The association between self-reported health status and adverse events: a comparison among coronary artery bypass grafting (CABG) versus percutaneous coronary intervention (PCI).

Qual Life Res. 2020 Nov;29(11):3017-3029

Authors: Nielsen SN, Rasmussen TB, Lassen JF, Berg SK, Thrysoee L, Møller JE, Jensen LO, Thuesen AL, Christensen AV, Ekholm O, Mols R, Thorup CB, Borregaard B

Abstract
PURPOSE: While several studies have investigated clinical outcomes following coronary artery bypass grafting (CABG) vs. percutaneous coronary intervention (PCI), studies investigating self-reported health and the association with adverse outcomes are limited. Thus, the aim was to investigate differences in health-related quality of life (HRQoL), anxiety and depression at discharge and the association with a composite endpoint of the first event of acute cardiac readmission, revascularisation or 1-year mortality among patients undergoing CABG vs. PCI.
METHODS: Data from the national cohort study, DenHeart, were used, including measures of HRQoL; EuroQoL-5D-5L (EQ-5D Index Score and VAS) and HeartQoL (Global, Physical and Emotional), anxiety and depression (Hospital Anxiety and Depression Scale, HADS) and register-based follow-up. A total of 7000 patients were included (CABG n = 652, PCI n = 6348) (median age 65, 75% men). Cox Proportional Hazard models were performed among a propensity-matched population of responders (n = 520).
RESULTS: HRQoL was significantly better among patients undergoing PCI vs. CABG, but with no differences in time to readmission or revascularisation. HRQoL, anxiety and depression were significantly associated with the risk of the composite endpoint among the PCI group (Hazard Ratio, HR (95% confidence intervals, CI) [EQ-5D index score 3.07 (1.67-5.67), EQ-5D VAS 0.97 (0.96-0.99), HeartQol Global 0.61 (0.38-0.95), HeartQol Emotional 0.56 (0.39-0.80), HADS-D ≥ 8 3.12 (1.61-6.01), HADS-A ≥ 8 2.08 (1.14-3.80)].
CONCLUSION: Patients undergoing PCI reported better HRQoL at discharge compared with patients undergoing CABG, whereas readmission rates were similar. Self-reported health was associated with the risk of adverse events among patients undergoing PCI, but not among patients undergoing CABG.
CLINICAL TRIAL REGISTRATION: NCT01926145.

PMID: 32857268 [PubMed - indexed for MEDLINE]

Pharmacogenetics for severe adverse drug reactions induced by molecular-targeted therapy.

Cancer Sci. 2020 Oct;111(10):3445-3457

Authors: Udagawa C, Zembutsu H

Abstract
Molecular-targeted drugs specifically interfere with molecules that are frequently overexpressed or mutated in cancer cells. As such, these drugs are generally considered to precisely attack cancer cells, thereby inducing fewer adverse drug reactions (ADRs). However, molecular-targeted drugs can still cause characteristic ADRs that, although rarely severe, can be life-threatening. Therefore, it is becoming increasingly important to be able to predict which patients are at risk of developing ADRs after treatment with molecular-targeted therapy. The emerging field of pharmacogenetics aims to better distinguish the genetic variants associated with drug toxicity and efficacy to improve the selection of therapeutic strategies for each genetic profile. Here, we provide an overview of the current reports on the relationship between genetic variants and molecular-targeted drug-induced severe ADRs in oncology.

PMID: 32780457 [PubMed - indexed for MEDLINE]

Lorlatinib in previously treated anaplastic lymphoma kinase-rearranged non-small cell lung cancer: Japanese subgroup analysis of a global study.

Cancer Sci. 2020 Oct;111(10):3726-3738

Authors: Seto T, Hayashi H, Satouchi M, Goto Y, Niho S, Nogami N, Hida T, Takahashi T, Sakakibara-Konishi J, Morise M, Nagasawa T, Suzuki M, Ohkura M, Fukuhara K, Thurm H, Peltz G, Nishio M

