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Phase II Study of Low-Dose Afatinib Maintenance Treatment Among Patients with EGFR-Mutated Non-Small Cell Lung Cancer: North Japan Lung Cancer Study Group Trial 1601 (NJLCG1601).

Oncologist. 2020 Jun 19;:

Authors: Nakamura A, Tanaka H, Saito R, Suzuki A, Harada T, Inoue S, Yamada T, Nakagawa T, Jingu D, Sugawara S

Abstract
TRIAL INFORMATION: ClinicalTrials.gov Identifier: UMIN 000020688 [EMBED URL: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000020688] Sponsor: North Japan Lung Cancer Study Group Principal Investigator: Atsushi Nakamura IRB Approved: Yes LESSONS LEARNED: Low-dose afatinib maintenance treatment among patients with EGFR-mutated NSCLC allowed for treatment continuation for longer with fewer treatment-related AEs without detracting from the therapeutic efficacy. This modified regimen represents a practical usage that balances effectiveness and safety.
BACKGROUND: Although afatinib is an effective therapy for patients with EGFR-mutated non-small cell lung cancer (NSCLC), drug-related adverse events (AEs) have often necessitated dose reductions. In a post hoc analysis of the LUX-Lung 3 and 6 trials, there was no difference in median progression-free survival (PFS) between patients who had the dose of afatinib reduced and those who did not. We thus evaluated the efficacy and tolerability of low-dose afatinib maintenance treatment among patients with NSCLC harboring EGFR mutations who had not been previously treated.
METHODS: Eligible patients received afatinib 40 mg orally once daily. When prescribed grade ≥ 2 AEs, rash of grade ≥ 3, or unacceptable toxicity occurred, the afatinib dose was reduced from 40 to 30 mg and if needed from 30 to 20 mg. The primary endpoint was the 1-year PFS rate. Secondary endpoints were PFS, overall response rate (ORR), and toxicity.
RESULTS: Among 30 patients, 93% had adenocarcinoma, 53% had exon 19 deletion, 37% had L858R, and 10% had minor mutations. The 1-year PFS rate was 50% (95% confidence interval [CI], 31.3-66.1) and the median PFS was 11.8 months (95% CI, 7.1-21.4). The incidence rate of grade ≥ 3 toxicities was 57%, including elevated aspartate aminotransferase/alanine aminotransferase level (13%), diarrhea (10%), and paronychia (10%).
CONCLUSION: Low-dose afatinib maintenance treatment reduced treatment-related AEs without detracting from the therapeutic efficacy.

PMID: 32559335 [PubMed - as supplied by publisher]

Systematic or Test-Guided Treatment for Tuberculosis in HIV-Infected Adults.

N Engl J Med. 2020 06 18;382(25):2397-2410

Authors: Blanc FX, Badje AD, Bonnet M, Gabillard D, Messou E, Muzoora C, Samreth S, Nguyen BD, Borand L, Domergue A, Rapoud D, Natukunda N, Thai S, Juchet S, Eholié SP, Lawn SD, Domoua SK, Anglaret X, Laureillard D, STATIS ANRS 12290 Trial Team

Abstract
BACKGROUND: In regions with high burdens of tuberculosis and human immunodeficiency virus (HIV), many HIV-infected adults begin antiretroviral therapy (ART) when they are already severely immunocompromised. Mortality after ART initiation is high in these patients, and tuberculosis and invasive bacterial diseases are common causes of death.
METHODS: We conducted a 48-week trial of empirical treatment for tuberculosis as compared with treatment guided by testing in HIV-infected adults who had not previously received ART and had CD4+ T-cell counts below 100 cells per cubic millimeter. Patients recruited in Ivory Coast, Uganda, Cambodia, and Vietnam were randomly assigned in a 1:1 ratio to undergo screening (Xpert MTB/RIF test, urinary lipoarabinomannan test, and chest radiography) to determine whether treatment for tuberculosis should be started or to receive systematic empirical treatment with rifampin, isoniazid, ethambutol, and pyrazinamide daily for 2 months, followed by rifampin and isoniazid daily for 4 months. The primary end point was a composite of death from any cause or invasive bacterial disease within 24 weeks (primary analysis) or within 48 weeks after randomization.
RESULTS: A total of 522 patients in the systematic-treatment group and 525 in the guided-treatment group were included in the analyses. At week 24, the rate of death from any cause or invasive bacterial disease (calculated as the number of first events per 100 patient-years) was 19.4 with systematic treatment and 20.3 with guided treatment (adjusted hazard ratio, 0.95; 95% confidence interval [CI], 0.63 to 1.44). At week 48, the corresponding rates were 12.8 and 13.3 (adjusted hazard ratio, 0.97 [95% CI, 0.67 to 1.40]). At week 24, the probability of tuberculosis was lower with systematic treatment than with guided treatment (3.0% vs. 17.9%; adjusted hazard ratio, 0.15; 95% CI, 0.09 to 0.26), but the probability of grade 3 or 4 drug-related adverse events was higher with systematic treatment (17.4% vs. 7.2%; adjusted hazard ratio 2.57; 95% CI, 1.75 to 3.78). Serious adverse events were more common with systematic treatment.
CONCLUSIONS: Among severely immunosuppressed adults with HIV infection who had not previously received ART, systematic treatment for tuberculosis was not superior to test-guided treatment in reducing the rate of death or invasive bacterial disease over 24 or 48 weeks and was associated with more grade 3 or 4 adverse events. (Funded by the Agence Nationale de Recherches sur le Sida et les Hépatites Virales; STATIS ANRS 12290 ClinicalTrials.gov number, NCT02057796.).

