. Calcitonin gene-related peptide (CGRP) has been identified as an integral part of migraine pathophysiology. There are currently seven CGRP antagonists under investigation, all of which are undergoing or have completed phase 3 clinical trials. Three of the investigated CGRP antagonists are approved for use within and outside of the United States. The trials have resulted in positive efficacy and safety data. The purpose of this review is to evaluate the seven CGRP antagonists and their future place in therapy.

PMID: 31763951 [PubMed - indexed for MEDLINE]

Standardized warfarin monitoring decreases adverse drug reactions.

BMC Fam Pract. 2019 11 07;20(1):151

Authors: Shields LBE, Fowler P, Siemens DM, Lorenz DJ, Wilson KC, Hester ST, Honaker JT

Abstract
BACKGROUND: While warfarin is the most commonly prescribed medication to prevent thromboembolic disorders, the risk of adverse drug reactions (ADR) poses a serious concern. This prospective study evaluated how primary care providers (PCP) and cardiologists at our Institution managed patients treated with warfarin with the goal of decreasing the number of warfarin ADRs.
METHODS: A multidisciplinary anticoagulation task force was established at our Institution in 2014 to standardize warfarin monitoring and management. Between 2013 and 2017, we analyzed patients who were prescribed warfarin by their PCP or cardiologist upon hospital discharge and in the ambulatory setting to determine the international normalized ratio (INR) within 5, 10, and 30 days after discharge, time in therapeutic range (TTR), number of severe warfarin ADRs, and total and average cost reduction of all severe warfarin ADRs to determine whether there was an organizational cost savings following the implementation of standardized warfarin care.
RESULTS: The warfarin ADR rate significantly decreased over the 5-year period, from 3.8 to 0.98% (p < 0.0001). The proportion of warfarin prescriptions out of all anticoagulants significantly decreased, from 72.2 to 42.1% (p < 0.001). The proportion of individuals who received an INR at 5, 10, and 30 days after hospital discharge compared to the total number of patients prescribed warfarin significantly increased (p < 0.001). The total cost of severe warfarin ADRs decreased by 57.6% between 2013 and 2017.
CONCLUSIONS: This study serves as a model to reduce the number of severe warfarin ADRs by the following tactics: (1) educating PCPs and cardiologists about evidence-based guidelines for warfarin management, (2) increasing the use of our Institution's electronic warfarin module, and (3) enhancing patient compliance with obtaining INR.

PMID: 31699045 [PubMed - indexed for MEDLINE]

Investigation of Sustained BMP Delivery in the Prevention of Medication-Related Osteonecrosis of the Jaw (MRONJ) in a Rat Model.

Macromol Biosci. 2019 11;19(11):e1900226

Authors: Brierly GI, Ren J, Baldwin J, Saifzadeh S, Theodoropoulos C, Tsurkan MV, Lynham A, Hsu E, Nikolarakos D, Werner C, Woodruff MA, Hutmacher DW, Bray LJ

Abstract
Medication-related osteonecrosis of the jaw (MRONJ) poses an ongoing challenge for clinicians and researchers. Currently, there is a lack of preventative measures available for at-risk patients undergoing tooth extractions, especially those with prior bisphosphonate treatment due to osteoporosis or bone metastasis diagnoses. Here, these issues are addressed using a preventative tissue engineering strategy against MRONJ development. This study evaluates the efficacy of a poly(ethylene glycol)-heparin hydrogel as a tool for the delivery of arginylglycylaspartic acid (RGD) and recombinant human bone morphogenic protein-2 (rhBMP-2). Three groups of skeletally mature rats each receive two doses of intravenous zoledronic acid prior to surgery and undergo extraction of the right first mandibular molar with gingival closure. Experimental groups either have the sockets left empty, filled with hydrogel minus rhBMP-2, or filled with hydrogel plus rhBMP-2. Eight weeks postoperatively specimens are analyzed using radiological, histological, and scanning electron microscopy (SEM) techniques. µCT analysis shows increased bone formation with hydrogel/rhBMP-2 delivery compared to the empty socket. Hydrogel-treated groups display increased presence of osteocytes and increased osteoclastic action compared to the empty sockets. These results represent the first step toward improved delivery of rhBMP-2 and a potential MRONJ preventative for patients undergoing bisphosphonate treatment.