Abstract
Lorlatinib is a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (ALK)/ROS proto-oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI) that is active against most known resistance mutations. This is an ongoing phase 1/2, multinational study (NCT01970865) investigating the efficacy, safety and pharmacokinetics of lorlatinib in ALK-rearranged/ROS1-rearranged advanced non-small cell lung cancer (NSCLC) with or without intracranial (IC) metastases. Because patterns of ALK TKI use in Japan differ from other regions, we present a subgroup analysis of Japanese patients. Patients were enrolled into six expansion (EXP) cohorts based on ALK/ROS1 mutation status and treatment history. The primary endpoint was the objective response rate (ORR) and the IC-ORR based on independent central review. Secondary endpoints included pharmacokinetic evaluations. At data cutoff, 39 ALK-rearranged/ROS1-rearranged Japanese patients were enrolled across the six expansion cohorts; all received lorlatinib 100 mg once daily. Thirty-one ALK-rearranged patients previously treated with ≥1 ALK TKI (EXP2 to EXP5) were evaluable for ORR and 15 were evaluable for IC-ORR. The ORR and the IC-ORR for Japanese patients in EXP2-5 were 54.8% (95% confidence interval [CI]: 36.0-72.7) and 46.7% (95% CI: 21.3-73.4), respectively. Among patients who had received prior alectinib only (EXP3B), the ORR was 42.9%; 95% CI: 9.9-81.6). The most common treatment-related adverse event (TRAE) was hypercholesterolemia (79.5%). Hypertriglyceridemia was the most common grade 3/4 TRAE (25.6%). Single-dose and multiple-dose pharmacokinetic profiles among Japanese patients were similar to those in non-Japanese patients. Lorlatinib showed clinically meaningful responses and IC responses among ALK-rearranged Japanese patients with NSCLC who received ≥1 prior ALK TKI, including meaningful responses among those receiving prior alectinib only. Lorlatinib was generally well tolerated.

PMID: 32681682 [PubMed - indexed for MEDLINE]

Clinicians versus patients subjective adverse events assessment: based on patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE).

Qual Life Res. 2020 Nov;29(11):3009-3015

Authors: Liu L, Suo T, Shen Y, Geng C, Song Z, Liu F, Wang J, Xie Y, Zhang Y, Tang T, Zhang L, Wang W

Abstract
PURPOSE: Adverse events (AEs) assessment by clinicians is a standard practice in a clinical setting. However, studies have found clinicians tend to report fewer AEs, especially subjective AEs. We aimed to explore the difference of subjective AEs assessment between clinicians and patients based on PRO-CTCAE, and to discuss the necessity of incorporating patient into the evaluation of AEs.
METHODS: Between April and July 2019, two different questionnaires with the same subjective AEs were given to patients and clinicians in the Day Chemotherapy ward of Breast Center in the Fourth Hospital of HeBei Medical University. Patients completed a Simplified Chinese version of PRO-CTCAE, including six common subjective AEs of chemotherapy: nausea, vomiting, diarrhea, fatigue, pain, and constipation. Clinicians completed the common terminology criteria for adverse events (CTCAE) with the same AEs. General information of enrolled patients and results from the questionnaires were collected and analyzed.
RESULTS: 384 paired questionnaires were collected. Clinicians reported less subjective AEs than patients, and the general agreement between patients and clinicians was poor. When considering the grade difference, we utilize weighted kappa coefficient to analysis, and agreement between patients and clinicians was poor (k < 0.4) regardless of the frequency, the severity and interfering with daily life of AEs, and the most discrepancies were within one point. Patients tended to grade severer than the clinician.
CONCLUSIONS: The results of this study showed that there were differences between clinicians and patients in subjective adverse events evaluation. Patient reporting of symptoms can be used as a supplementary method to incorporate the current approach to monitor subjective AEs, to improve the timeliness and accuracy of clinical evaluation of subjective AEs.

PMID: 32564293 [PubMed - indexed for MEDLINE]

Three-dimensional liver models: state of the art and their application for hepatotoxicity evaluation.