PMID: 32558469 [PubMed - in process]

Physical Functioning in Patients with Chronic Obstructive Pulmonary Disease Treated with Tiotropium/Olodaterol Respimat in Routine Clinical Practice in Italy.

Pulm Ther. 2020 Jun 18;:

Authors: Carone M, Pennisi A, D'Amato M, Donati AF, Ricci A, Scognamillo C, Chun L, Aliani M, Ronsivalle V, Pelaia G

Abstract
INTRODUCTION: Clinical studies have shown significant improvements in exercise capacity in patients with chronic obstructive pulmonary disease (COPD) who are treated with a tiotropium/olodaterol fixed-dose combination (FDC). However, the effects of this treatment, which is administered in a single device, on physical functioning in a real-life setting of patients with COPD had not been fully determined.
METHODS: An open-label, observational study was conducted in 309 patients with COPD from 29 sites across Italy who received tiotropium/olodaterol FDC for 6 weeks. Physical functioning was evaluated using the Physical Functioning Questionnaire (PF-10). The primary endpoint was the proportion of patients with therapeutic success, defined as a ten-point increase in the PF-10 score from the baseline visit. Secondary endpoints were absolute changes in PF-10 score from baseline visit, the patient's general condition assessed by the Physician's Global Evaluation (PGE) score, and patient satisfaction with treatment, inhaling and handling of the device.
RESULTS: According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) multimodality assessment, most patients were allocated to groups B (44.4%) and D (24.5%). Comorbidities were present in 73.9% of the patients. The primary endpoint was reached in more than half of the patients (52.5%), especially in groups B and D of GOLD. Patients' satisfaction with treatment, inhaling and handling of device was high, with a range of more than 86% to more than 89%, and very high in both groups B and D. The rates of drug-related adverse events were very low.
CONCLUSIONS: This real-life study showed that the tiotropium/olodaterol FDC treatment delivered via the Respimat device improves physical functioning and general patients' condition and is associated with a high degree of satisfaction and very low rates of drug-related adverse events, regardless of the group they belong to and their comorbidities.
CLINICAL TRIAL ID: NCT03003494.

PMID: 32557394 [PubMed - as supplied by publisher]

Hyponatremia-Inducing Drugs.

Front Horm Res. 2019;52:167-177

Authors: Liamis G, Megapanou E, Elisaf M, Milionis H

Abstract
In clinical practice, several medications such as diuretics, psychotropic drugs, and anticonvulsants have been reported to be a frequent cause of hyponatremia. Drugs may cause hyponatremia either by affecting the homeostasis of sodium and water (e.g., diuretics) or by altering the water homeostasis as a consequence of the syndrome of inappropriate secretion of antidiuretic hormone. On the contrary, drugs commonly prescribed in everyday clinical practice, including proton pump inhibitors, antibiotics, angiotensin-converting enzyme inhibitors, hypoglycemic agents and, amiodarone, have been infrequently 'incriminated' as causes of hyponatremia. Therefore, in the diagnostic approach of patients with low serum [Na+] levels, meticulous history taking and recording of pharmacotherapy is warranted to identify potentially culprit medications. Taking into account the adverse outcomes associated with even mild hyponatremia (i.e., impaired cognition, falls and fractures, mortality), recognition of drug-induced hyponatremia is of vital importance, while responsible agents should be discontinued and "re-challenge" should be avoided by informing the patient and involved caregivers.

PMID: 32097944 [PubMed - indexed for MEDLINE]

Management of Glaucoma in Pregnancy.

