[Completeness of pharmacovigilance reporting in general medicine in France.]

Sante Publique. 2019 July August;Vol. 31(4):561-566

Authors: Humbert X, Jacquot J, Alexandre J, Sassier M, Robin N, Pageot C, Kheloufi F, Joyau C, Coquerel A, Durrieu G, Fedrizzi S

Abstract
INTRODUCTION: Spontaneous reporting remains one of the cornerstones of post-marketing drug safety surveillance. One of its main limitations is a lack of completeness.The main aim of this study was to assess the completeness of pharmacovigilance reports sent by general practitioners (GPs) to regional pharmacovigilance centers (RPC) reported in the French pharmacovigilance database (FPVD). Secondary aim was to identify factors associated with complete reports.
METHOD: All adverse drugs reactions (ADRs) sent by GPs in France in 2015 were analyzed. According to information provided in ADR reports (ADR, date of occurrence, clinical description, drugs suspected, etc.), completeness was analyzed from “mandatory” criteria (age, gender, ADR and suspected drug(s)) and “non-mandatory” criteria (medical history, concomitant drugs, symptoms evolution and complementary exams) and classified as “well-documented”, “slightly-documented” or “poorly-documented”.
RESULTS: In 2015, the FPVD contained 3,020 ADR reports realized by GPs. Only 16.4% of these reports were classified as “well-documented”, in accordance with study criteria. The most poorly documented items were concomitant drugs (41.4%) and complementary exams (37.4%). An association between a “well-documented” ADR report and its “seriousness” (OR = 3,02 [95% CI 2,44; 3,23], P < 10–3) and elderly compared to adults (OR = 1,76 [95% CI 1,42; 2,18], P < 10–3) or children (OR = 4,59 [95% CI 2,51; 8,39], P < 10–3).
CONCLUSION: Our study shows that only one out of six ADR reports was “well-documented”. It appears to be important to promote pharmacovigilance to improve completeness of ADR reports.

PMID: 31959257 [PubMed - indexed for MEDLINE]

Genetic literacy series: clinical application of pharmacogenetics for adverse reactions to antiepileptic drugs.

Epileptic Disord. 2019 Aug 01;21(4):330-336

Authors: Zhang Z, Wu Y, Tan NC, Jiang Y

Abstract
Adverse drug reactions are a leading cause of treatment failure with antiepileptic drugs. Adverse drug reactions are also a major source of morbidity and mortality, and a substantial burden on the use and costs of health care. Recent pharmacogenetic studies have shown that some adverse drug reactions are associated with genetic variants, which has changed how we select antiepileptic drugs for individual patients. This article, beginning with a case of an adverse drug reaction induced by carbamazepine, will answer four key questions about pharmacogenetics of adverse drug reactions: (1) What types of adverse drug reactions can be caused by antiepileptic drugs? (2) What is pharmacogenetics? (3) How does pharmacogenetics play a role in the adverse drug reactions of antiepileptic drugs? and (4) How do we apply pharmacogenetic testing in clinical practice? Our goal is to increase awareness of the contributions of genetic variation to adverse drug reactions of antiepileptic drugs.

PMID: 31403464 [PubMed - indexed for MEDLINE]

Efficacy and safety of combination antifungal therapy in Korean haematological patients with invasive aspergillosis.