Crit Rev Toxicol. 2020 04;50(4):279-309

Authors: Zhang X, Jiang T, Chen D, Wang Q, Zhang LW

Abstract
While alternative methods for toxicity testing using re-constructed human skin and cornea have been written into guidelines and adopted by regulatory authorities, three-dimensional (3D) liver models are currently applied in the industrial settings for hepatotoxicity screening and prediction. These 3D liver models can recapitulate the architecture, functionality and toxicity response of the native liver, demonstrated by a set of related hallmarks. In this comprehensive review, non-scaffold and scaffold-based methods available for 3D liver model formation are introduced, with an emphasis on their advantages and drawbacks. We then focus on the characteristics of primary human hepatocytes, stem cell derived hepatocyte like cells, and immortalized hepatic cell lines as cell resources for model reconstruction. Primary hepatocytes are generally regarded to be superior to other cell types due to their comparable metabolic profiles to the native liver. Additionally, the application of 3D liver models (mostly liver spheroids) on the evaluation of drug induced liver injury and chronic liver diseases (steatosis, cirrhosis, cholestasis), as well as the potential of nanomaterials to introduce hepatotoxicity are summarized. Finally, the global 3D cell market from 3D liver model manufacturing to the contract service of in vitro hepatotoxicity testing using the models is extensively explored. However, 3D liver models face cultural and regulatory barriers in different countries, and therefore the business development of 3D liver models is not easy. Toxicologists, material scientists, engineers should work together to develop, validate and apply 3D liver models for hepatotoxicity testing under the support from industrial organizations and governmental agencies.

PMID: 32419588 [PubMed - indexed for MEDLINE]

57 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 2020/12/15

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.

57 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 2020/12/15

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.

A Rare, Unreported Cognitive Side Effect of Topiramate: Do We Know It All Yet?

Cureus. 2020 Nov 05;12(11):e11342

Authors: Karim N, Sheikh AA

Abstract
This report describes a unique, dose dependent side effect of a commonly used drug, topiramate. Although cognitive side effects of this drug have previously been reported in literature, we present a case of drug-induced amnesia, with support from Naranjo Nomogram, as a hitherto unreported side effect of topiramate. Here, we highlight the importance of being cognizant of such rare cognitive side effects, with the aim of improving patient outcome by timely recognition, and discontinuation of the offending drug, as the side effect was fortunately found to be reversible.

PMID: 33304678 [PubMed]

A systematic review on treatment-related mucocutaneous reactions in COVID-19 patients.

Dermatol Ther. 2020 Dec 10;:

Authors: Najar Nobari N, Seirafianpour F, Mashayekhi F, Goodarzi A

Abstract
Most of drugs could have certain mucocutaneous reactions and COVID-19 drugs are not an exception that we focused. We systematically reviewed databases until August/15/2020 and among initial 851 articles, 30 articles entered this study (20 case reports, 4 cohorts and 6 controlled clinical trials). The types of reactions included AGEP, morbiliform drug eruptions, vasculitis, DRESS syndrome, urticarial vasculitis and etc. The treatments have been used before side effects occur, included: antimalarial, anti-viral, antibiotics, tocilizumab, enoxaparin and etc. In pandemic, we found 0.004% to 4.15% of definite drug-induced mucocutaneous reactions. The interval between drug usage and the eruption varied about few hours to 1 month; tightly dependent to the type of drug and hydroxychloroqine seems to be the drug with highest mean interval. Antivirals, antimalarials, azithromycin and tocilizumab are most responsive drugs for adverse drug reactions, but antivirals especially in combination with antimalarial drugs are in the first step. Types of skin reactions are usually morbilliform/exanthematous maculopapular rashes or urticarial eruptions which mostly may manage by steroids during few days. In the setting of HCQ, specific reactions like AGEP should be considered. lopinavir/ritonavir is the most prevalent used drug among antivirals with the highest skin adverse reaction; ribarivin and remdisivir also could induce cutaneous drug reactions but favipiravir has no or less adverse effects. Logically the rate of dermatologic adverse effects among anivirals may relate to their frequency of usage. Rarely, potentially life-threatening reactions may occur. Better management strategies could achieve by knowing more about drug-induced mucocutaneous presentations of COVID-19. This article is protected by copyright. All rights reserved.

PMID: 33301232 [PubMed - as supplied by publisher]

[Mesalazine-induced myocarditis].

