Risk of renal events during tenofovir disoproxil fumarate and entecavir antiviral prophylaxis in HBsAg-positive cancer patients undergoing chemotherapy.

J Viral Hepat. 2018 12;25(12):1599-1607

Authors: Lee IC, Chao Y, Li CP, Su CW, Lan KH, Lin HC, Hou MC, Huang YH

Abstract
The risk of renal events in HBsAg-positive cancer patients receiving tenofovir disoproxil fumarate (TDF) or entecavir (ETV) antiviral prophylaxis during chemotherapy has not been evaluated. This study aimed to evaluate the renal safety of TDF and ETV during chemotherapy. Consecutive, 219 HBsAg-positive cancer patients treated with TDF (n = 106) or ETV (n = 113) for antiviral prophylaxis during chemotherapy with baseline serum creatinine (SCr) <1.2 mg/dL were retrospectively enrolled. Serial SCr levels and estimated glomerular filtration rate (eGFR) were monitored. The incidence of acute kidney injury (AKI) during antiviral prophylaxis was 33% and 38.9% in TDF and ETV groups, respectively (P = 0.441), while the incidence of sustained kidney injury was 11.3% and 11.5%, respectively (P = 1.000). By multivariate analysis, diuretics use (hazard ratio (HR) = 2.011, P = 0.042) and serum albumin levels (HR = 0.441, P = 0.001) were independent predictors of AKI; serum albumin levels (HR = 0.252, P = 0.002) was the only factor associated with sustained kidney injury; age (HR = 2.752, P < 0.001), baseline SCr levels (HR = 3.386, P < 0.001), and serum albumin levels (HR = 0.437, P = 0.001) were factors associated with a new eGFR <60 mL/min. 34.9% of patients in TDF group and 35.4% in ETV group had deteriorated chronic kidney disease (CKD) stage at the end of follow-up, respectively. There were no significant differences in the risk of renal events or CKD stage migration between TDF and ETV groups. Renal events may develop in about one-third of HBsAg-positive cancer patients undergoing chemotherapy. The risk of renal function impairment was comparable between patients treated with TDF and ETV antiviral prophylaxis.

PMID: 30125436 [PubMed - indexed for MEDLINE]

Amantadine Extended-Release (GOCOVRI™): A Review in Levodopa-Induced Dyskinesia in Parkinson's Disease.

CNS Drugs. 2018 08;32(8):797-806

Authors: Paik J, Keam SJ

Abstract
Amantadine extended-release (ER) capsules (GOCOVRI™) are approved in the USA for the treatment of dyskinesia in patients with Parkinson's disease (PD) receiving levodopa-based therapy, with or without concomitant dopaminergic medications. With a recommended dosage of 274 mg once daily at bedtime, this new formulation of amantadine allows a more gradual time to peak plasma amantadine concentration and higher drug concentrations in the morning and throughout the day, the time period when levodopa-induced dyskinesia (LID) is the most problematic. In 13-week (EASE LID 3) and 25-week (EASE LID), randomized, double-blind phase III trials, once-daily amantadine ER 274 mg capsules significantly improved levodopa-induced dyskinesia (LID), while also increasing ON time without troublesome dyskinesia and reducing OFF time and ON time with troublesome dyskinesia from the morning and throughout the day, compared with placebo. In the ongoing, longer-term EASE LID 2 study (with interim results reported for up to 64 weeks), patients previously treated with amantadine ER maintained improvements in LID, as per patient-reported Unified Dyskinesia Rating Scale (UDysRS) scoring and ON/OFF times. Amantadine ER was generally well tolerated, with most adverse events (AEs) being transient and mild or moderate in severity. The most common (incidence > 15%) treatment-related AEs in the placebo-controlled trials were hallucinations, dizziness, dry mouth and peripheral oedema. While long-term data are needed to establish durability of response and safety, including the completion of the ≈ 2-year EASE LID 2 study, current evidence indicates that amantadine ER is an effective treatment option to consider in the management of LID in PD patients.

PMID: 30088203 [PubMed - indexed for MEDLINE]

Safety and Efficiency of Intravenous Push Lacosamide Administration.