Mycoses. 2019 Oct;62(10):969-978

Authors: Lee DG, Lee HJ, Yan JL, Lin SS, Aram JA

Abstract
This randomised, double-blind, placebo-controlled trial assessed the efficacy, safety and tolerability of voriconazole+anidulafungin (combination) or voriconazole+placebo (monotherapy) for invasive aspergillosis (IA; NCT00531479). We present a post hoc analysis of Korean and non-Korean patients with IA (including baseline positive serum galactomannan [GM]). Immunocompromised patients ≥ 16 years with IA were randomised 1:1, combination or monotherapy, for ≥ 2 weeks' treatment. The primary endpoint was 6- and 12-week all-cause mortality (Korean modified intent-to-treat [mITT] population). Overall, 454 patients enrolled (Koreans: 56 [combination: 28, monotherapy: 28], non-Koreans: 398 [combination: 200, monotherapy: 198]). The mITT population comprised 40 Koreans (combination: 23; monotherapy: 17) and 237 non-Koreans (combination: 112; monotherapy: 125). Week 6 treatment difference in mortality rate between combination and monotherapy was -6.4% in non-Koreans. This reduction was more marked in Koreans (-22.4%). Week 12 difference in all-cause mortality between combination and monotherapy was -17.7% (Koreans) and -20.2% at Week 6 (Koreans; positive baseline GM). Week 6 mortality (Koreans [mITT]; baseline GM >0.5-2.0) was 0/13 (combination) and 2/6 (monotherapy). Serious adverse events were numerically higher for combination than monotherapy (Koreans: 57.1%, 46.4%; non-Koreans: 49.5%, 46.0%). In Koreans, combination therapy was associated with marginally better outcomes than monotherapy and more so than in non-Koreans.

PMID: 31355956 [PubMed - indexed for MEDLINE]

Post-Transfusion Purpura Mimicking Idiopathic Thrombocytopenic Purpura: A Case Report.

Lab Med. 2019 Oct 10;50(4):396-400

Authors: Milito C, Masel D, Henrichs K, Schmidt AE, Kirkley S, Aljitawi O, Becker M, Blumberg N, Refaai MA

Abstract
The main clinical distinction between post-transfusion purpura (PTP) and idiopathic thrombocytopenic purpura (ITP) is the sudden development of severe thrombocytopenia in the days after transfusion. Herein, we report the case of a 53-year-old Caucasian woman who developed multiple myeloma (MM) after peripheral blood-stem-cell transplant (PBSCT), along with severe thrombocytopenia (with a nadir of 1 × 109/L); she also experienced severe adverse events after each platelet transfusion, including the first one. These reactions were absent with any other transfused blood products. The results of an human leukocyte antigen (HLA) class-1 panel reactive antibody assay were 0%, and the results of a platelet-antibody screening assay were positive for HLA class-1 antibodies and glycoprotein (Gp)IIb/IIIa antibodies. Her platelet count reached 42 × 109 per L on day 50, after rituximab on day 22 and daratumumab on day 29. Her clinical scenario was most consistent with the course of PTP.

PMID: 30915450 [PubMed - indexed for MEDLINE]

The effect of SENATOR (Software ENgine for the Assessment and optimisation of drug and non-drug Therapy in Older peRsons) on incident adverse drug reactions (ADRs) in an older hospital cohort - Trial Protocol.

BMC Geriatr. 2019 02 13;19(1):40

Authors: Lavan AH, O'Mahony D, Gallagher P, Fordham R, Flanagan E, Dahly D, Byrne S, Petrovic M, Gudmundsson A, Samuelsson O, Cherubini A, J Cruz-Jentoft A, Soiza RL, Eustace JA