J Glaucoma. 2019 10;28(10):937-944

Authors: Mathew S, Harris A, Ridenour CM, Wirostko BM, Burgett KM, Scripture MD, Siesky B

Abstract
Management of glaucoma during pregnancy represents a challenge for the physician. Important disease and patients' health decisions begin even before conception and continue throughout pregnancy and breastfeeding. The data on this topic is limited due to ethical and legal constraints and challenges of conducting large, prospective, and randomized clinical trials on this patient population. Our review suggests that individually, intraocular pressure is lower in a pregnant woman when compared with a nonpregnant woman. Importantly, the medical management of glaucoma during pregnancy poses special challenges due to the possibility of adverse effects of medications on the fetus and newborn. Laser trabeculoplasty and traditional filtration surgery, and minimally invasive glaucoma surgery, represent nondrug management options. Thus, managing glaucoma in pregnancy is a delicate balance between treatment to prevent damage to the optic nerve in the mother and avoidance of interventions potentially harmful to the fetus. This literature review of published individual and population-based studies was performed to explore current knowledge and guidelines in the management of glaucoma in pregnancy.

PMID: 31283700 [PubMed - indexed for MEDLINE]

Interventions for Unhealthy Drug Use—Supplemental Report: A Systematic Review for the U.S. Preventive Services Task Force

Book. 2020 06

Authors: Chou R, Dana T, Blazina I, Grusing S, Fu R, Bougatsos C

Abstract
BACKGROUND: A U.S. Preventive Services Task Force (USPSTF) report found no consistent evidence that counseling interventions are effective at reducing drug use or improving other health outcomes in populations whose drug use was identified through primary care-based screening with questions about drug use or drug-related risks (i.e., “screen-detected populations”). Evidence from studies of persons seeking or referred for treatment for substance use or with clinical signs or symptoms of substance use (i.e., “treatment-seeking populations”) might also be useful for informing assessments regarding screening in primary care settings.
PURPOSE: This report updates a 2008 USPSTF report on screening for illicit drug use and supplements an updated USPSTF report on screening for any drug use, focusing on the benefits and harms of pharmacotherapy and psychosocial interventions for persons whose drug use was identified when seeking substance use treatment, when presenting with signs or symptoms of drug use, when screened for drug use in primary care or other settings with questions about drug use or drug-related risks, or other means.
DATA SOURCES: The Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Ovid MEDLINE, Embase, and PsycINFO from inception to September 2018; surveillance for new literature was conducted through November 22, 2019.
STUDY SELECTION: We included trials of Food and Drug Administration (FDA)-approved pharmacotherapies for opioid use disorder (methadone, buprenorphine, and naltrexone) and trials of psychosocial interventions for persons engaging in opioid, stimulant, cannabis, and mixed drug or polysubstance use. We also included trials of preemptive prescribing of naloxone in primary care settings as a rescue medication for opioid-related overdose. Trials compared included interventions against placebo, a minimal intervention, waitlist control, or usual care, and evaluated outcomes at ≥3 months for drug use or other risky behaviors; health, social, and legal consequences of drug use; or harms of treatment.
DATA EXTRACTION: One investigator abstracted data and a second investigator checked data abstraction for accuracy. Two investigators independently assessed study quality using methods developed by the USPSTF.
DATA SYNTHESIS (RESULTS): We included a total of 71 trials, with 19 trials of pharmacotherapies and 52 trials of psychosocial interventions. All trials of pharmacotherapies and 25 trials of psychosocial interventions were conducted in treatment-seeking populations. Psychosocial interventions commonly incorporated cognitive-behavioral or motivational interventions and ranged from brief interventions consisting of one or two sessions of no more than one hour to multiple treatment sessions over weeks or months. In most pharmacotherapy trials, drug use counseling was provided to all patients. No study evaluated benefits or harms of preemptive naloxone prescribed in primary care settings versus placebo or no naloxone as a rescue medication for opioid-related overdose. In treatment-seeking populations with opioid use disorder, naltrexone (12 trials; relative risk [RR] 0.73, 95% confidence interval [CI] 0.62 to 0.85; number needed to treat [NNT] 5.3) and opioid agonist therapy with methadone or buprenorphine (4 trials; RR 0.75, 95% CI 0.59 to 0.82; NNT 2.9) were associated with decreased risk of drug use relapse compared with placebo or no pharmacotherapy. Naltrexone and methadone/buprenorphine therapy were also associated with increased likelihood of retention in substance use treatment (9 trials; RR 1.71, 95% CI 1.13 to 2.49; NNT 6.7 and 7 trials; RR 2.58, 95% CI 1.78 to 4.59; NNT 2.6; respectively). Evidence on harms of pharmacotherapies was limited, but indicated no increased risk of serious adverse events. Psychosocial interventions were associated with increased likelihood of abstinence from drug use versus control conditions at 3 to 4 months (15 trials, RR 1.60, 95% CI 1.24 to 2.13; NNT 11) and at 6 to 12 months (14 trials; RR 1.25, 95% CI 1.11 to 1.52; NNT 17), based on trials primarily conducted in treatment-seeking populations. Psychosocial interventions were also associated with a greater decrease versus control conditions in the number of drug use days (19 trials; mean difference −0.49 day in the last 7 days, 95% CI −0.85 to −0.13) and a small but statistically significant greater decrease in drug use severity (16 trials; standard mean difference −0.18, 95% CI −0.32 to −0.05) at 3- to 4-month followup. There was no difference between psychosocial interventions versus controls on drug use days or severity at longer (6 to 12 month) followup. Effects of psychosocial interventions were generally stronger in trials of treatment-seeking than screen-detected populations, trials that evaluated cannabis use than other types of drug use, and trials of more intensive than brief interventions. Few trials evaluated effects of psychosocial interventions for opioid or stimulant use, and estimates were imprecise.
LIMITATIONS: Limitations included restriction to English-language articles, statistical heterogeneity in pooled analyses, and little evidence on drug-related health, social, or legal outcomes; most trials had methodological limitations. Evidence was lacking on effectiveness of treatments for opioid use disorder related to prescription drug use or stimulant use and evidence was limited for adolescents or pregnant persons.
CONCLUSIONS: Pharmacotherapy and psychosocial interventions are effective at improving drug use outcomes, but evidence of effectiveness remains primarily derived from trials conducted in treatment-seeking populations. Although the applicability of data from such trials to persons whose drug use is identified through primary care-based screening is uncertain, intervention trials that enrolled patients based on screening identified a spectrum of drug use, ranging from mild drug use to more severe, untreated disease. The applicability of current evidence on drug use interventions to screening might be greater for the subset of patients screened in primary care settings with severe, untreated drug use who could utilize pharmacotherapies or more intensive psychosocial interventions.