PMID: 31549786 [PubMed - indexed for MEDLINE]

Health related quality of life aspects not captured by EQ-5D-5L: Results from an international survey of patients.

Health Policy. 2019 02;123(2):159-165

Authors: Efthymiadou O, Mossman J, Kanavos P

Abstract
BACKGROUND: In this paper we discuss and present evidence on whether a generic Health Related Quality of Life (HRQoL) measurement tool, the EQ-5D-5L, captures the dimensions of quality of life (QoL) which patients consider significant.
METHODS: An online survey, of individuals with a chronic condition, mainly breast cancer (BC), blood cancers (BLC), rheumatoid arthritis (RA), asthma, and rare diseases (RD) was conducted to collect data on HRQoL and important QoL aspects that respondents thought were not captured by the EQ-5D-5L. Patient organisations across 47 countries were invited to voluntarily share the survey tool with their membership network.
RESULTS: 767 responses from 38 countries showed that important QoL aspects were not captured by EQ-5D-5L for 51% of respondents, including fatigue (19%) and medication side effects (12%), among others. Fatigue (17%) was also the most commonly reported QoL aspect that changed over the course of patients' illness, suggesting that the current version of the EQ-5D-5L might miss capturing significant clinical changes in important QoL domains.
CONCLUSIONS: Utilisation of the EQ-5D-5L in HRQoL measurement raises inconsistencies in capturing QoL attributes and changes in disease-specific patient populations. Further research is needed to clarify the extent to which other generic HRQoL measurement tools capture the aspects of health that really matter for patients.

PMID: 30598239 [PubMed - indexed for MEDLINE]

An update and systematic review on the treatment of primary dysmenorrhea.

JBRA Assist Reprod. 2019 01 31;23(1):51-57

Authors: Sharghi M, Mansurkhani SM, Larky DA, Kooti W, Niksefat M, Firoozbakht M, Behzadifar M, Azami M, Servatyari K, Jouybari L

Abstract
OBJECTIVES: Primary dysmenorrhea is a painful uterine contraction caused by endometrial laceration. Drug therapies and complementary medicine have been used to treat dysmenorrhea. The aim of this study was to investigate and offer an updated perspective on the treatments for dysmenorrhea.
METHODS: The present study was conducted in accordance with the PRISMA checklist for systematic reviews and meta-analyses. The required information was collected based on searches for the following keywords: treatment, primary dysmenorrhea, medicinal plants, chemical drugs, and herbs. Searches were performed on databases Pubmed, Web of Sciences, Scopus, Iran medex, and SID by March 2018 to find literature in the English and Persian languages on this subject without a time limit.
RESULTS: This review included 17 papers, 10 of which on complementary medicine, three on drug therapies, and four on acupuncture and acupressure. The largest and smallest samples had 303 and 24 patients, respectively. Length of treatment ranged from one to six months and the measures most commonly used in the studies were the visual analogue scale and clinical efficacy. Reported complications included gastrointestinal events, nausea, vomiting, diarrhea, abdominal pain, and liver and kidney disorders.
CONCLUSION: Medicinal plants, drugs, and acupressure seem to suppress pain by reducing the level of prostaglandins, mediating nitric oxide, increasing beta-endorphin levels, blocking the calcium channel, and enhancing circulatory flow through the uterine pathway. Further trials are required to confirm the benefits of the procedures described and ensure the absence of complications.

PMID: 30521155 [PubMed - indexed for MEDLINE]

A Drug-Side Effect Context-Sensitive Network approach for drug target prediction.