Abstract
BACKGROUND: The aim of this trial is to evaluate the effect of SENATOR software on incident, adverse drug reactions (ADRs) in older, multimorbid, hospitalized patients. The SENATOR software produces a report designed to optimize older patients' current prescriptions by applying the published STOPP and START criteria, highlighting drug-drug and drug-disease interactions and providing non-pharmacological recommendations aimed at reducing the risk of incident delirium.
METHODS: We will conduct a multinational, pragmatic, parallel arm Prospective Randomized Open-label, Blinded Endpoint (PROBE) controlled trial. Patients with acute illnesses are screened for recruitment within 48 h of arrival to hospital and enrolled if they meet the relevant entry criteria. Participants' medical history, current prescriptions, select laboratory tests, electrocardiogram, cognitive status and functional status are collected and entered into a dedicated trial database. Patients are individually randomized with equal allocation ratio. Randomization is stratified by site and medical versus surgical admission, and uses random block sizes. Patients randomized to either arm receive standard routine pharmaceutical clinical care as it exists in each site. Additionally, in the intervention arm an individualized SENATOR-generated medication advice report based on the participant's clinical and medication data is placed in their medical record and a senior medical staff member is requested to review it and adopt any of its recommendations that they judge appropriate. The trial's primary outcome is the proportion of patients experiencing at least one adjudicated probable or certain, non-trivial ADR, during the index hospitalization, assessed at 14 days post-randomization or at index hospital discharge if it occurs earlier. Potential ADRs are identified retrospectively by the site researchers who complete a Potential Endpoint Form (one per type of event) that is adjudicated by a blinded, expert committee. All occurrences of 12 pre-specified events, which represent the majority of ADRs, are reported to the committee along with other suspected ADRs. Participants are followed up 12 (+/- 4) weeks post-index hospital discharge to assess medication quality and healthcare utilization. This is the first clinical trial to examine the effectiveness of a software intervention on incident ADRs and associated healthcare costs during hospitalization in older people with multi-morbidity and polypharmacy.
TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT02097654 , 27 March 2014.

PMID: 30760204 [PubMed - indexed for MEDLINE]

Pharmacist-led medication reviews for geriatric residents in German long-term care facilities.

BMC Geriatr. 2019 02 11;19(1):39

Authors: Bitter K, Pehe C, Krüger M, Heuer G, Quinke R, Jaehde U

Abstract
BACKGROUND: The benefit of medication reviews for long-term care (LTC) residents has been generally recognized throughout health care systems. Whereas many studies showed the impact of comprehensive medication reviews performed by specialized clinical pharmacists, little is known about the impact of medication reviews performed by community pharmacists. Involving them in the provision of medication reviews may help satisfy the increasing demand for ensuring medication safety.
METHODS: Community pharmacists supplying drugs to the LTC facilities performed a medication review for German LTC residents aged at least 65 years and taking five or more drugs per day based on the patients' medication only. Documented potential drug-related problems (DRPs) and the implementation rate of pharmaceutical interventions were evaluated descriptively. To assess the quality of the medication reviews, we developed a corresponding reference system based on the analysis of two experienced clinical pharmacists.
RESULTS: Twelve pharmacies performed medication reviews for 94 LTC residents. Overall, the pharmacists documented 154 potential DRPs (mean 1.6 per patient, SD 1.5) of which the most common were drug-drug interactions (40%) followed by potentially inappropriate medication (PIM) (16%) and inappropriate dosages (14%). 33% of the pharmacists' interventions to solve DRPs were successfully implemented, mostly dosage adjustments. The identification of potentially severe drug-drug interactions and PIM showed the highest agreement (88 and 73%) with the reference system.
CONCLUSIONS: The medication review program of community pharmacists for LTC residents led to the identification of relevant DRPs. The reference system assessing the quality of the service can contribute to its transparency and reveals the potential for its improvement. The community pharmacists' knowledge of the LTC residents and their relation to the prescribers is crucial for providing successful medication reviews.

PMID: 30744564 [PubMed - indexed for MEDLINE]

A comparative study of the efficacy of NAXOZOL compared to celecoxib in patients with osteoarthritis.