Neurocrit Care. 2018 Dec;29(3):491-495

Authors: Davidson KE, Newell J, Alsherbini K, Krushinski J, Jones GM

Abstract
BACKGROUND/OBJECTIVE: Intravenous (IV) lacosamide use for status epilepticus has increased in recent years and is recommended for refractory status epilepticus by current guidelines. Per the lacosamide package labeling, the preferred route of administration is diluted and infused over 30-60 min; however, administration undiluted is also acceptable and recent literature demonstrated safety at a maximum rate of 80 mg per minute (Kellinghaus et al. in Acta Neurol Scand 123:137-141, 2011). Undiluted administration as an IV push has potential to increase efficiency of administration to patients needing urgent seizure control since it may be dispensed from automatic dispensing cabinets in patient care areas. This study aims to compare safety outcomes and efficiency of administration in patients receiving lacosamide IV push compared to IV piggyback.
METHODS: We present a single-center, retrospective cohort study of patients receiving lacosamide via IV piggyback or IV push from June 2016 to July 2017. Baseline characteristics, data related to potential safety concerns and timing of ordering, verification, and administration were collected. The primary safety outcomes were incidence of infusion site reactions, hypotension (systolic blood pressure [SBP] < 90 mm Hg), and bradycardia (heart rate [HR] < 50 beats per minute) documented within 2 h of each lacosamide dose. Secondary safety outcomes included the incidence of PR interval prolongation in patients with at least one electrocardiogram measured. The primary efficiency outcome was the time between order verification and administration.
RESULTS: Patients in the IV piggyback (n = 88) and IV push (n = 78) groups had similar baseline characteristics, initial dose, SBP, and HR. Hypotension (8 vs. 10.3%) and bradycardia (2.3 vs. 2.6%) rates were similar among both groups (p > 0.05). Only one patient in each group had documented PR prolongation, and no documented infusion reactions occurred. Median time from order verification to administration was significantly reduced in the IV push group (35 min vs. 1 h 49 min; p < 0.001).
CONCLUSIONS: Administration of lacosamide via IV push results in similar adverse effect rates to IV piggyback preparations with more efficient time to administration.

PMID: 29949010 [PubMed - indexed for MEDLINE]

Adverse Drug Reactions Reported by Healthcare Professionals: Reaction Characteristics and Time to Reporting.

J Clin Pharmacol. 2018 10;58(10):1332-1339

Authors: Aung AK, Tang MJ, Adler NR, de Menezes SL, Goh MSY, Tee HW, Trubiano JA, Puy R, Zubrinich CM, Graudins LV

Abstract
We describe adverse drug reaction (ADR) reporting characteristics and factors contributing to length of time to report by healthcare professionals. This is a retrospective study of voluntary reports to an Australian healthcare ADR Review Committee over a 2-year period (2015-2016). Descriptive and univariate models were used for outcomes, employing standardized ADR definitions. Hospital pharmacists reported 84.8% of the 555 ADRs: 70.3% were hospital onset reactions, and 71.7% were at least of moderate severity. Immunologically mediated reactions were most commonly reported (409, 73.7%). The median time to submit an ADR report was 3 (interquartile range 1-10) days. Longer median times to reporting were associated with multiple implicated agents and delayed hypersensitivity reactions, especially severe cutaneous adverse reactions. A total of 650 medications were implicated that involved multiple agents in 165/555 (29.7%) reports. Antimicrobials were the most commonly implicated agents. Immunologically mediated reactions were most commonly associated with antimicrobials and radiocontrast agents (P < .0001, odds ratio [OR] 3.6, 95%CI 2.4-5.5, and P = .04, OR 4.2, 95%CI 1.2-18.2, respectively). Opioids and psychoactive medications were more commonly implicated in nonimmunological reported ADRs (P = .0002, OR 3.9, 95%CI 1.9-7.9, and P < .0001, OR 11.4, 95%CI 4.6-27.8, respectively). Due to the predominant reporting of immunologically mediated reactions, a targeted education program is being planned to improve identification and accuracy of ADR reports, with the overall aim of improved management to ensure quality service provision and patient safety.