Bioinformatics. 2019 06 01;35(12):2100-2107

Authors: Zhou M, Chen Y, Xu R

Abstract
SUMMARY: Computational drug target prediction has become an important process in drug discovery. Network-based approaches are commonly used in computational drug-target interaction (DTI) prediction. Existing network-based approaches are limited in capturing the contextual information on how diseases, drugs and genes are connected. Here, we proposed a context-sensitive network (CSN) model for DTI prediction by modeling contextual drug phenotypic relationships. We constructed a Drug-Side Effect Context-Sensitive Network (DSE-CSN) of 139 760 drug-side effect pairs, representing 1480 drugs and 5868 side effects. We also built a protein-protein interaction network (PPIN) of 15 267 gene nodes and 178 972 weighted edges. A heterogeneous network was built by connecting the DSE-CSN and the PPIN through 3684 known DTIs. For each drug on the DSE-CSN, its genetic targets were predicted and prioritized using a network-based ranking algorithm. Our approach was evaluated in both de novo and leave-one-out cross-validation analysis using known DTIs as the gold standard. We compared our DSE-CSN-based model to the traditional similarity-based network (SBN)-based prediction model. The results suggested that the DSE-CSN-based model was able to rank known DTIs highly. In a de novo cross-validation, the area under the receiver operating characteristic (ROC) curve was 0.95. In a leave-one-out cross-validation, the average rank was top 3.2% for known DTIs. When it was compared to the SBN-based model using the Precision-Recall curve, our CSN-based model achieved a higher mean average precision (MAP) (0.23 versus 0.19, P-value<1e-4) in a de novo cross-validation analysis. We further improved the CSN-based DTI prediction by differentially weighting the drug-side effect pairs on the network and showed a significant improvement of the MAP (0.29 versus 0.23, P-value<1e-4). We also showed that the CSN-based model consistently achieved better performances than the traditional SBN-based model across different drug classes. Moreover, we demonstrated that our novel DTI predictions can be supported by published literature. In summary, the CSN-based model, by modeling the context-specific inter-relationships among drugs and side effects, has a high potential in drug target prediction.
AVAILABILITY AND IMPLEMENTATION: nlp/case/edu/public/data/DSE/CSN_DTI.

PMID: 30428013 [PubMed - indexed for MEDLINE]

Validation of Bleeding Risk Prediction Scores for Patients With Major Bleeding on Direct Oral Anticoagulants.

Ann Pharmacother. 2020 Jun 09;:1060028020933186

Authors: Tchen S, Ryba N, Patel V, Cavanaugh J, Sullivan JB

Abstract
Background: Direct oral anticoagulants (DOACs) offer many benefits over vitamin K antagonists (VKAs) but still carry a significant risk of major bleeding. Bleeding risk prediction scores such as the Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile International Normalized Ratio, Elderly, and Drugs/Alcohol (HAS-BLED), Hepatic or Renal Disease, Ethanol Abuse, Malignancy, Older Age, Reduced Platelet Count or Function, Re-Bleeding, Hypertension, Anemia, Genetic Factors, Excessive Fall Risk, and Stroke (HEMORR2HAGES), Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA), Registro Informatizado Enfermedad TromboEmbólica (RIETE), and CHEST scores were validated or evaluated for use with VKAs and parenteral anticoagulants, but evidence for use with DOACs is lacking. Objective: This study aims to evaluate bleeding risk prediction scores for DOAC patients presenting with major bleeding. Methods: A retrospective analysis of patients presenting from 2015 to 2018 was performed. Patients were separated into bleed and nonbleed groups. The primary objective was to assess the diagnostic accuracy of the bleeding risk prediction scores utilizing the receiver operating characteristic (ROC) curve. Results: A total of 126 patients were included in the analyses. The areas under the curve (AUC) for the ROC curves of the HAS-BLED, HEMORR2HAGES, ATRIA, RIETE, and CHEST scores were 0.645, 0.675, 0.580, 0.638, and 0.667, respectively. Conclusion and Relevance: The HAS-BLED, HEMORR2HAGES, RIETE, and CHEST scores were found to have sufficient diagnostic accuracy for predicting risk of major bleeding in our study population; however, no score was identified as having an AUC greater than 0.7. Caution may be considered when utilizing these scores for patients on DOACs.

PMID: 32517484 [PubMed - as supplied by publisher]

Influence of GRK5 gene polymorphisms on ritodrine efficacy and adverse drug events in preterm labor treatment.