PLoS One. 2020;15(1):e0226184

Authors: Park MS, Kang CN, Lee WS, Kim HJ, Lee S, Kim JH, Shin SJ, Moon SH

Abstract
OBJECTIVE: Selective cyclooxygenase-2 inhibitors (celecoxib) can minimize the gastrointestinal complications related to non-steroidal anti-inflammatory drug (NSAID) use. NAXOZOL is a new combination formulation designed to provide sequential delivery of a non-enteric-coated, immediate-release esomeprazole strontium tetrahydrate 20 mg mantle followed by an enteric-coated naproxen 500 mg core. However, there have been no studies comparing NAXOZOL to celecoxib with respect to gastrointestinal tract protection and pain relief in patients with osteoarthritis. This study was undertaken to compare the effects of NAXOZOL and celecoxib with respect to gastrointestinal tract protection and pain relief in patients with osteoarthritis.
METHODS: The randomized enrolled patients were divided into two treatment groups: a NAXOZOL group and a celecoxib group. All participants received treatments (NAXOZOL, 500/20 mg (naproxen 500 mg, esomeprazole strontium tetrahydrate 20 mg) twice per day versus celecoxib, 200 mg daily) on a 1:1 allocation basis for 12 weeks. The primary outcome was the Leeds Dyspepsia Questionnaire (LDQ) score used for non-inferiority testing. Secondary outcome measures included the Gastrointestinal Symptom Rating Scale (GSRS) score, Visual Analogue Scale (VAS) score, European Quality of Life-5 dimensions (EQ-5D) scale and the EQ-5D Visual Analogue Scale (EQ VAS). Other outcome measures included the use of supplementary or rescue drugs, and the incidence of adverse events.
RESULTS: The baseline-adjusted LDQ scores immediately after 12 weeks of treatment in NAXOZOL group were not inferior to those in celecoxib group. The overall change in the baseline-adjusted GSRS score, VAS score, EQ-5D, and EQ VAS was not different between the two groups. The usage of supplementary drugs and the drug-related incidence of adverse events were not different. However, the days to use rescue drug were longer in celecoxib group than in NAXOZOL group.
CONCLUSION: NAXOZOL was not inferior to celecoxib in protecting the gastrointestinal tract and providing pain relief in patients with osteoarthritis.

PMID: 31986170 [PubMed - in process]

A phase 1 study of nevanimibe HCl, a novel adrenal-specific sterol O-acyltransferase 1 (SOAT1) inhibitor, in adrenocortical carcinoma.

Invest New Drugs. 2020 Jan 27;:

Authors: Smith DC, Kroiss M, Kebebew E, Habra MA, Chugh R, Schneider BJ, Fassnacht M, Jafarinasabian P, Ijzerman MM, Lin VH, Mohideen P, Naing A

Abstract
Background Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with very limited treatment options. Nevanimibe HCl (formerly ATR-101), a novel adrenal-specific sterol O-acyltransferase 1 (SOAT1) inhibitor, has been shown in nonclinical studies to decrease adrenal steroidogenesis at lower doses and to cause apoptosis of adrenocortical cells at higher doses. Methods This phase 1, multicenter, open-label study assessed the safety and pharmacokinetics (PK) of nevanimibe in adults with metastatic ACC (NCT01898715). A "3 + 3" dose-escalation design was used. Adverse events (AEs), PK, and tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were evaluated every 2 months. Results 63 patients with metastatic ACC, all of whom had previously failed systemic chemotherapy and only 2 of whom were mitotane-naïve, were dosed with oral nevanimibe at doses ranging from 1.6 mg/kg/day to 158.5 mg/kg/day. Subjects who did not experience tumor progression or a dose-limiting toxicity (DLT) could continue to receive additional cycles. No patients experienced a complete or partial response; however, 13 of the 48 (27%) patients who underwent imaging at 2 months had stable disease (SD), and 4 of these had SD > 4 months. In addition, drug-related adrenal insufficiency, considered a pharmacologic effect of nevanimibe, was observed in two patients. The most common treatment-emergent AEs were gastrointestinal disorders (76%), including diarrhea (44%) and vomiting (35%). A maximum tolerated dose (MTD) could not be defined, as very few dose-limiting toxicities (DLTs) occurred. Because the large number of tablets required at the highest dose (i.e., ~24 tablets/day) resulted in low-grade gastrointestinal adverse effects, a maximum feasible dose of 128.2 mg/kg/day was established as a dose that could be taken on a long-term basis. Conclusions This study demonstrated the safety of nevanimibe at doses of up to ~6000 mg BID. As the total number of tablets required to achieve an MTD exceeded practical administration limits, a maximum feasible dose was defined. Given that the expected exposure levels necessary for an apoptotic effect could not be achieved, the current formulation of nevanimibe had limited efficacy in patients with advanced ACC.