PMID: 29733431 [PubMed - indexed for MEDLINE]

Ex-Lax®.

Skinmed. 2018;16(1):49

Authors: Bernhardt M

PMID: 29551115 [PubMed - indexed for MEDLINE]

Pharmacogenomics: Prescribing Precisely.

Med Clin North Am. 2019 Nov;103(6):977-990

Authors: Wake DT, Ilbawi N, Dunnenberger HM, Hulick PJ

Abstract
Pharmacogenomics (PGx) is a powerful tool that can predict increased risks of adverse effects and sub-therapeutic response to medications. This article establishes the core principles necessary for a primary care provider to meaningfully and prudently use PGx testing. Key topics include in which patients PGx testing should be considered, how PGx tests are ordered, how the results are translated into clinical recommendations, and what further advancements are likely in the near future. This will provide clinicians with a foundational knowledge of PGx that can allow incorporation of this tool into their practice or support further personal investigation.

PMID: 31582008 [PubMed - indexed for MEDLINE]

[Drug fever among Swiss' most sold drugs in primary care].

Rev Med Suisse. 2019 Aug 28;15(660):1516-1520

Authors: Eidenbenz D, Hirschel T, Schürmann G, Genné D

Abstract
Drug fever is a little known side effect and should be considered as a differential diagnosis in the presence of fever. Its early recognition is important to avoid unnecessary investigations. Among the 70 most prescribed drugs in primary care in Switzerland, 8 have been linked to drug fever : amoxicillin, atorvastatin, rosuvastatin, esomeprazole, pantoprazole, rivaroxaban, salbutamol and trazodone. There are no specific criterias to distinguish a drug-induced fever. The diagnosis is confirmed with a positive rechallenge test. If a drug fever is suspected, it is recommended to stop the offending agent.

PMID: 31496177 [PubMed - indexed for MEDLINE]

Usability of an online application for reporting the burden of side effects in cancer patients.

Support Care Cancer. 2019 Sep;27(9):3411-3419

Authors: van Eenbergen MC, van den Hurk C, Mols F, van de Poll-Franse LV

Abstract
PURPOSE: In the Netherlands, online patient reporting of side effects is a new phenomenon. The aim of this study was to gain insight into patients' user experiences and the benefits of the web application BijKanker ('AlongsideCancer').
METHODS: Patients in seven hospitals were asked to make entries in BijKanker at least once a week. On logging in to the application for the first time (T1), patients were asked to complete a questionnaire on information needs and Internet use. Four months after starting their treatment (T2), they were asked to complete a second questionnaire on their experiences with BijKanker and its four functions: information; reporting side effects; communication with oncology nurses and clinicians; and data feedback.
RESULTS: Ninety-nine patients logged in to BijKanker, 60 patients (61%) had completed the first questionnaire (T1) and 40 (40%) had also completed the second questionnaire (T2). In total, 1661 side effects were reported. Generally, patients experienced BijKanker as user-friendly and patients appreciated the attention given to their side effects.
CONCLUSIONS: The user-centred design gives ample insight into user experiences and usability. The results provide useful starting points for improvements to the online application. We recommend to put much effort into supporting oncology nurses in the implementation of the application.

PMID: 30656400 [PubMed - indexed for MEDLINE]

Efficacy and safety of continuous infusions with elastomeric pumps for outpatient parenteral antimicrobial therapy (OPAT): an observational study.

J Antimicrob Chemother. 2018 09 01;73(9):2540-2545

Authors: Voumard R, Gardiol C, André P, Arensdorff L, Cochet C, Boillat-Blanco N, Decosterd L, Buclin T, de Vallière S

