Association between ATT and Hepatotoxicity: Food for Thought.

Indian J Pediatr. 2019 03;86(3):211-213

Authors: Mathew JL

Abstract

PMID: 30762203 [PubMed - indexed for MEDLINE]

Postmarketing Safety-Related Modifications of Drugs Approved by the US Food and Drug Administration Between 1999 and 2014 Without Randomized Controlled Trials.

Mayo Clin Proc. 2019 01;94(1):74-83

Authors: Shepshelovich D, Tibau A, Goldvaser H, Ocana A, Seruga B, Amir E

Abstract
OBJECTIVE: To investigate whether US Food and Drug Administration approval of new drugs without randomization or an active drug comparator is associated with more postmarketing safety-related label modifications.
METHODS: We searched Drugs@FDA for new drugs approved from January 1, 1999, through December 31, 2014. Drugs approved without supporting randomized controlled trials (RCTs) were matched to between 1 and 2 controls from similar therapeutic categories approved with supporting RCTs within 3 years of the reference drug. Study characteristics, regulatory pathways, and label modifications up to December 2017 were collected from drug labels. Differences in postmarketing safety modifications between cases and controls were assessed using conditional logistic regression.
RESULTS: The study cohort included 52 drugs approved without supporting RCTs and 91 matched controls. Drug approvals not supported by RCTs were associated with lower sample size (odds ratio [OR] per 100 patients, 0.77; 95% CI, 0.68-0.87) and were more likely to receive orphan drug designation (OR, 5.10; 95% CI, 2.23-11.69), fast-track designation (OR, 4.80; 95% CI, 2.25-10.23), and accelerated approval (OR, 7.00; 95% CI, 3.14-15.60). Drugs approved without supporting RCTs were associated with more modifications in black box warnings (28.8% vs 13.2%; OR, 2.67; 95% CI, 1.13-6.27), warnings and precautions (73.1% vs 52.7%; OR, 2.43; 95% CI, 1.16-5.09), and common adverse reactions (48.1% vs 23.1%; OR, 3.09; 95% CI, 1.49-6.41).
CONCLUSION: Food and Drug Administration approval of new drugs without supporting RCTs is associated with more postmarketing safety-related label modifications than drugs approved with supporting RCTs. Robust postmarketing studies are required for drugs approved without supporting RCTs. Health care professionals should be vigilant for unrecognized adverse effects when prescribing these drugs.

PMID: 30611457 [PubMed - indexed for MEDLINE]

Reply to Iuga and Genaidy 'Comment on Falconer et al. (2018) - the need for specific adverse drug reaction outcomes'.

Br J Clin Pharmacol. 2018 08;84(8):1857

Authors: Falconer N, Barras M, Cottrell N

PMID: 29873096 [PubMed - indexed for MEDLINE]

Prevention of pertussis: An unresolved problem.

Hum Vaccin Immunother. 2018;14(10):2452-2459

Authors: Esposito S, Principi N

Abstract
Pertussis is a highly contagious respiratory disease caused by Bordetella pertussis. However, after the introduction of the whole-cell pertussis vaccine (wP), the annual incidence rates of the disease progressively declined. Despite this result, the inclusion of wP in the national immunization schedule of infants and young children was debated regarding its safety. Several efforts to produce vaccines based on B. pertussis components capable of evoking protective immunity with no or limited adverse events were made. Of these others, five pertussis antigens were considered possible components of acellular vaccines (aPs): pertussis toxin (PT), filamentous haemagglutinin (FHA), pertactin (PRN) and fimbria proteins 2 and 3. However, the introduction of aPs was followed by a slight but progressive increase in the incidence of pertussis. This paper discusses the potential reasons for reduced aPs efficacy. Moreover, it attempts to evaluate the real effectiveness of aPs and the potential differences between available preparations. Data analysis showed that several boosters are needed to maintain protection against pertussis and additional studies are needed to confirm the antigens that should be included in aPs to improve the prevention of pertussis.