PMID: 31984451 [PubMed - as supplied by publisher]

Medication-related pruritis in older adults with long-term conditions.

Br J Community Nurs. 2019 Aug 02;24(8):380-382

Authors: Peters J

PMID: 31369306 [PubMed - indexed for MEDLINE]

Summaries of safety labeling changes approved by FDA-Boxed warnings highlights, January-March 2019.

Am J Health Syst Pharm. 2019 06 18;76(13):e8-e9

Authors:

PMID: 31361888 [PubMed - indexed for MEDLINE]

Cancer in older adults: understanding cause and effects of chemotherapy-related toxicities.

Future Oncol. 2019 Aug;15(22):2557-2560

Authors: Bhatt VR

PMID: 31339058 [PubMed - indexed for MEDLINE]

Evaluation of the effectiveness of caspofungin against febrile neutropenia and the factors related to the alteration in its plasma concentration.

J Infect Chemother. 2019 Oct;25(10):801-805

Authors: Shibata Y, Miyahara Y, Sadaka Y, Yasue M, Fujimura M, Soda M, Yamamoto M, Kato H, Suzuki A, Tsukamoto K, Hara T, Tsurumi H, Kitaichi K

Abstract
Caspofungin (CPFG) is an echinocandin antifungal agent that inhibits the synthesis of β-1, 3-D-glucan, a critical component of the cell wall of target fungi. Several clinical studies have confirmed the efficacy and safety of CPFG in patients with febrile neutropenia (FN); however, there are no reports available in Japanese patients with FN. Therefore, we investigated the therapeutic efficacy and pharmacokinetics of CPFG as an empirical therapy in a Japanese hospital. Twenty-four Japanese patients, who were diagnosed with FN at Gifu University Hospital from February 2014 to August 2017, were enrolled. Blood samples were collected at the end of CPFG dosing (0.5 h after the infusion) on day 1 and immediately prior to the next infusion on days 2, 3, and 4. The concentration of CPFG in plasma was measured by high-performance liquid chromatography. The efficacy was assessed by five of the component endpoints, and safety was monitored according to the Common Terminology Criteria for Adverse Events. CPFG showed an excellent effect against FN (75%, 18/24), without any serious hepatic or renal toxicity. Regarding the pharmacokinetics, the plasma concentration of CPFG was significantly correlated with body weight; although, no correlation was observed between the plasma concentration of CPFG and the other factors investigated, such as gender or laboratory results. These results suggest the high efficacy, safety, and tolerability of CPFG as an empirical antifungal therapy for Japanese patients with FN.

PMID: 31047782 [PubMed - indexed for MEDLINE]

First-in-human phase I clinical trial of the NY-ESO-1 protein cancer vaccine with NOD2 and TLR9 stimulants in patients with NY-ESO-1-expressing refractory solid tumors.

Cancer Immunol Immunother. 2020 Jan 24;:

Authors: Ishihara M, Tono Y, Miyahara Y, Muraoka D, Harada N, Kageyama S, Sasaki T, Hori Y, Soga N, Uchida K, Shiraishi T, Sato E, Kanda H, Mizuno T, Webster GA, Ikeda H, Katayama N, Sugimura Y, Shiku H