Sci Rep. 2020 Jan 28;10(1):1351

Authors: Chung JE, Yee J, Hwang HS, Park JY, Lee KE, Kim YJ, Gwak HS

Abstract
The present prospective follow-up study aimed to evaluate the effects of GRK5 polymorphisms on ritodrine efficacy and adverse drug events (ADEs) in pregnant women undergoing preterm labor. A total of 162 women undergoing preterm labor were included in the study. Seven single nucleotide polymorphisms (SNPs) in the GRK5 gene (rs915120, rs2230345, rs2230349, rs7923896, rs1020672, rs4752308, and rs4752292) were assessed. Homozygous variant carriers of rs4752292 and rs1020672 had 0.6 times the hazard of delivery compared to wild-type allele carriers (95% confidence interval [CI], 0.41~0.99 and 0.38~0.99, respectively). In addition, homozygous variant carriers of rs4752292 and rs1020672 had 2.4-fold more (95% CI, 1.10~4.98) and 2.3-fold more (95% CI, 1.04~5.06) ADEs compared to those with the wild-type homozygotes, respectively. Among demographic variables, gestational age and modified Bishop score were significant factors associated with time to delivery, while body weight and maximum ritodrine infusion rate were significant factors associated with ADEs. In silico analysis showed that both rs4752292 and rs1020672 had the potential to affect mRNA splicing by alteration of splicing motifs. The present study shows that ritodrine efficacy and ADEs are associated with GRK5 gene polymorphisms in pregnant women undergoing preterm labor.

PMID: 31992805 [PubMed - indexed for MEDLINE]

Challenge of Rechallenge: When to Resume Immunotherapy Following an Immune-Related Adverse Event.

J Clin Oncol. 2019 10 20;37(30):2714-2718

Authors: Nakajima EC, Lipson EJ, Brahmer JR

Abstract
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.

PMID: 31461381 [PubMed - indexed for MEDLINE]

Sequence symmetry analysis graphic adjustment for prescribing trends.

BMC Med Res Methodol. 2019 07 09;19(1):143

Authors: Preiss AK, Roughead EE, Pratt NL

Abstract
BACKGROUND: Sequence symmetry analysis (SSA) is a signal detection method that can be used to assist with adverse drug event detection. It provides both a risk estimate and a data visualisation. Published methods provide results in the form of an adjusted sequence ratio, which adjusts for underlying market trends of medicine use, however no method for adjusting the visualisation is available. We aimed to develop and evaluate another method of adjustment for prescribing trends and apply it to the SSA visualisation.
METHODS: The SSA method relies on incident prescriptions for pairs of medicines of interest. Smoothing curves were fitted to the frequency distributions of incident medicine use. When divided and normalised, these curves yielded a set of proportions related to differences in prescribing trends over follow-up. These were then used to adjust the unit counts for incident prescriptions in the SAA visualisation and to calculate the sequence ratio. Curve fitting was also used to identify the proportional relationship between sequences over time for SSA and is presented as a supplementary visualisation to the SSA. We compared the sensitivity and specificity of our method with that from the SSA method of Tsiropolous et al. RESULTS: Curve-fit adjusted SSA visualisations yielded adjusted sequence ratios very close to those of Tsiropolous, with a p-value of 0.999 for the two sample Kolmogorov-Smirnov test. Results for sensitivity and specificity derived from adjusted sequence ratios were also practically the same. The curve-fit method graphically indicates the proportionality of the sequence and provides a useful supplement of net differences between the two sides of the SSA visualisation. Additionally, we found that incident prescriptions for patients common to both distributions are best precluded from adjustment calculations, leaving only incident prescriptions for patients unique to one or other distribution. This improved the accuracy of SSA in some atypical instances with negligible affect on accuracy elsewhere.
CONCLUSIONS: Our curve-fit method is equivalent to current methods in the literature for adjusting prescribing trends in SAA, with the advantage of providing adjustment incorporated in the SAA visualisation.

PMID: 31288743 [PubMed - indexed for MEDLINE]

Treatment Outcomes of Immune-Related Cutaneous Adverse Events.

J Clin Oncol. 2019 10 20;37(30):2746-2758

Authors: Phillips GS, Wu J, Hellmann MD, Postow MA, Rizvi NA, Freites-Martinez A, Chan D, Dusza S, Motzer RJ, Rosenberg JE, Callahan MK, Chapman PB, Geskin L, Lopez AT, Reed VA, Fabbrocini G, Annunziata MC, Kukoyi O, Pabani A, Yang CH, Chung WH, Markova A, Lacouture ME