PMID: 32550674

Pentosan Polysulfate Sodium Exposure and Drug-Induced Maculopathy in Commercially Insured Patients in the United States.

Ophthalmology. 2020 04;127(4):535-543

Authors: Ludwig CA, Vail D, Callaway NF, Pasricha MV, Moshfeghi DM

Abstract
PURPOSE: To determine the association and cumulative dose-response pattern between pentosan polysulfate sodium (PPS) use for interstitial cystitis (IC) and maculopathy.
DESIGN: Large, multicenter, retrospective cohort study of commercially insured patients in the MarketScan database (Truven Health Analytics, San Jose, CA).
PARTICIPANTS: Two hundred twenty-seven thousand three hundred twenty-five patients with IC who were enrolled continuously in the MarketScan database.
METHODS: Cox proportional hazards models (controlling for patient gender, age at index diagnosis of IC, and diagnosis with diabetes mellitus) followed up patients from index diagnosis of IC for 5 years, or until patients discontinued insurance coverage, or until patients' first diagnosis with a maculopathy. As a sensitivity analysis, we re-estimate all models after excluding all patients with diabetes. To assess for dose response, we calculated the total days of PPS prescriptions filled and created a categorical variable indicating total exposure.
MAIN OUTCOME MEASURES: The primary outcome measure was association between binary PPS exposure and any maculopathy. Secondary outcome measures included exposure between binary and categorical, time-dependent, exposure to PPS and to drusen, nonexudative age-related macular degeneration (AMD), exudative AMD, hereditary maculopathy, and toxic maculopathy.
RESULTS: The most common diagnoses of maculopathy in patients with IC were exudative AMD (1.5%), drusen (0.8%), nonexudative AMD (0.3%), toxic maculopathy (0.1%), and hereditary dystrophy (0.04%). In unadjusted analyses, the percentage of patients who filled a PPS prescription and were diagnosed later with a maculopathy (2.37%) was very similar to the percentage of patients who did not fill a prescription (2.77%). Survival models using a binary variable indicating PPS exposure showed no significant associations between PPS exposure and diagnosis of drusen, nonexudative AMD, exudative AMD, toxic maculopathy, hereditary dystrophy, or an aggregate variable of any maculopathy. Similarly, there was no dose-dependent relationship between PPS exposure and diagnosis of any maculopathy. These findings remained stable in sensitivity analysis models that excluded patients with diabetes mellitus.
CONCLUSIONS: In this large, commercial claims database analysis, no association was found between PPS exposure and subsequent diagnosis of maculopathy.

PMID: 31899034 [PubMed - indexed for MEDLINE]

Impact of FDA black box warning on fluoroquinolone and alternative antibiotic use in southeastern US hospitals.