Abstract
Cholesteryl pullulan (CHP) is a novel antigen delivery system. CHP and New York esophageal squamous cell carcinoma 1 (NY-ESO-1) antigen complexes (CHP-NY-ESO-1) present multiple epitope peptides to the MHC class I and II pathways. Adjuvants are essential for cancer vaccines. MIS416 is a non-toxic microparticle that activates immunity via the nucleotide-binding oligomerization domain 2 (NOD2) and TLR9 pathways. However, no reports have explored MIS416 as a cancer vaccine adjuvant. We conducted a first-in-human clinical trial of CHP-NY-ESO-1 with MIS416 in patients with NY-ESO-1-expressing refractory solid tumors. CHP-NY-ESO-1/MIS416 (μg/μg) was administered at 100/200, 200/200, 200/400 or 200/600 (cohorts 1, 2, 3 and 4, respectively) every 2 weeks for a total of 6 doses (treatment phase) followed by one vaccination every 4 weeks until disease progression or unacceptable toxicity (maintenance phase). The primary endpoints were safety and tolerability, and the secondary endpoint was the immune response. In total, 26 patients were enrolled. Seven patients (38%) continued vaccination in the maintenance phase. Grade 3 drug-related adverse events (AEs) were observed in six patients (23%): anorexia and hypertension were observed in one and five patients, respectively. No grade 4-5 drug-related AEs were observed. Eight patients (31%) had stable disease (SD). Neither augmentation of the NY-ESO-1-specific IFN-γ-secreting CD8+ T cell response nor an increase in the level of anti-NY-ESO-1 IgG1 was observed as the dose of MIS416 was increased. In a preclinical study, adding anti-PD-1 monoclonal antibody to CHP-NY-ESO-1 and MIS416 induced significant tumor suppression. This combination therapy is a promising next step.

PMID: 31980914 [PubMed - as supplied by publisher]

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Management of Systemic Hypersensitivity Reactions to Gonadotropin-Releasing Hormone Analogues during Treatment of Central Precocious Puberty.

Horm Res Paediatr. 2020 Jan 23;:1-7

Authors: Kirkgoz T, Karakoc-Aydiner E, Bugrul F, Yavas Abali Z, Helvacioglu D, Kiykim A, Bilgic Eltan S, Aruci Kasap N, Baris S, Ozen A, Guran T, Bereket A, Turan S

Abstract
BACKGROUND: Besides local reactions, systemic hypersensitivity reactions such as urticaria, anaphylaxis, serum sickness and Henoch-Schönlein purpura (HSP) have been reported during gonadotropin-releasing hormone (GnRH) analogue treatment.
AIM: To present the clinical presentation of 9 cases with systemic hypersensitivity reactions to GnRH analogues and discuss the management of such reactions based on our experience.
PATIENTS AND METHODS: Nine of 232 (3.8%) patients with central precocious puberty receiving GnRH analogue treatment had systemic hypersensitivity reactions in 4 years' period. Six patients had a type 1 hypersensitivity reaction (generalized hives, pruritus, and/or edema) to triptorelin acetate (TA), 2 patients to leuprolide acetate (LA), and 1 patient to both medications who also developed anaphylaxis to LA during intradermal test (IDT). Another patient on TA had skin lesions suggestive of HSP. GnRH analogue treatment was discontinued in 2 patients after discussion with the parents. Treatment was changed to another GnRH analogue preparation in 6 patients and was maintained with the same medication with antihistamines and corticosteroid premedication in 1 patient. None of the patients developed new reactions after these precautions.
CONCLUSION: Systemic hypersensitivity reactions should be carefully evaluated and cross-reaction to the other GnRH analogues should be kept in mind. Discontinuation of GnRH analogue is always an option. However, if continuation of GnRH analogue is elected, we recommend switching to an alternative GnRH analogue, which should be considered only after a skin prick test (SPT) and IDT. In the lack of the possibility to perform SPT and IDT, injections may be administered under strict medical supervision in a well-equipped facility to manage anaphylaxis. We discuss additional options in situations where alternative GnRH analogues are unavailable, which enabled us to continue treatment in most cases without further problems.

PMID: 31972562 [PubMed - as supplied by publisher]

Study of mastoparan analog peptides against Candida albicans and safety in zebrafish embryos (Danio rerio).