Nihon Shokakibyo Gakkai Zasshi. 2020;117(12):1093-1099

Authors: Koh Y, Nagaya T, Saegusa H, Ikeuchi H, Kodama R, Ushimaru H

Abstract
A 30-year-old man presented with constipation and abdominal pain. He was suspected of having ulcerative colitis, and administration of 2400mg/day of oral mesalazine was initiated. After 10 days of treatment, he experienced fever and chest pain. Blood examination, electrocardiography, and cardiac ultrasonography revealed elevated cardiac enzymes, ST-segment elevation, and diffuse hypokinesis, respectively. Mesalazine-induced acute myocarditis was diagnosed based on a positive drug-induced lymphocyte stimulation test and the absence of other myocarditis-causing conditions. Prompt cessation of mesalazine quickly improved his heart function and test results. Although rare, clinicians should consider the possibility of cardiac adverse events caused by mesalazine.

PMID: 33298675 [PubMed - in process]

Risk factors for emergency department revisit in elderly patients with gastrointestinal bleeding secondary to anticoagulant therapy.

Eur J Hosp Pharm. 2020 Dec 08;:

Authors: Ruiz J, López-Vinardell L, Juanes A, Riera-Magallon A, Puig M, Mangues MA

Abstract
OBJECTIVE: To evaluate the frequency of emergency department (ED) revisits among elderly patients with gastrointestinal bleeding secondary to anticoagulant treatment and identify factors associated with an increased risk of ED revisits.
METHODS: A 3-year retrospective observational study was designed, including elderly patients (≥65 years) with atrial fibrillation and undergoing oral anticoagulation therapy who visited the ED for gastrointestinal bleeding. To evaluate the risk factors for 30-day revisit, a multivariate analysis was designed including comorbidities, concomitant treatment, change in anticoagulant treatment and prescription of direct-acting oral anticoagulants.
RESULTS: 80 patients were included. At discharge, anticoagulation therapy was modified in 21 (26.2%) patients; and changed from an oral anticoagulant to heparin in 17 (21.2%) patients and to another oral anticoagulant in 4 (5.0%) patients. Anticoagulant treatment was withdrawn in 5 (6.3%) patients at discharge. Eleven (13.7%) patients revisited the ED 30 days after hospital discharge for bleeding episodes. No differences in the frequency of revisit to the ED were observed in the patients who changed their anticoagulant treatment at discharge. In the multivariate analysis, chronic kidney disease was the only factor significantly associated with revisits at 30 days.
CONCLUSIONS: Elderly patients who experience a first episode of gastrointestinal bleeding have a high risk of revisiting the ED for a bleeding episode, with no particular differences between the types of anticoagulant prescribed at discharge.

PMID: 33293283 [PubMed - as supplied by publisher]

Safety and efficacy of the cystic fibrosis transmembrane conductance regulator potentiator icenticaftor (QBW251).

J Cyst Fibros. 2020 Dec 05;:

Authors: Kazani S, Rowlands DJ, Bottoli I, Milojevic J, Alcantara J, Jones I, Kulmatycki K, Machineni S, Mostovy L, Nicholls I, Nick JA, Rowe SM, Simmonds NJ, Vegesna R, Verheijen J, Danahay H, Gosling M, Ayalavajjala PS, Salman M, Strieter R

Abstract
BACKGROUND: This is the first-in-human study of icenticaftor, an oral potentiator of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) channel. Restoration of CFTR activity has shown significant clinical benefits, but more studies are needed to address all CFTR mutations.
METHODS: Safety, pharmacodynamics/pharmacokinetics of icenticaftor were evaluated in a randomized, double-blind, placebo-controlled study in healthy volunteers. Efficacy was assessed in adult CF patients with ≥1 pre-specified CFTR Class III or IV mutation (150 and 450 mg bid), or homozygous for F508del mutation (450 mg bid). Primary efficacy endpoint was change from baseline in lung clearance index (LCI2.5). Secondary endpoints included %predicted FEV1 and sweat chloride level.
RESULTS: Class IV mutations were present in 22 patients, Class III in 2 (both S549N), and 25 were homozygous for F508del. Icenticaftor was well-tolerated in healthy and CF subjects with no unexpected events or discontinuations in the CF groups. The most frequent study-drug related adverse events in CF patients were nausea (12.2%), headache (10.2%), and fatigue (6.1%). Icenticaftor 450 mg bid for 14 days showed significant improvements in all endpoints versus placebo in patients with Class III and IV mutations; mean %predicted FEV1 increased by 6.46%, LCI2.5 decreased by 1.13 points and sweat chloride decreased by 8.36 mmol/L. No significant efficacy was observed in patients homozygous for a single F508del.
CONCLUSIONS: Icenticaftor was safe and well-tolerated in healthy volunteers and CF patients, and demonstrated clinically meaningful changes in lung function and sweat chloride level in CF patients with Class III and IV CFTR mutations. ClinicalTrials.gov: NCT02190604.