Abstract
Objectives: This study aimed to evaluate the efficacy and safety of continuous antimicrobial infusion using elastomeric pumps in an outpatient setting, while simultaneously documenting circulating antibiotic concentration exposure achieved with this mode of administration.
Methods: Clinical outcomes, adverse events and antibiotic plasma concentrations were recorded for all patients treated by continuous infusion with elastomeric pumps at the outpatient parenteral antimicrobial therapy (OPAT) unit of the University Hospital of Lausanne between December 2013 and January 2017. The study was registered under ClinicalTrials.gov identifier NCT03221140.
Results: One hundred and fifty outpatients were treated by continuous intravenous infusions using flucloxacillin (70 patients), cefepime (36), vancomycin (32) and piperacillin/tazobactam (12). The calculated free fractions of each antibiotic were above the epidemiological cut-off values for resistance (ECOFF) of the treated microorganisms in 92% of measurements. Cure was achieved in 143 patients (95%) 3 months after the end of treatment. Four patients needed unexpected readmission and three had a relapse. In none of the patients with unsuccessful treatment was the ratio of free antibiotic plasma concentration/ECOFF <1. Sixteen patients (11%) had an adverse event, none of them being of severity grade 4 or 5.
Conclusions: Continuous infusions of flucloxacillin, cefepime, vancomycin and piperacillin/tazobactam using elastomeric pumps seem to be an effective and safe approach to treat outpatients. The number of treatment successes was very high and adverse events occurred at a similar rate as reported by other OPAT centres. The measured antibiotic plasma concentrations confirmed adequate drug concentration exposure for the vast majority of patients.

PMID: 29982449 [PubMed - indexed for MEDLINE]

Drug metabolism and transport gene polymorphisms and efavirenz adverse effects in Brazilian HIV-positive individuals.

J Antimicrob Chemother. 2018 09 01;73(9):2460-2467

Authors: de Almeida TB, de Azevedo MCVM, Pinto JFDC, Ferry FRA, da Silva GAR, de Castro IJ, Baker P, Tanuri A, Haas DW, Cardoso CC

Abstract
Objectives: There are limited data regarding efavirenz pharmacogenetics in admixed populations. The Brazilian population is highly admixed. In a Brazilian cohort, we sought to characterize associations between efavirenz adverse effects (all-cause and CNS) and polymorphisms in seven genes known or suspected to affect efavirenz metabolism and transport.
Methods: We studied 225 HIV-positive individuals who had been prescribed efavirenz-containing regimens at a hospital in Rio de Janeiro, Brazil. Eighty-nine cases had efavirenz adverse effects, including 43 with CNS adverse effects, while 136 controls had no adverse effect of any antiretroviral after treatment for at least 6 months. A total of 67 candidate polymorphisms in ABCB1, CYP2A6, CYP2B6, CYP3A4, CYP3A5, NR1I2 and NR1I3 genes were selected for association analysis. Admixture was assessed using 28 ancestry-informative polymorphisms previously validated for the Brazilian population. Associations were evaluated with logistic regression models adjusted for sex and genetic ancestry.
Results: There was extensive African, European and Native American admixture in the cohort. Increased all-cause adverse effects were associated with the CYP2B6 genotype combination 15582CC-516TT-983TT (OR = 7.26, P = 0.003) and with the CYP2B6 slow metabolizer group 516TT or 516GT-983CT (OR = 3.10, P = 0.04). CNS adverse effects were nominally associated with CYP3A4 rs4646437 (OR = 4.63, P = 0.014), but not after adjusting for multiple comparisons.
Conclusions: In a highly admixed Brazilian cohort, the CYP2B6 slow metabolizer genotype was associated with an increased risk of efavirenz adverse effects.

PMID: 29868865 [PubMed - indexed for MEDLINE]

Model of population pharmacokinetics of cidofovir in immunocompromised children with cytomegalovirus and adenovirus infection.

J Antimicrob Chemother. 2018 09 01;73(9):2422-2429

Authors: Neant N, Klifa R, Bouazza N, Moshous D, Neven B, Leruez-Ville M, Blanche S, Treluyer JM, Hirt D, Frange P