PMID: 29856680 [PubMed - indexed for MEDLINE]

Comment on Falconer et al. (2018) - the need for specific adverse drug reaction outcomes.

Br J Clin Pharmacol. 2018 08;84(8):1856

Authors: Iuga A, Genaidy A

PMID: 29736905 [PubMed - indexed for MEDLINE]

A model-based assay design to reproduce in vivo patterns of acute drug-induced toxicity.

Arch Toxicol. 2018 Jan;92(1):553-555

Authors: Kuepfer L, Clayton O, Thiel C, Cordes H, Nudischer R, Blank LM, Baier V, Heymans S, Caiment F, Roth A, Fluri DA, Kelm JM, Castell J, Selevsek N, Schlapbach R, Keun H, Hynes J, Sarkans U, Gmuender H, Herwig R, Niederer S, Schuchhardt J, Segall M, Kleinjans J

PMID: 28852801 [PubMed - indexed for MEDLINE]

15 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 2019/05/24

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.

14 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 2019/05/24

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.

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 2019/05/23

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.

The efficacy and safety of sitafloxacin and garenoxacin for the treatment of pneumonia in elderly patients: A randomized, multicenter, open-label trial.

J Infect Chemother. 2019 May 18;:

Authors: Miyazaki T, Nakamura S, Hashiguchi K, Kobayashi T, Fukushima K, Fukuda Y, Kondo A, Inoue Y, Koga H, Sasaki E, Nagayoshi Y, Higashiyama Y, Yoshida M, Takazono T, Saijo T, Morinaga Y, Yamamoto K, Imamura Y, Mikushi S, Izumikawa K, Yanagihara K, Kohno S, Mukae H

Abstract
Oral treatment for elderly outpatients with pneumonia is becoming increasingly important in this super-aged society from the perspective of cost-effectiveness and limited hospital capacities. We evaluated the efficacy and safety of two oral respiratory quinolones, sitafloxacin and garenoxacin, in elderly patients with pneumonia. This randomized, multicenter, open-label trial was conducted among patients aged ≥65 years with clinically and radiographically confirmed pneumonia in Japan. Patients were randomly assigned (1:1) to receive either sitafloxacin (100 mg/day) or garenoxacin (400 mg/day) for 3-10 days. The primary efficacy endpoint was the clinical cure rate at 5-10 days after the end of treatment. From December 2013 to November 2017, we enrolled 120 patients at 11 hospitals and randomly assigned 59 patients to the sitafloxacin group (1 patient withdrew) and 61 patients to the garenoxacin group. These included 30 patients with nursing and healthcare-associated pneumonia (NHCAP) (18 receiving sitafloxacin, 12 receiving garenoxacin) and 37 patients with aspiration pneumonia (16 receiving sitafloxacin, 21 receiving garenoxacin). The clinical cure rates in the sitafloxacin and garenoxacin groups were 88.5% (95% confidence interval: 76.6-95.6) and 88.9% (95% confidence interval: 77.4-95.8), respectively. No significant differences were observed in the incidence rates of drug-related adverse events between the sitafloxacin (20.7%; 12/58 patients) and garenoxacin (27.9%; 17/61 patients) groups. The most common adverse event was hepatic dysfunction, which occurred in seven patients in each group. We conclude that sitafloxacin and garenoxacin are comparably effective and safe for the treatment of pneumonia, including NHCAP and aspiration pneumonia, in elderly patients.

PMID: 31113725 [PubMed - as supplied by publisher]

Initial Experience With Radium-223 Chloride Treatment at the Kanazawa University Hospital.