Infect Control Hosp Epidemiol. 2019 11;40(11):1297-1300

Authors: Yarrington ME, Anderson DJ, Dodds Ashley E, Jones T, Davis A, Johnson M, Lokhnygina Y, Sexton DJ, Moehring RW

Abstract
We analyzed antibiotic use data from 29 southeastern US hospitals over a 5-year period to determine changes in antibiotic use after the fluoroquinolone US Food and Drug Administration (FDA) advisory update in 2016. Fluoroquinolone use declined both before and after the FDA announcement, and the use of select, alternative antibiotics increased after the announcement.Fluoroquinolones are among the 4 most commonly prescribed antibiotic classes.1,2 Postmarketing reports of serious adverse events linked to fluoroquinolones include tendonitis, neuropathy, hypoglycemia, psychiatric side effects, and possible aortic vessel rupture, leading to safety label changes in July 2008 and August 2013.3 In July 2016, the US Food and Drug Administration (FDA) strengthened the "black box" warning following an initial safety announcement in May 2016, recommending avoidance of fluoroquinolones for uncomplicated infections such as acute exacerbation of chronic bronchitis, uncomplicated urinary tract infections, and acute bacterial sinusitis.4 Concerns over safety and the association with Clostridiodes difficile infection have led inpatient antimicrobial stewardship programs (ASPs) to develop initiatives to promote avoidance of quinolones. The objective of this study was to quantify the effect of the 2016 FDA "black box" update on inpatient antibiotic use among a cohort of southeastern US hospitals.

PMID: 31474240 [PubMed - indexed for MEDLINE]

Management of sexual adverse effects induced by atypical antipsychotic medication

J Psychiatry Neurosci. 2019 07 01;44(4):287-288

Authors: Downing L, Kim DD, Procyshyn RM`, Tibbo P

PMID: 31245972 [PubMed - indexed for MEDLINE]

Analysis of Adverse Drug Reactions Identified in Nursing Notes Using Reinforcement Learning.

Healthc Inform Res. 2020 Apr;26(2):104-111

Authors: Jeon E, Kim Y, Park H, Park RW, Shin H, Park HA

Abstract
Objectives: Electronic Health Records (EHRs)-based surveillance systems are being actively developed for detecting adverse drug reactions (ADRs), but this is being hindered by the difficulty of extracting data from unstructured records. This study performed the analysis of ADRs from nursing notes for drug safety surveillance using the temporal difference method in reinforcement learning (TD learning).
Methods: Nursing notes of 8,316 patients (4,158 ADR and 4,158 non-ADR cases) admitted to Ajou University Hospital were used for the ADR classification task. A TD(λ) model was used to estimate state values for indicating the ADR risk. For the TD learning, each nursing phrase was encoded into one of seven states, and the state values estimated during training were employed for the subsequent testing phase. We applied logistic regression to the state values from the TD(λ) model for the classification task.
Results: The overall accuracy of TD-based logistic regression of 0.63 was comparable to that of two machine-learning methods (0.64 for a naïve Bayes classifier and 0.63 for a support vector machine), while it outperformed two deep learning-based methods (0.58 for a text convolutional neural network and 0.61 for a long short-term memory neural network). Most importantly, it was found that the TD-based method can estimate state values according to the context of nursing phrases.
Conclusions: TD learning is a promising approach because it can exploit contextual, time-dependent aspects of the available data and provide an analysis of the severity of ADRs in a fully incremental manner.

PMID: 32547807 [PubMed]

[Medication use during pregnancy and lactation; urgent need for one independent source of information].

Ned Tijdschr Geneeskd. 2019 06 19;163:

Authors: de Vries TW, Duvekot JJ, Ter Horst PGJ

Abstract
It is important for healthcare professionals and pregnant women to have knowledge of the risks of using medicines during pregnancy and lactation. This not only concerns the influence of the medicinal product on the pregnant woman and the pregnancy, but also its impact on the growth and development of the (unborn) child, neonatal adaptation, possible precautions regarding child-birth, drug excretion in breast milk, and the short-term and long-term consequences for the newborn child. At present, information and advices are often fragmentary, sometimes contradictory, not easily accessible, or even not available at all. It is high time for one independent source to provide unambiguous, scientifically substantiated information and advice, accessible to both healthcare professionals and pregnant women - preferably in a digital format.

PMID: 31283123 [PubMed - indexed for MEDLINE]

Rationale and design of OPtimising thERapy to prevent Avoidable hospital admissions in Multimorbid older people (OPERAM): a cluster randomised controlled trial.