PMID: 33293212 [PubMed - as supplied by publisher]

Paediatric formulations of artemisinin-based combination therapies for treating uncomplicated malaria in children.

Cochrane Database Syst Rev. 2020 Dec 08;12:CD009568

Authors: Bélard S, Ramharter M, Kurth F

Abstract
BACKGROUND: In endemic malarial areas, young children have high levels of malaria morbidity and mortality. The World Health Organization recommends oral artemisinin-based combination therapy (ACT) for treating uncomplicated malaria. Paediatric formulations of ACT have been developed to make it easier to treat children.
OBJECTIVES: To evaluate evidence from trials on the efficacy, safety, tolerability, and acceptability of paediatric ACT formulations compared to tablet ACT formulations for uncomplicated P falciparum malaria in children up to 14 years old.
SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; Embase; the Latin American and Caribbean Health Science Information database (LILACS); ISI Web of Science; Google Scholar; Scopus; and the metaRegister of Controlled Trials (mRCT) to 11 December 2019.
SELECTION CRITERIA: We included randomised controlled clinical trials (RCTs) of paediatric versus non-paediatric formulated ACT in children aged 14 years or younger with acute uncomplicated malaria.
DATA COLLECTION AND ANALYSIS: Two authors independently assessed eligibility and risk of bias, and carried out data extraction. We analyzed the primary outcomes of efficacy, safety and tolerability of paediatric versus non-paediatric ACT using risk ratios (RR) and 95% confidence intervals (CI). Secondary outcomes were: treatment failure on the last day of observation (day 42), fever clearance time, parasite clearance time, pharmacokinetics, and acceptability.
MAIN RESULTS: Three trials met the inclusion criteria. Two compared a paediatric dispersible tablet formulation against crushed tablets of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHA-PQ), and one trial assessed artemether-lumefantrine formulated as powder for suspension compared with crushed tablets. The trials were carried out between 2006 and 2015 in sub-Saharan Africa (Benin, Mali, Mozambique, Tanzania, Kenya, Democratic Republic of the Congo, Burkina Faso, and The Gambia). In all three trials, the paediatric and control ACT achieved polymerase chain reaction (PCR)-adjusted treatment failure rates of < 10% on day 28 in the per-protocol (PP) population. For the comparison of dispersible versus crushed tablets, the two trials did not detect a difference for treatment failure by day 28 (PCR-adjusted PP population: RR 1.35, 95% CI 0.49 to 3.72; 1061 participants, 2 studies, low-certainty evidence). Similarly, for the comparison of suspension versus crushed tablet ACT, we did not detect any difference in treatment failure at day 28 (PCR-adjusted PP population: RR 1.64, 95% CI 0.55 to 4.87; 245 participants, 1 study). We did not detect any difference in serious adverse events for the comparison of dispersible versus crushed tablets (RR 1.05, 95% CI 0.38 to 2.88; 1197 participants, 2 studies, low-certainty evidence), or for the comparison of suspension versus crushed tablet ACT (RR 0.74, 95% CI 0.17 to 3.26; 267 participants, 1 study). In the dispersible ACT arms, drug-related adverse events occurred in 9% of children in the AL study and 34% of children in the DHA-PQ study. In the control arms, drug-related adverse events occurred in 12% of children in the AL study and in 42% of children in the DHA-PQ study. Drug-related adverse events were lower in the dispersible ACT arms (RR 0.78, 95% CI 0.62 to 0.99; 1197 participants, 2 studies, moderate-certainty evidence). There was no detected difference in the rate of drug-related adverse events for suspension ACT versus crushed tablet ACT (RR 0.66, 95% CI 0.33 to 1.32; 267 participants, 1 study). Drug-related vomiting appeared to be less common in the dispersible ACT arms (RR 0.75, 95% CI 0.56 to 1.01; 1197 participants, 2 studies, low-certainty evidence) and in the suspension ACT arm (RR 0.66, 95% CI 0.33 to 1.32; 267 participants, 1 study), but both analyses were underpowered. No study assessed acceptability.
AUTHORS' CONCLUSIONS: Trials did not demonstrate a difference in efficacy between paediatric dispersible or suspension ACT when compared with the respective crushed tablet ACT for treating uncomplicated P falciparum malaria in children. However, the evidence is of low to moderate certainty due to limited power. There appeared to be fewer drug-related adverse events with dispersible ACT compared to crushed tablet ACT. None of the included studies assessed acceptability of paediatric ACT formulation.