Abstract
Objectives: To describe cidofovir pharmacokinetics and assess the link between concentration and safety/efficacy in children.
Patients and methods: An observational study was conducted in 13 immunocompromised children receiving cidofovir for adenovirus and/or cytomegalovirus infection. A population pharmacokinetic model was built and AUC0-24 was derived for each patient. Virological success was defined as a decrease of the viraemia by ≥1 log10 copies/mL within 15 days of cidofovir initiation. The association between AUC0-24 and virological success was assessed using a Wilcoxon test. An AUC0-24 cut-off value was determined using a Fisher's exact test.
Results: Overall, 86 blood samples were analysed. A two-compartment model with first-order absorption and elimination best described the cidofovir data. Virological success (VS) was reached in 6/8 children with adenovirus viraemia and in 1/4 children with cytomegalovirus viraemia. Patients with VS displayed a non-significant higher median AUC0-24 compared with patients with virological failure: 48.6 (range 8.9-72.6) versus 19.1 (6.9-22.7) mg·h/L. Adenovirus-viraemic patients with an AUC0-24 value below 19.1 mg·h/L had a higher probability of treatment failure (P = 0.03). Aviraemic children with stool and/or nasopharyngeal adenovirus carriage cleared the viral carriage within a month of cidofovir initiation. During treatment, 1/13 children developed a tubulopathy but none of them had an increase in creatininaemia.
Conclusions: Cidofovir appears safe and reasonably well tolerated and seemed to have efficacy in a subset of patients with adenovirus/cytomegalovirus infection. Therapeutic drug monitoring may be useful in children receiving cidofovir and, in the case of adenovirus infection, targeting an AUC0-24 above 19.1 mg·h/L could be associated with higher probability of virological success.

PMID: 29860512 [PubMed - indexed for MEDLINE]

14 day sequential therapy versus 10 day bismuth quadruple therapy containing high-dose esomeprazole in the first-line and second-line treatment of Helicobacter pylori: a multicentre, non-inferiority, randomized trial.

J Antimicrob Chemother. 2018 09 01;73(9):2510-2518

Authors: Liou JM, Chen CC, Fang YJ, Chen PY, Chang CY, Chou CK, Chen MJ, Tseng CH, Lee JY, Yang TH, Chiu MC, Yu JJ, Kuo CC, Luo JC, Hsu WF, Hu WH, Tsai MH, Lin JT, Shun CT, Twu G, Lee YC, Bair MJ, Wu MS, Members of the Taiwan Gastrointestinal Disease and Helicobacter Consortium

Abstract
Background: Whether extending the treatment length and the use of high-dose esomeprazole may optimize the efficacy of Helicobacter pylori eradication remains unknown.
Objectives: To compare the efficacy and tolerability of optimized 14 day sequential therapy and 10 day bismuth quadruple therapy containing high-dose esomeprazole in first-line therapy.
Methods: We recruited 620 adult patients (≥20 years of age) with H. pylori infection naive to treatment in this multicentre, open-label, randomized trial. Patients were randomly assigned to receive 14 day sequential therapy or 10 day bismuth quadruple therapy, both containing esomeprazole 40 mg twice daily. Those who failed after 14 day sequential therapy received rescue therapy with 10 day bismuth quadruple therapy and vice versa. Our primary outcome was the eradication rate in the first-line therapy. Antibiotic susceptibility was determined. ClinicalTrials.gov: NCT03156855.
Results: The eradication rates of 14 day sequential therapy and 10 day bismuth quadruple therapy were 91.3% (283 of 310, 95% CI 87.4%-94.1%) and 91.6% (284 of 310, 95% CI 87.8%-94.3%) in the ITT analysis, respectively (difference -0.3%, 95% CI -4.7% to 4.4%, P = 0.886). However, the frequencies of adverse effects were significantly higher in patients treated with 10 day bismuth quadruple therapy than those treated with 14 day sequential therapy (74.4% versus 36.7% P < 0.0001). The eradication rate of 14 day sequential therapy in strains with and without 23S ribosomal RNA mutation was 80% (24 of 30) and 99% (193 of 195), respectively (P < 0.0001).
Conclusions: Optimized 14 day sequential therapy was non-inferior to, but better tolerated than 10 day bismuth quadruple therapy and both may be used in first-line treatment in populations with low to intermediate clarithromycin resistance.

PMID: 29846605 [PubMed - indexed for MEDLINE]

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Benefit, burden, and impact for a cohort of post-approval cancer combination trials.