Anticancer Res. 2019 May;39(5):2607-2614

Authors: Nakashima K, Makino T, Kadomoto S, Iwamoto H, Yaegashi H, Iijima M, Kawaguchi S, Nohara T, Shigehara K, Izumi K, Kadono Y, Matsuo S, Mizokami A

Abstract
BACKGROUND/AIM: To evaluate our initial experience with radium-223 chloride (Ra-223).
MATERIALS AND METHODS: A total of 26 castration-resistant prostate cancer (CRPC) patients with bone metastases, treated with Ra-223 at our hospital were evaluated. This study aimed to observe adverse events (AEs) and changes in serum markers, and Bone Scan Index (BSI). Additionally, the relationship between these values and OS was investigated.
RESULTS: The observed AEs mainly included fatigue and nausea. Alkaline phosphatase (ALP) and bone-type alkaline phosphatase (BAP) levels decreased following the treatment; however, those of PSA and 1-CTP tended to increase, regardless of Ra-223 administration. Overall survival (OS) was significantly improved in cases with a baseline BSI value of <2 compared with those with a baseline BSI value of ≥2. Moreover, the decrease in BSI after administration of Ra-223 was an independent factor, significantly prolonging OS.
CONCLUSION: ALP and BAP levels and BSI values are suitable evaluation markers during treatment with Ra-223. Also, baseline BSI values and the decrease in BSI following treatment are independent factors predicting OS.

PMID: 31092459 [PubMed - indexed for MEDLINE]

An Update on Drug-Induced Pigmentation.

Am J Clin Dermatol. 2019 Feb;20(1):75-96

Authors: Nahhas AF, Braunberger TL, Hamzavi IH

Abstract
Drug-induced pigmentation accounts for up to 20% of all cases of acquired pigmentation. A thorough review of medical history and previous and ongoing medications as well as a complete skin examination can guide diagnosis. Implicated agents include alkylating/cytotoxic agents, analgesics, antiarrhythmics, anticoagulants, antiepileptics, antimalarials, antimicrobials, antiretrovirals, metals, prostaglandin analogs, and psychotropic agents, among others. Confirming true drug associations can be challenging, especially in the setting of delayed onset of pigmentation and coexisting polypharmacy.

PMID: 30374894 [PubMed - indexed for MEDLINE]

Combination inhaled glucocorticoid/long-acting beta-agonist safety: The long and winding road.

Ann Allergy Asthma Immunol. 2018 10;121(4):428-433

Authors: Spahn JD

PMID: 30056153 [PubMed - indexed for MEDLINE]

What can we learn from the public's understanding of drug information and safety? A population survey.

Int J Pharm Pract. 2019 Feb;27(1):96-104

Authors: Salgueiro E, Gurruchaga C, Jimeno FJ, Martínez-Múgica C, Martín Arias LH, Manso G

Abstract
OBJECTIVE: The aim of our study was to analyse the perceptions of the public on medicine information and safety and on consumer reporting of suspected adverse drug reactions (ADR).
METHODS: A voluntary survey was conducted in a population ≥18 years of age in Asturias, a region in northern Spain. The survey was designed to be completed in a face-to-face street interview or completed independently by the public. The survey consisted of structured questions organised in four sections: (1) demographic data, (2) use of medicines, (3) reading and understanding of the patient information leaflet (PIL) and (4) awareness and perception about consumer reporting of ADR.
KEY FINDINGS: A total of 402 surveys were given and analysed; 295 were completed independently and 107 were completed in street interviews. Of the population surveyed, 82.3% had taken some drug(s) in the previous 3 months, although only 62.4% had performed so by medical prescription. A quarter of respondents claimed that they never read the PIL of medicines, 12.7% that they sometimes read it, and 61.4% that they always read this information. A high percentage (82.8%) of respondents reported that they were not aware of consumer reporting of ADR, and 86.1% stated their agreement with this option.
CONCLUSIONS: The public has great interest in useful information about all aspects involved in the use of medicines. This includes consumer reporting of suspected ADR, which is still unknown to many people.

PMID: 29770980 [PubMed - indexed for MEDLINE]

Improving Assessment of Drug Safety Through Proteomics: Early Detection and Mechanistic Characterization of the Unforeseen Harmful Effects of Torcetrapib.