PMID: 33289099 [PubMed - in process]

Safety of oral fluconazole in early pregnancy.

Drug Ther Bull. 2020 Dec 07;:

Authors:

Abstract
Every month, DTB scans sources of information on treatments, disease management and other healthcare topics for key items to bring to our readers' attention and help them keep up to date. To do this, we produce succinct, contextualised summaries of the information concerned.

PMID: 33288501 [PubMed - as supplied by publisher]

Computerised risk scores to guide recognition and diagnosis in patients with possible heparin-induced thrombocytopenia.

Br J Haematol. 2020 Sep 10;:

Authors: Gallo T, Curry SC, Raschke RA

Abstract
The heparin-induced thrombocytopenia computerised risk (HIT-CR) score is designed to aid in the diagnosis of HIT. We sought to evaluate its potential clinical utility. In this retrospective cohort study, we collected HIT-CR scores on all inpatients receiving heparin over a 4-month period and performed chart reviews on the subset who independently underwent clinical diagnostic testing for HIT to identify patients with HIT. In all, 34 342 patients received heparin, 1744 had high-risk HIT-CR scores of ≥3 and 220 had the maximal risk score of 4. Only 6% of high-risk and 10% of maximal-risk patients underwent testing for HIT. Conversely, among all 317 patients who underwent independent testing for HIT, 67% had low-risk HIT-CR scores (<3). Among patients independently tested, the positive predictive value (PPV) was 6·6% [95% confidence interval (CI) 4·9-8·8%] and the negative predictive value (NPV) was 99·5% (95% CI 97·1-99·9%) at a HIT-CR score cut-off of 3, and the PPV was 22·7% (95% CI 12·7-37·4%) and NPV was 99·0% (95% CI 97·6-99·6%) at a cut-off of 4. This study suggests clinicians fail to test most high-risk patients and unnecessarily test many low-risk patients for HIT. A reasonable approach to clinical application of HIT-CR scores would be recommending no testing for patients with a score of <3 and recommend testing for patients with a score of 4.

PMID: 33280095 [PubMed - as supplied by publisher]

Safety, Tolerability and Pharmacokinetics of Single and Repeat Doses of Vixotrigine in Healthy Volunteers.

Clin Transl Sci. 2020 Dec 05;:

Authors: Naik H, Steiner DJ, Versavel M, Palmer J, Fong R

Abstract
Neuropathic pain affects ~ 6.9-10% of the general population and leads to loss of function, anxiety, depression, sleep disturbance, and impaired cognition. Here we report the safety, tolerability, and pharmacokinetics of a voltage- and use-dependent sodium channel blocker, vixotrigine, currently under investigation for the treatment of neuropathic pain conditions. The randomized, placebo-controlled, phase I clinical trials were split into single (SAD) and multiple ascending dose (MAD) studies. Healthy volunteers received oral vixotrigine as either single doses followed by a ≥ 7-day washout period for up to five dosing sessions (SAD, n = 30), or repeat doses (once or twice daily) for 14 and 28 days (MAD, n = 51). Adverse events (AEs), maximum observed vixotrigine plasma concentration (Cmax ), area under the concentration-time curve from predose to 24 hours postdose (AUC0-24 ), time to Cmax (Tmax ), and terminal half-life (t1/2 ), among others, were assessed. Drug-related AEs were reported in 47% and 53% of volunteers in the SAD and MAD studies, respectively, with dizziness as the most commonly reported drug-related AE. SAD results showed that Cmax and AUC increased with dose, Tmax was 1-2 hours, and t1/2 was ~ 11 hours. A two-fold increase in accumulation was observed when vixotrigine was taken twice vs. once daily (MAD). Steady state was achieved from day 5 onward. These data indicate that oral vixotrigine is well tolerated when administered as single doses up to 825 mg and multiple doses up to 450 mg twice daily.