BMJ Open. 2019 06 03;9(6):e026769

Authors: Adam L, Moutzouri E, Baumgartner C, Loewe AL, Feller M, M'Rabet-Bensalah K, Schwab N, Hossmann S, Schneider C, Jegerlehner S, Floriani C, Limacher A, Jungo KT, Huibers CJA, Streit S, Schwenkglenks M, Spruit M, Van Dorland A, Donzé J, Kearney PM, Jüni P, Aujesky D, Jansen P, Boland B, Dalleur O, Byrne S, Knol W, Spinewine A, O'Mahony D, Trelle S, Rodondi N

Abstract
INTRODUCTION: Multimorbidity and polypharmacy are important risk factors for drug-related hospital admissions (DRAs). DRAs are often linked to prescribing problems (overprescribing and underprescribing), as well as non-adherence with drug regimens for different reasons. In this trial, we aim to assess whether a structured medication review compared with standard care can reduce DRAs in multimorbid older patients with polypharmacy.
METHODS AND ANALYSIS: OPtimising thERapy to prevent Avoidable hospital admissions in Multimorbid older people is a European multicentre, cluster randomised, controlled trial. Hospitalised patients ≥70 years with ≥3 chronic medical conditions and concurrent use of ≥5 chronic medications are included in the four participating study centres of Bern (Switzerland), Utrecht (The Netherlands), Brussels (Belgium) and Cork (Ireland). Patients treated by the same prescribing physician constitute a cluster, and clusters are randomised 1:1 to either standard care or Systematic Tool to Reduce Inappropriate Prescribing (STRIP) intervention with the help of a clinical decision support system, the STRIP Assistant. STRIP is a structured method performing customised medication reviews, based on Screening Tool of Older People's Prescriptions/Screening  Tool to Alert to Right Treatment criteria to detect potentially inappropriate prescribing. The primary endpoint is any DRA where the main reason or a contributory reason for the patient's admission is caused by overtreatment or undertreatment, and/or inappropriate treatment. Secondary endpoints include number of any hospitalisations, all-cause mortality, number of falls, quality of life, degree of polypharmacy, activities of daily living, patient's drug compliance, the number of significant drug-drug interactions, drug overuse and underuse and potentially inappropriate medication.
ETHICS AND DISSEMINATION: The local Ethics Committees in Switzerland, Ireland, The Netherlands and Belgium approved this trial protocol. We will publish the results of this trial in a peer-reviewed journal.
MAIN FUNDING: European Union's Horizon 2020 programme.
TRIAL REGISTRATION NUMBER: NCT02986425 , SNCTP000002183 , NTR6012, U1111-1181-9400.

PMID: 31164366 [PubMed - indexed for MEDLINE]

Olaparib and α-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-expansion phase 1b trial.

Lancet Oncol. 2019 04;20(4):570-580

Authors: Konstantinopoulos PA, Barry WT, Birrer M, Westin SN, Cadoo KA, Shapiro GI, Mayer EL, O'Cearbhaill RE, Coleman RL, Kochupurakkal B, Whalen C, Curtis J, Farooq S, Luo W, Eismann J, Buss MK, Aghajanian C, Mills GB, Palakurthi S, Kirschmeier P, Liu J, Cantley LC, Kaufmann SH, Swisher EM, D'Andrea AD, Winer E, Wulf GM, Matulonis UA

Abstract
BACKGROUND: Based on preclinical work, we found that combination of poly (ADP-ribose) polymerase (PARP) inhibitors with drugs that inhibit the homologous recombination repair (HRR) pathway (such as PI3K inhibitors) might sensitise HRR-proficient epithelial ovarian cancers to PARP inhibitors. We aimed to assess the safety and identify the recommended phase 2 dose of the PARP inhibitor olaparib in combination with the PI3K inhibitor alpelisib in patients with epithelial ovarian cancer and in patients with breast cancer.
METHODS: In this multicentre, open-label, phase 1b trial following a 3 + 3 dose-escalation design, we recruited patients aged 18 years or older with the following key eligibility criteria: confirmed diagnosis of either recurrent ovarian, fallopian tube, or primary peritoneal cancer of high-grade serous histology; confirmed diagnosis of either recurrent ovarian, fallopian tube, or primary peritoneal cancer of any histology with known germline BRCA mutations; confirmed diagnosis of recurrent breast cancer of triple-negative histology; or confirmed diagnosis of recurrent breast cancer of any histology with known germline BRCA mutations. Additional patients with epithelial ovarian cancer were enrolled in a dose-expansion cohort. Four dose levels were planned: the starting dose level of alpelisib 250 mg once a day plus olaparib 100 mg twice a day (dose level 0); alpelisib 250 mg once a day plus olaparib 200 mg twice a day (dose level 1); alpelisib 300 mg once a day plus olaparib 200 mg twice a day (dose level 2); and alpelisib 200 mg once a day plus olaparib 200 mg twice a day (dose level 3). Both drugs were administered orally, in tablet formulation. The primary objective was to identify the maximum tolerated dose and the recommended phase 2 dose of the combination of alpelisib and olaparib for patients with epithelial ovarian cancer and patients with breast cancer. Analyses included all patients who received at least one dose of the study drugs. The trial is active, but closed to enrolment; follow-up for patients who completed treatment is ongoing. This trial is registered with ClinicalTrials.gov, number NCT01623349.
FINDINGS: Between Oct 3, 2014, and Dec 21, 2016, we enrolled 34 patients (28 in the dose-escalation cohort and six in the dose-expansion cohort); two in the dose-escalation cohort were ineligible at the day of scheduled study initiation. Maximum tolerated dose and recommended phase 2 dose were identified as alpelisib 200 mg once a day plus olaparib 200 mg twice a day (dose level 3). Considering all dose levels, the most common treatment-related grade 3-4 adverse events were hyperglycaemia (five [16%] of 32 patients), nausea (three [9%]), and increased alanine aminotransferase concentrations (three [9%]). No treatment-related deaths occurred. Dose-limiting toxic effects included hyperglycaemia and fever with decreased neutrophil count. Of the 28 patients with epithelial ovarian cancer, ten (36%) achieved a partial response and 14 (50%) had stable disease according to Response Evaluation Criteria in Solid Tumors 1.1.
INTERPRETATION: Combining alpelisib and olaparib is feasible with no unexpected toxic effects. The observed activity provides preliminary clinical evidence of synergism between olaparib and alpelisib, particularly in epithelial ovarian cancer, and warrants further investigation.
FUNDING: Ovarian Cancer Dream Team (Stand Up To Cancer, Ovarian Cancer Research Alliance, National Ovarian Cancer Coalition), Breast Cancer Research Foundation, Novartis.