Abstract
PURPOSE: The aim of the current study was to report the efficacy of topical and systemic treatments for immune-related cutaneous adverse events (ircAEs) attributed to checkpoint inhibitors in an uncontrolled cohort of patients referred to oncodermatology clinics.
METHODS: A retrospective analysis of patients with ircAEs evaluated by dermatologists from January 1, 2014, to December 31, 2017, at three tertiary care hospitals and cancer centers were identified through electronic medical records. Clinicopathologic characteristics, dermatologic therapy outcome, and laboratory data were analyzed.
RESULTS: A total of 285 patients (median age, 65 years [range, 17 to 89 years]) with 427 ircAEs were included: pruritus (n = 138; 32%), maculopapular rash (n = 120; 28%), psoriasiform rash (n = 22; 5%), and others (n = 147; 34%). Immune checkpoint inhibitor class was associated with ircAE phenotype (P = .007), where maculopapular rash was predominant in patients who received combination therapy. Severity of ircAEs was significantly reduced (mean Common Terminology Criteria for Adverse Events grade: 1.74 v 0.71; P < .001) with dermatologic interventions, including topical corticosteroids, oral antipruritics, and systemic immunomodulators. A total of 88 ircAEs (20%) were managed with systemic immunomodulators. Of these, 22 (25%) of 88 persisted or worsened. In seven patients with corticosteroid-refractory ircAEs, improvement resulted from targeted biologic immunomodulatory therapies that included rituximab and dupilumab. Serum interleukin-6 (IL-6) was elevated in 34 (52%) of 65 patients; grade 3 or greater ircAEs were associated with increased absolute eosinophils (odds ratio, 4.1; 95% CI, 1.3 to 13.4) and IL-10 (odds ratio, 23.8; 95% CI, 2.1 to 262.5); mean immunoglobulin E serum levels were greater in higher-grade ircAEs: 1,093 kU/L (grade 3), 245 kU/L (grade 2), and 112 kU/L (grade 1; P = .043).
CONCLUSION: Most ircAEs responded to symptom- and phenotype-directed dermatologic therapies, whereas biologic therapies were effective in patients with corticosteroid-refractory disease. Increased eosinophils, IL-6, IL-10, and immunoglobulin E were associated with ircAEs, and they may represent actionable therapeutic targets for immune-related skin toxicities.

PMID: 31216228 [PubMed - indexed for MEDLINE]

Opioid medication discontinuation and risk of adverse opioid-related health care events.

J Subst Abuse Treat. 2019 08;103:58-63

Authors: Mark TL, Parish W

Abstract
BACKGROUND: Between 2012 and 2017, the United States dramatically reduced opioid prescribing rates. While this may be appropriate given the opioid epidemic, there has been little research to guide the clinical practice of discontinuing patients from opioid medications and opioid death rates have continued to increase.
OBJECTIVE: To determine the relationship between time to opioid discontinuation and the risk of an opioid-related emergency department visit or hospitalization among high dose opioid users.
DESIGN: We applied Cox proportional hazard models to 2013-2017 Medicaid claims data to research this relationship.
PARTICIPANTS: Medicaid beneficiaries in Vermont who filled prescription opioids at high daily doses (at least 120 morphine milligram equivalents) for 90 or more consecutive days and who subsequently discontinued opioid prescriptions (n = 494).
MAIN MEASURES: The outcome was an opioid-related adverse event defined as an emergency department visit or hospitalization with a primary or secondary diagnosis of opioid poisoning or substance use disorder.
KEY RESULTS: The median length of time to discontinuation was 1 day indicating that half of patients had no dose reduction prior to discontinuation. 86% of patients discontinued within 21 days (considered rapid tapering in recent clinical guidelines). 49% of members had an opioid-related hospitalization or emergency department visit. After controlling for sociodemographic and clinical factors, each additional week of discontinuation time was associated with a 7% reduction in the probability of having opioid related adverse event (p < 0.01). Although 60% of members had a diagnosed substance use disorder prior to tapering, <1% of beneficiaries were transitioned onto an opioid use disorder medication.
CONCLUSIONS: Faster rates of opioid tapering were associated with a greater probability of adverse events and many patients discontinued opioids suddenly, with no dose reduction. Additional clinical guidance, research, and interventions are needed to ensure that patients' opioid prescriptions are discontinued safely.

PMID: 31079950 [PubMed - indexed for MEDLINE]

Can acetylcysteine ameliorate cisplatin-induced toxicities and oxidative stress without decreasing antitumor efficacy? A randomized, double-blind, placebo-controlled trial involving patients with head and neck cancer.