PMID: 33278330 [PubMed - as supplied by publisher]

Risk of serious spinal adverse events associated with epidural corticosteroid injections in the Medicare population.

Reg Anesth Pain Med. 2020 Dec 04;:

Authors: Eworuke E, Crisafi L, Liao J, Akhtar S, Van Clief M, Racoosin JA, Wernecke M, MaCurdy TE, Kelman JA, Graham DJ

Abstract
BACKGROUND: Epidural corticosteroid injections (ESIs) are widely performed and have an unquantified risk of serious spinal adverse events (SSAEs). We sought to determine the rate of SSAEs following ESI and to compare the rates by spinal level, injection approach and corticosteroid formulation.
METHODS: We included patients enrolled in Medicare parts A and B who had an ESI between 1 January 2009 and 30 September 2015. We identified potential cases as patients with spine-related diagnoses within 3 days after the first eligible ESI. Event categorization as probable, possible or non-case was based on review of medical records. The rates of probable and possible cases were expressed per 1 000 000 patients overall, and by spinal level, injection approach and corticosteroid formulation. A score test was used to compare these rates.
RESULTS: We identified 1 355 957 eligible ESIs during the study period. Of the 110 potential cases, 43 were selected for medical record review and 11 were categorized as probable, yielding a rate of 8.1 per 1 000 000 patients (95% CI 4.5 to 14.5). Risk of SSAEs was statistically higher with cervical/thoracic injections (29.4, 95% CI 12.5 to 68.8) compared with lumbar/sacral injections (5.1, 95% CI 2.3 to 11.0) (p value 0.001). Event rates for lumbar/sacral non-transforaminal injections was 8.8 (95% CI 4.0 to 19.1). Event rates for particulate (7.5, 95% CI 3.9 to 14.2) and non-particulate formulations (13.1, 95% CI 3.6 to 47.9) appeared similar (p value 0.47).
CONCLUSION: Between 2009 and 2015, rates of SSAEs following ESI in the Medicare population were low. Patients receiving cervical/thoracic ESIs were at higher risk of SSAE than those receiving lumbar/sacral ESIs. Event rates were similar for each corticosteroid formulation.

PMID: 33277405 [PubMed - as supplied by publisher]

Phase I trial of 131I-GMIB-Anti-HER2-VHH1, a new promising candidate for HER2-targeted radionuclide therapy in breast cancer patients.

J Nucl Med. 2020 Dec 04;:

Authors: D'Huyvetter M, De Vos J, Caveliers V, Vaneycken I, Heemskerk J, Duhoux FP, Fontaine C, Vanhoeij M, Windhorst AD, van der Aa F, Hendrikse NH, Eersels JLE, Everaert H, Gykiere P, Devoogdt N, Raes G, Lahoutte T, Keyaerts M

Abstract
Introduction: 131I-GMIB-Anti-HER2-VHH1 is a targeted radionuclide theranostic agent directed at HER2 expressing cancers. VHH1 is a single domain antibody fragment covalently linked to therapeutic radio-iodine 131I via the linker SGMIB. The Phase I study presented was aimed at evaluating the safety, biodistribution, radiation dosimetry and tumor imaging potential of 131I-GMIB-Anti-HER2-VHH1 in healthy volunteers and breast cancer patients. Methods: In a first cohort, six healthy volunteers were included. The biodistribution of 131I-GMIB-Anti-HER2-VHH1 was assessed using whole body (anterior and posterior) planar images obtained at 40 min., 2, 4, 24 and 72 h following i.v. administered (38 ± 9 MBq) 131I-GMIB-VHH1. Imaging data were analyzed using OLINDA/EXM software 1.0 to determine the dosimetry. Blood and urine samples were obtained over 72h. In the second cohort, three patients with metastatic HER2 positive breast cancer were included. Planar whole-body imaging was performed at 2 h and 24 h after injection. Additional SPECT/CT images were obtained following the whole body images at 2 and 24 h in case of relevant uptake in known cancer lesions Results: No drug related adverse events (AEs) were observed throughout the study. The biological half-life of 131I-GMIB-Anti-HER2-VHH1 in healthy subjects was about 8 h. After i.v. administration, the compound is eliminated from the blood with a 2.5 h half-life. The drug is primarily eliminated via the kidneys. The drug was stable in circulation and there was no increased accumulation in thyroid or stomach. The absorbed dose to the kidneys was 1.54 ± 0.25 mGy/MBq, while to bone marrow 0.03 ± 0.01 mGy/MBq. SPECT/CT imaging in patients with advanced breast cancer showed focal uptake of 131I-GMIB-Anti-HER2-VHH1 in metastatic lesions. Conclusion: No AEs were observed after iv administration of 131I-GMIB-Anti-HER2-VHH1 at low activity. Unbound drug is rapidly eliminated via the kidneys. In patients with stage IV HER2 positive breast cancer accumulation of 131I-GMIB-Anti-HER2-VHH1 in metastatic sites was observed. Dosimetry predicts kidneys as the dose limiting organ upon dose escalation, but kidney toxicity should only occur at very high injected activities. Dose escalation is planned in a subsequent phase I/II study to assess the therapeutic window of this compound (NCT04467515).