PMID: 30880072 [PubMed - indexed for MEDLINE]

Surufatinib in neuroendocrine tumours.

Lancet Oncol. 2019 Apr;20(4):e196

Authors: Das M

PMID: 30880071 [PubMed - indexed for MEDLINE]

Sacituzumab govitecan-hziy for triple-negative breast cancer.

Lancet Oncol. 2019 Apr;20(4):e194

Authors: Stirrups R

PMID: 30827748 [PubMed - indexed for MEDLINE]

Cabozantinib in advanced non-clear-cell renal cell carcinoma: a multicentre, retrospective, cohort study.

Lancet Oncol. 2019 04;20(4):581-590

Authors: Martínez Chanzá N, Xie W, Asim Bilen M, Dzimitrowicz H, Burkart J, Geynisman DM, Balakrishnan A, Bowman IA, Jain R, Stadler W, Zakharia Y, Narayan V, Beuselinck B, McKay RR, Tripathi A, Pachynski R, Hahn AW, Hsu J, Shah SA, Lam ET, Rose TL, Mega AE, Vogelzang N, Harrison MR, Mortazavi A, Plimack ER, Vaishampayan U, Hammers H, George S, Haas N, Agarwal N, Pal SK, Srinivas S, Carneiro BA, Heng DYC, Bosse D, Choueiri TK, Harshman LC

Abstract
BACKGROUND: Cabozantinib is approved for patients with metastatic renal cell carcinoma on the basis of studies done in clear-cell histology. The activity of cabozantinib in patients with non-clear-cell renal cell carcinoma is poorly characterised. We sought to analyse the antitumour activity and toxicity of cabozantinib in advanced non-clear-cell renal cell carcinoma.
METHODS: We did a multicentre, international, retrospective cohort study of patients with metastatic non-clear-cell renal cell carcinoma treated with oral cabozantinib during any treatment line at 22 centres: 21 in the USA and one in Belgium. Eligibility required patients with histologically confirmed non-clear-cell renal cell carcinoma who received cabozantinib for metastatic disease during any treatment line roughly between 2015 and 2018. Mixed tumours with a clear-cell histology component were excluded. No other restrictive inclusion criteria were applied. Data were obtained from retrospective chart review by investigators at each institution. Demographic, surgical, pathological, and systemic therapy data were captured with uniform database templates to ensure consistent data collection. The main objectives were to estimate the proportion of patients who achieved an objective response, time to treatment failure, and overall survival after treatment.
FINDINGS: Of 112 identified patients with non-clear-cell renal cell carcinoma treated at the participating centres, 66 (59%) had papillary histology, 17 (15%) had Xp11.2 translocation histology, 15 (13%) had unclassified histology, ten (9%) had chromophobe histology, and four (4%) had collecting duct histology. The proportion of patients who achieved an objective response across all histologies was 30 (27%, 95% CI 19-36) of 112 patients. At a median follow-up of 11 months (IQR 6-18), median time to treatment failure was 6·7 months (95% CI 5·5-8·6), median progression-free survival was 7·0 months (5·7-9·0), and median overall survival was 12·0 months (9·2-17·0). The most common adverse events of any grade were fatigue (58 [52%]), and diarrhoea (38 [34%]). The most common grade 3 events were skin toxicity (rash and palmar-plantar erythrodysesthesia; five [4%]) and hypertension (four [4%]). No treatment-related deaths were observed. Across 54 patients with available next-generation sequencing data, the most frequently altered somatic genes were CDKN2A (12 [22%]) and MET (11 [20%]) with responses seen irrespective of mutational status.
INTERPRETATION: While we await results from prospective studies, this real-world study provides evidence supporting the antitumour activity and safety of cabozantinib across non-clear-cell renal cell carcinomas. Continued support of international collaborations and prospective ongoing studies targeting non-clear-cell renal cell carcinoma subtypes and specific molecular alterations are warranted to improve outcomes across these rare diseases with few evidence-based treatment options.
FUNDING: None.