Cancer Med. 2019 05;8(5):2020-2030

Authors: Visacri MB, Quintanilha JCF, de Sousa VM, Amaral LS, de F L Ambrósio R, Calonga L, Curi SFBB, de T Leme MF, Chone CT, Altemani JMC, Mazzola PG, Malaguti C, Vercesi AE, Lima CSP, Moriel P

Abstract
The protective antioxidant activity of acetylcysteine (NAC) against toxicity due to cisplatin has been reported in experimental models; however, its efficacy in patients has not been elucidated. The aim of this study was to investigate the possible protective effect of NAC on cisplatin-induced toxicity and the effect of NAC on clinical response and oxidative stress in patients treated for head and neck cancer. This was a randomized, double-blind, placebo-controlled trial conducted in patients receiving high-dose cisplatin chemotherapy concomitant to radiotherapy. Patients were randomly assigned to groups and received: (a) 600 mg NAC syrup, orally once daily at night for 7 consecutive days or (b) placebo, administered similarly to NAC. Nephro-, oto-, hepato-, myelo-, and gastrointestinal toxicities, clinical responses, and plasma and cellular markers of oxidative stress were evaluated. Fifty-seven patients were included (n = 28, NAC arm; and n = 29, placebo arm). A high prevalence of most types of toxicities was observed after cisplatin chemotherapy; however, the parameters were similar between the two groups. There was a predominance of partial response to treatment. In the cellular and plasmatic oxidative stress analyses, minor differences were observed. Overall, there was no statistically significant difference between the groups for all outcomes. These findings show that low-dose oral NAC does not protect patients with head and neck cancer from cisplatin-induced toxicities and oxidative stress. The antitumor efficacy of cisplatin was apparently not impaired by NAC.

PMID: 30977273 [PubMed - indexed for MEDLINE]

Fixed combination of oral NEPA (netupitant-palonosetron) for the prevention of acute and delayed chemotherapy-induced nausea and vomiting in patients receiving multiple cycles of chemotherapy: Efficacy data from 2 randomized, double-blind phase III studies.

Cancer Med. 2019 05;8(5):2064-2073

Authors: Schwartzberg L, Karthaus M, Rossi G, Rizzi G, Borroni ME, Rugo HS, Jordan K, Hansen V

Abstract
AIM: To assess the efficacy of oral NEPA (netupitant-palonosetron 300/0.50 mg) over multiple chemotherapy cycles.
METHODS: Two randomized phase III studies evaluated a single dose of oral NEPA given on day 1 in chemotherapy-naive patients receiving anthracycline-cyclophosphamide (AC)-based (Study 1) or highly (HEC)/moderately (MEC) emetogenic chemotherapy (safety Study 2). Oral NEPA was compared with oral palonosetron 0.50 mg (Study 1) or oral aprepitant 125 mg day 1, 80 mg days 2-3/palonosetron 0.50 mg (Study 2; no formal statistical comparisons). Oral dexamethasone was administered in all treatment groups. Complete response (CR; no emesis/no rescue medication), no emesis, and no significant nausea (NSN) rates during acute (0-24 h) and delayed (>24-120 h) phases of chemotherapy cycles 1-4 in each study were evaluated.
RESULTS: In Study 1, 1450 patients received 5969 chemotherapy cycles; in Study 2, 412 patients received 1961 chemotherapy cycles. In each study, ≥75% of patients completed 4 or more cycles. In Study 1, oral NEPA was superior to palonosetron in preventing chemotherapy-induced nausea and vomiting (CINV) in the acute and delayed phases of cycle 1, with higher rates of CR (all P < 0.05), no emesis (all P < 0.05), and NSN (delayed phase P < 0.05 cycles 1, 2, and 4) reported across 4 cycles. In Study 2, oral NEPA had numerically higher CR and NSN rates in the acute and delayed phases than aprepitant-palonosetron in MEC/HEC patients.
CONCLUSION: Oral NEPA was highly effective in preventing both acute and delayed CINV over multiple chemotherapy cycles of HEC, AC, and MEC regimens.
CLINICAL TRIAL REGISTRATION NUMBERS: Study 1, NCT01339260; Study 2, NCT01376297.

PMID: 30968588 [PubMed - indexed for MEDLINE]