PMID: 33277400 [PubMed - as supplied by publisher]

Palliative- and non-palliative indications for glucocorticoids use in course of immune-checkpoint inhibition. Current evidence and future perspectives.

Crit Rev Oncol Hematol. 2020 Nov 17;157:103176

Authors: Marinelli D, Giusti R, Mazzotta M, Filetti M, Krasniqi E, Pizzuti L, Landi L, Tomao S, Cappuzzo F, Ciliberto G, Barba M, Vici P, Marchetti P

Abstract
Immune-checkpoint inhibitors significantly reshaped treatment landscapes in several solid tumors. Concurrently with disease-oriented therapies, cancer patients often require proper management of drug-related adverse events and/or cancer-related symptoms. Glucocorticoids (GC) are a cornerstone of symptom management in advanced cancer care and in the management of immune-related adverse events (irAEs) due to immune-modulating therapies. Moreover, GC are often administered in patients with autoimmune diseases (AID), either alone or in combination with other treatments. While handling of irAEs with GC is supported by multiple guidelines, it is unclear whether GC administration because of pre-existing AID or because of palliative needs is associated with inferior outcomes in cancer patients treated with immune-checkpoint inhibitors (ICIs). When globally considered, the available evidence seems to orient towards less favorable survival outcomes when GC administration is driven by a palliative intent. Conversely, steroid administration for non-palliative intent seems to be associated with stable or negligibly reduced survival outcomes.

PMID: 33276183 [PubMed - as supplied by publisher]

Immunosuppressant-induced cutaneous drug reactions in solid organ transplant recipients.

Transpl Immunol. 2020 Nov 29;:101355

Authors: Miotto IZ, de Castro E Souza B, Tyring SK, de Oliveira WRP

Abstract
Solid organ transplant recipients (SOTRs) are susceptible to various cutaneous side effects as a consequence of long-term immunosuppressive therapy. Skin cancers and infections are well-studied complications that can cause death and/or allograft rejection. Other cutaneous drug reactions, such as inflammatory manifestations, have a high prevalence but are rarely studied. We analyzed these manifestations' prevalence and their association with immunosuppressants in transplant recipients from a Brazilian tertiary center. Among 532 SOTRs followed at our dermatology clinic, 60 (11.3%) developed some cutaneous adverse reactions to the immunosuppressants, with a median age at transplantation of 50.5 years and a median life span posttransplantation of seven years. Acneiform eruption was the most common drug reaction found (21 patients, 30.4%), followed by diffuse non-scarring alopecia (16 patients, 23.1%), lymphedema (10 patients, 14.5%), gingival hyperplasia (7 patients, 10.1%), hypertrichosis (6 patients, 8.7%) and sebaceous hyperplasia (9 patients, 13.1%). Adequate immunosuppression is an essential prerequisite for successful organ transplantation. In the immediate post-transplant period, significant immunosuppression is needed, but after that, the complications of excessive immunosuppression outweigh the risk of organ rejection. SORTs may present with a broad spectrum of inflammatory and cosmetic findings due to immunosuppressants that can impair life quality.

PMID: 33264680 [PubMed - as supplied by publisher]