PMID: 30827746 [PubMed - indexed for MEDLINE]

Novel genetically-modified chimpanzee adenovirus and MVA-vectored respiratory syncytial virus vaccine safely boosts humoral and cellular immunity in healthy older adults.

J Infect. 2019 05;78(5):382-392

Authors: Green CA, Sande CJ, Scarselli E, Capone S, Vitelli A, Nicosia A, Silva-Reyes L, Thompson AJ, de Lara CM, Taylor KS, Haworth K, Hutchings CL, Cargill T, Angus B, Klenerman P, Pollard AJ

Abstract
OBJECTIVES: Respiratory syncytial virus (RSV) causes respiratory infection across the world, with infants and the elderly at particular risk of developing severe disease and death. The replication-defective chimpanzee adenovirus (PanAd3-RSV) and modified vaccinia virus Ankara (MVA-RSV) vaccines were shown to be safe and immunogenic in young healthy adults. Here we report an extension to this first-in-man vaccine trial to include healthy older adults aged 60-75 years.
METHODS: We evaluated the safety and immunogenicity of a single dose of MVA-RSV given by intra-muscular (IM) injection (n = 6), two doses of IM PanAd3-RSV given 4-weeks apart (n = 6), IM PanAd3-RSV prime and IM MVA-RSV boost 8-weeks later (n = 6), intra-nasal (IN) spray of PanAd3-RSV prime and IM MVA-RSV boost 8-weeks later (n = 6), or no vaccine (n = 6). Safety measures included all adverse events within one week of vaccination and blood monitoring. Immunogenicity measures included serum antibody responses (RSV- and PanAd3-neutralising antibody titres measured by plaque-reduction neutralisation and SEAP assays, respectively), peripheral B-cell immune responses (frequencies of F-specific IgG and IgA antibody secreting cells and memory B-cells by ex vivo and cultured dual-colour ELISpot assays respectively), and peripheral RSV-specific T-cell immune responses (frequencies of IFNγ-producing T-cells by ex vivo ELISpot and CD4+/CD8+/Tfh-like cell frequencies by ICS/FACS assay).
RESULTS: The vaccines were safe and well tolerated. Compared with each individual baseline immunity the mean fold-changes in serum RSV-neutralising antibody, appearance and magnitude of F-specific IgG and IgA ASCs and expansion of CD4+/CD8+ IFNγ-producing T-cells in peripheral circulation were comparable to the results seen from younger healthy adults who received the same vaccine combination and dose. There were little/no IgA memory B-cell responses in younger and older adults. Expansion of IFNγ-producing T-cells was most marked in older adults following IM prime, with balanced CD4+ and CD8+ T cell responses. The RSV-specific immune responses to vaccination did not appear to be attenuated in the presence of PanAd3 (vector) neutralising antibody.
CONCLUSIONS: PanAd3-RSV and MVA-RSV was safe and immunogenic in older adults and the parallel induction of RSV-specific humoral and cellular immunity merits further assessment in providing protection from severe disease.

PMID: 30742894 [PubMed - indexed for MEDLINE]

L-DOPA for Parkinson's disease-a bittersweet pill.

Eur J Neurosci. 2019 02;49(3):384-398

Authors: Lane EL

Abstract
3,4-dihydroxy-L-phenylalanine (L-DOPA) is the gold standard treatment for Parkinson's disease. It has earned that title through its highly effective treatment of some of the motor symptoms in the early stages of the disease but it is a far from perfect drug. The inevitable long-term treatment that comes with this chronic neurodegenerative condition raises the risk significantly of the development of motor fluctuations including disabling L-DOPA-induced dyskinesia. Being unsurpassed as a therapy means that understanding the mechanisms of dyskinesia priming and induction is vital to the search for therapies to treat these side effects and allow optimal use of L-DOPA. However, L-DOPA use may also have consequences (positive or negative) for the development of other interventions, such as cell transplantation, which are designed to treat or repair the ailing brain. This review looks at the issues around the use of L-DOPA with a focus on its potential impact on advanced reparative interventions.

PMID: 30118169 [PubMed - indexed for MEDLINE]

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