Future Microbiol. 2019 09;14:1087-1097

Authors: Galeane MC, Gomes PC, L Singulani J, de Souza BM, Palma MS, Mendes-Giannini MJ, Almeida AM

Abstract
Aim: In this work, mastoparan analog peptides from wasp venom were tested against Candida albicans and safety assays were performed using cell culture and model zebrafish. Materials & methods: Minimal inhibitory concentration was determined and toxicity was performed using human skin keratinocyte and embryo zebrafish. Also, permeation of peptides through embryo chorion was performed. Results: The peptides demonstrated anti-C. albicans activity, with low cytotoxicity and nonteratogenicity in Danio rerio. The compounds had different permeation through chorion, suggesting that this occurs due to modifications in their amino acid sequence. Conclusion: The results showed that the studied peptides can be used as structural study models for novel potential antifungal agents.

PMID: 31512522 [PubMed - indexed for MEDLINE]

Drug tolerability and reasons for discontinuation of seven biologics in elderly patients with rheumatoid arthritis -The ANSWER cohort study.

PLoS One. 2019;14(5):e0216624

Authors: Ebina K, Hashimoto M, Yamamoto W, Hirano T, Hara R, Katayama M, Onishi A, Nagai K, Son Y, Amuro H, Yamamoto K, Maeda Y, Murata K, Jinno S, Takeuchi T, Hirao M, Kumanogoh A, Yoshikawa H

Abstract
BACKGROUND: The aim of this study is to evaluate the retention rates and reasons for discontinuation for seven biological disease-modifying antirheumatic drugs (bDMARDs) in a real-world setting of elderly patients (65 years of age or older) with rheumatoid arthritis (RA).
METHODS: This multi-center, retrospective study assessed 1,098 treatment courses of 661 patients with bDMARDs from 2009 to 2018 (females, 80.7%; baseline age, 71.7 years; disease duration 10.5 years; rheumatoid factor positivity 81.3%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate, 4.6; concomitant prednisolone dose 2.8 mg/day (45.6%) and methotrexate dose 4.4 mg/week (56.4%); and 60.2% patients were bio-naïve). Treatment courses included abatacept (ABT; n = 272), tocilizumab (TCZ; n = 234), etanercept (ETN; n = 184), golimumab (GLM; n = 159), infliximab (IFX; n = 101), adalimumab (ADA; n = 97), and certolizumab pegol (CZP; n = 51). Drug retention rates and discontinuation reasons were estimated at 36 months using the Kaplan-Meier method and adjusted for potential clinical confounders (age, sex, disease duration, concomitant PSL and MTX, starting date and switched number of bDMARDs) by Cox proportional hazards modeling.
RESULTS: A total of 51.2% of treatment courses were stopped, with 25.1% stopping due to lack of effectiveness, 11.8% due to toxic adverse events, 9.7% due to non-toxic reasons, and 4.6% due to remission. Drug retention rates for each discontinuation reason were as follows; lack of effectiveness [from 55.4% (ETN) to 81.6% (ABT); with significant differences between groups (Cox P<0.001)], toxic adverse events [from 79.3% (IFX) to 95.4% (ABT), Cox P = 0.043], and remission [from 94.2% (TCZ) to 100.0% (CZP), Cox P = 0.58]. Finally, overall retention rates excluding non-toxic reasons and remission for discontinuation ranged from 50.0% (ETN) to 78.1% (ABT) (Cox P<0.001).
CONCLUSIONS: ABT showed lowest discontinuation rate by lack of effectiveness and by toxic adverse events, which lead to highest overall retention rates (excluding non-toxic reasons and remission) among seven bDMARDs in adjusted model of elderly RA patients.

PMID: 31067271 [PubMed - indexed for MEDLINE]

STOPP/START criteria for potentially inappropriate medications/potential prescribing omissions in older people: origin and progress.