Circulation. 2018 03 06;137(10):999-1010

Authors: Williams SA, Murthy AC, DeLisle RK, Hyde C, Malarstig A, Ostroff R, Weiss SJ, Segal MR, Ganz P

Abstract
BACKGROUND: Early detection of adverse effects of novel therapies and understanding of their mechanisms could improve the safety and efficiency of drug development. We have retrospectively applied large-scale proteomics to blood samples from ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events), a trial of torcetrapib (a cholesterol ester transfer protein inhibitor), that involved 15 067 participants at high cardiovascular risk. ILLUMINATE was terminated at a median of 550 days because of significant absolute increases of 1.2% in cardiovascular events and 0.4% in mortality with torcetrapib. The aims of our analysis were to determine whether a proteomic analysis might reveal biological mechanisms responsible for these harmful effects and whether harmful effects of torcetrapib could have been detected early in the ILLUMINATE trial with proteomics.
METHODS: A nested case-control analysis of paired plasma samples at baseline and at 3 months was performed in 249 participants assigned to torcetrapib plus atorvastatin and 223 participants assigned to atorvastatin only. Within each treatment arm, cases with events were matched to controls 1:1. Main outcomes were a survey of 1129 proteins for discovery of biological pathways altered by torcetrapib and a 9-protein risk score validated to predict myocardial infarction, stroke, heart failure, or death.
RESULTS: Plasma concentrations of 200 proteins changed significantly with torcetrapib. Their pathway analysis revealed unexpected and widespread changes in immune and inflammatory functions, as well as changes in endocrine systems, including in aldosterone function and glycemic control. At baseline, 9-protein risk scores were similar in the 2 treatment arms and higher in participants with subsequent events. At 3 months, the absolute 9-protein derived risk increased in the torcetrapib plus atorvastatin arm compared with the atorvastatin-only arm by 1.08% (P=0.0004). Thirty-seven proteins changed in the direction of increased risk of 49 proteins previously associated with cardiovascular and mortality risk.
CONCLUSIONS: Heretofore unknown effects of torcetrapib were revealed in immune and inflammatory functions. A protein-based risk score predicted harm from torcetrapib within just 3 months. A protein-based risk assessment embedded within a large proteomic survey may prove to be useful in the evaluation of therapies to prevent harm to patients.
CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00134264.

PMID: 28974520 [PubMed - indexed for MEDLINE]

When Respecting Autonomy Is Harmful: A Clinically Useful Approach to the Nocebo Effect.

Am J Bioeth. 2017 Jun;17(6):36-42

Authors: Fortunato JT, Wasserman JA, Menkes DL

Abstract
Nocebo effects occur when an adverse effect on the patient arises from the patient's own negative expectations. In accordance with informed consent, providers often disclose information that results in unintended adverse outcomes for the patient. While this may adhere to the principle of autonomy, it violates the doctrine of "primum non nocere," given that side-effect disclosure may cause those side effects. In this article we build off previous work, particularly by Wells and Kaptchuk ( 2012 ) and by Cohen ( 2013 ), to suggest ethical guidelines that permit nondisclosure in the case when a nocebo effect is likely to occur on of the basis of nonmaleficence. We accept that that autonomy vis-à-vis informed consent must be forestalled, but salvage much of its role by elaborating a practical clinical approach to postencounter follow-up. In doing so, we reconcile a clinically practicable process of determining conditions of disclosure with long-standing ethical commitments to patients.

PMID: 28537834 [PubMed - indexed for MEDLINE]

Pharmacovigilance: Importance, concepts, and processes.

Am J Health Syst Pharm. 2017 Apr 15;74(8):606-612

Authors: Kumar A

PMID: 28235869 [PubMed - indexed for MEDLINE]

Imputability of Adverse Events to Anticancer Drugs.

N Engl J Med. 2019 05 09;380(19):1873-1874

Authors: Moreau-Bachelard C, Coquan E, Le Tourneau C

PMID: 31067382 [PubMed - indexed for MEDLINE]

Safety of combining radiotherapy with immune-checkpoint inhibition.