Expert Rev Clin Pharmacol. 2020 Jan;13(1):15-22

Authors: O'Mahony D

Abstract
Introduction: STOPP (Screening Tool of Older Persons' Prescriptions) and START (Screening Tool to Alert to Right Treatment) are explicit criteria that facilitate medication review in multi-morbid older people in most clinical settings. This review examines the clinical trial evidence pertaining to STOPP/START criteria as an intervention.Areas covered: The literature was searched for registered clinical trials that used STOPP/START criteria as an intervention. In single-center trials, applying STOPP/START criteria improved medication appropriateness, reduced polypharmacy, reduced adverse drug reactions (ADRs), led to fewer falls, and lower medication costs. Two large-scale multi-center trials (SENATOR and OPERAM) examined the impact of computer-generated STOPP/START criteria on incident ADRs (SENATOR) and drug-related hospitalizations (OPERAM) in multi-morbid older people. Results of these trials will be publicized in 2020.Expert opinion: Applying STOPP/START criteria improves clinical outcomes in multi-morbid older people. Electronic deployment of STOPP/START criteria is a substantial technical challenge; however, recent clinical trials of software prototypes demonstrate feasibility. Even with well-functioning software for the application of STOPP/START criteria, the need remains for face-to-face interaction between attending clinicians and appropriately trained personnel (likely pharmacists) to explain and qualify specific STOPP/START recommendations in individual multi-morbid older patients. Such interaction is essential for the implementation of relevant STOPP/START recommendations.

PMID: 31790317 [PubMed - indexed for MEDLINE]

Oral adverse effects of drugs: Taste disorders.

Oral Dis. 2020 Jan;26(1):213-223

Authors: Rademacher WMH, Aziz Y, Hielema A, Cheung KC, de Lange J, Vissink A, Reinder Rozema F

Abstract
OBJECTIVE: Oral healthcare professionals are frequently confronted with patients using drugs on a daily basis. These drugs can cause taste disorders as adverse effect. The literature that discusses drug-induced taste disorders is fragmented. This article aims to support oral healthcare professionals in their decision making whether a taste disorder can be due to use of drugs by providing a comprehensive overview of drugs with taste disorders as an adverse effect.
MATERIALS AND METHODS: The national drug information database for Dutch pharmacists, based on scientific drug information, guidelines, and summaries of product characteristics, was analyzed for drug-induced taste disorders. "MedDRA classification" and "Anatomic Therapeutical Chemical codes" were used to categorize the results.
RESULTS: Of the 1,645 drugs registered in the database, 282 (17%) were documented with "dysgeusia" and 61 (3.7%) with "hypogeusia." Drug-induced taste disorders are reported in all drug categories, but predominantly in "antineoplastic and immunomodulating agents," "antiinfectives for systemic use," and "nervous system." In ~45%, "dry mouth" coincided as adverse effect with taste disorders.
CONCLUSION: Healthcare professionals are frequently confronted with drugs reported to cause taste disorders. This article provides an overview of these drugs to support clinicians in their awareness, diagnosis, and treatment of drug-induced taste disorders.

PMID: 31532870 [PubMed - indexed for MEDLINE]

In Silico Prediction of Drug-Induced Liver Injury Based on Ensemble Classifier Method.

Int J Mol Sci. 2019 Aug 22;20(17):

Authors: Wang Y, Xiao Q, Chen P, Wang B

Abstract
Drug-induced liver injury (DILI) is a major factor in the development of drugs and the safety of drugs. If the DILI cannot be effectively predicted during the development of the drug, it will cause the drug to be withdrawn from markets. Therefore, DILI is crucial at the early stages of drug research. This work presents a 2-class ensemble classifier model for predicting DILI, with 2D molecular descriptors and fingerprints on a dataset of 450 compounds. The purpose of our study is to investigate which are the key molecular fingerprints that may cause DILI risk, and then to obtain a reliable ensemble model to predict DILI risk with these key factors. Experimental results suggested that 8 molecular fingerprints are very critical for predicting DILI, and also obtained the best ratio of molecular fingerprints to molecular descriptors. The result of the 5-fold cross-validation of the ensemble vote classifier method obtain an accuracy of 77.25%, and the accuracy of the test set was 81.67%. This model could be used for drug-induced liver injury prediction.

PMID: 31443562 [PubMed - indexed for MEDLINE]