Nat Rev Clin Oncol. 2018 08;15(8):477-494

Authors: Hwang WL, Pike LRG, Royce TJ, Mahal BA, Loeffler JS

Abstract
Immune-checkpoint inhibitors targeting cytotoxic T- lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), or programmed cell death 1 ligand 1 (PD-L1) have transformed the care of patients with a wide range of advanced-stage malignancies. More than half of these patients will also have an indication for treatment with radiotherapy. The effects of both radiotherapy and immune-checkpoint inhibition (ICI) involve a complex interplay with the innate and adaptive immune systems, and accumulating evidence suggests that, under certain circumstances, the effects of radiotherapy synergize with those of ICI to augment the antitumour responses typically observed with either modality alone and thus improve clinical outcomes. However, the mechanisms by which radiotherapy and immune-checkpoint inhibitors synergistically modulate the immune response might also affect both the type and severity of treatment-related toxicities. Moreover, in patients receiving immune-checkpoint inhibitors, the development of immune-related adverse events has been linked with superior treatment responses and patient survival durations, suggesting a relationship between the antitumour and adverse autoimmune effects of these agents. In this Review, we discuss the emerging data on toxicity profiles related to immune-checkpoint inhibitors and radiotherapy, both separately and in combination, their potential mechanisms, and the approaches to managing these toxicities.

PMID: 29872177 [PubMed - indexed for MEDLINE]

Efficacy and Safety of a Two-Drug Direct-Acting Antiviral Agent Regimen Ruzasvir 180 mg and Uprifosbuvir 450 mg for 12 Weeks in Adults with Chronic Hepatitis C Virus Genotype 1, 2, 3, 4, 5, or 6.

J Viral Hepat. 2019 May 20;:

Authors: Lawitz E, Gane E, Feld JJ, Buti M, Foster GR, Rabinovitz M, Burnevich E, Katchman H, Tomasiewicz K, Lahser F, Jackson B, Shaughnessy M, Klopfer S, Yeh WW, Robertson MN, Hanna GJ, Barr E, Platt HL, C-BREEZE-2 Study Investigators

Abstract
Ruzasvir (MK-8408, an NS5A inhibitor) and uprifosbuvir (MK-3682, a nonstructural protein 5B nucleotide inhibitor) are highly potent direct-acting antiviral agents for the treatment of hepatitis C virus (HCV) infection. A phase III clinical trial evaluating the two-drug combination of ruzasvir 60 mg plus uprifosbuvir 450 mg suggested suboptimal efficacy in certain HCV genotypes (C-BREEZE 1; NCT02759315). The aim of the present study was to evaluate the efficacy and safety of rusasvir in combination with uprifosbuvir administered at a higher dose than that assessed in the earlier study (C-BREEZE 2: NCT02956629 /Merck protocol PN041). Treatment-naive or interferon (with or without ribavirin)-experienced participants with or without compensated cirrhosis were enrolled. All participants received ruzasvir 180 mg plus uprifosbuvir 450 mg once daily for 12 weeks. The primary objectives were the proportion of participants with HCV RNA <15 lU/mL at 12 weeks after the end of study therapy (SVR12), and safety and tolerability of the study drug. Overall, 282 participants were enrolled. SVR12 (n/N) was 91.3% (42/46) in participants infected with HCV genotype (GT) 1a; GT1b, 96.7% (29/30); GT2, 91.5% (43/47); GT3, 73.8% (45/61); GT4, 98.2% (55/56); GT5, 100.0% (18/18); GT6, 90.9% (20/22). Adverse events (AEs) were reported by 61.3% of participants; drug-related AEs were reported by 33.3%. The most frequent (≥5% of participants) drug-related AEs in all participants were fatigue (7.8%) and headache (7.4%). In conclusion, the two-drug combination of ruzasvir 180 mg plus uprifosbuvir 450 mg for 12 weeks was highly effective and well-tolerated in participants infected with HCV GT1, GT2, GT4, GT5, and GT6, with a lower efficacy in GT3-infected persons. This article is protected by copyright. All rights reserved.

PMID: 31108015 [PubMed - as supplied by publisher]