Clin Trials. 2019 Oct 03;:1740774519873883

Authors: Carlisle BG, Doussau A, Kimmelman J

Abstract
BACKGROUND: After approval, drug developers often pursue trials aimed at extending the uses of a new drug by combining it with other drugs. Little is known about the risk and benefits associated with such research.
METHODS: To establish a historic benchmark of risk and benefit, we searched Medline and Embase for clinical trials testing anti-cancer drugs in combination within 5 years of approval by the Food and Drug Administration of 12 anti-cancer "index" drugs first licensed 2005-2007 inclusive. Risk was assessed based on grade 3 or above drug-related adverse events; benefit was assessed based on efficacy outcomes and advancement of combinations into clinical practice guidelines or approval by the Food and Drug Administration.
RESULTS: We captured 323 published post-approval trials exploring combinations, including 266 unique combination-indication pairings and enrolling 29,835 patients. The pooled risk ratios for treatment-related grade 3-4 severe adverse events and deaths attributed to the study drugs for trials randomized between a combination arm and a comparator were 1.54 (1.33-1.79) and 1.51 (1.16-1.97), respectively. The pooled hazard ratios for overall survival and progression-free survival were 0.99 (0.92-1.05) and 0.85 (0.79-0.93), respectively. None of the combination-indication pairings launched after initial drug approval received approval by the Food and Drug Administration, and 13 pairings (4.9%) were recommended by the National Comprehensive Cancer Network within 5 years of the first trial within that pairing. The proportion of patients in our sample who participated in trials leading to an approval by the Food and Drug Administration or a National Comprehensive Cancer Network guideline recommendation was 12.7% with 5 years of follow-up, and 22.3% among pairings for which there were 8 years of follow-up.
CONCLUSION: Patients were just as likely to benefit in the treatment arm as the control arm in terms of overall survival, but they were more likely to experience a treatment-related severe adverse event in post-approval trials of combination therapy.

PMID: 31580145 [PubMed - as supplied by publisher]

Severe hepatotoxicity induced by efavirenz in a treatment-naïve, low body mass index HIV-infected, female patient with no hepatitis and other virus co-infections.

Ultrastruct Pathol. 2019 Oct 02;:1-4

Authors: Dragovic G, Nikolic K, Dimitrijevic B, Jevtovic D, Salemovic D, Tomanovic N, Boricic I

Abstract
Combined antiretroviral therapy (cART) consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) and one non-nucleoside reverse transcriptase inhibitor (NNRTI), such as efavirenz, is still the first-line treatment in resource-limited settings. However, efavirenz has shown strong prominence of disadvantages with variance in plasma concentration and central nervous side effects. Our study presents HIV infected, drug naïve, female patient with relatively low BMI, CYP2B6 516G>T (rs3745274) genotype with high efavirenz plasma concentration. In this case report, the patient was admitted at the hospital 6 months after cART initiation with drug-induced severe hepatotoxicity. Furthermore, pathophysiological findings proved confluent parenchymal necrosis after aspiration liver biopsy, with mild to moderate inflammation in portal tracts with focal interface hepatitis. All other possible causes were excluded. Thus, we conclude that efavirenz has a potential harmful effect in patients with low BMI, specific genotyping and interindividual pharmacokinetics affecting high plasma concentration.

PMID: 31578116 [PubMed - as supplied by publisher]

REVERSIBLE NEUROTROPHIC KERATOPATHY ASSOCIATED WITH ROSUVASTATIN THERAPY: A CASE REPORT.

J Popul Ther Clin Pharmacol. 2019 Aug 16;26(2):e38-e42

Authors: Elnahry AG, Elnahry GA

Abstract
BACKGROUND: Rosuvastatin is a 3-hydroxy-3-methyl-glutaryl-CoA reductase enzyme inhibitor that is in wide use with few reported ocular adverse events.
OBJECTIVES: To report a case of bilateral neurotrophic keratopathy associated with rosuvastatin therapy that dramatically improved following drug discontinuation.
CASE PRESENTATION: A 65-year-old female presented with painless diminution of vision in both eyes of gradual onset and progressive course for 1 month. She had recently started rosuvastatin therapy for hyperlipidemia. Examination revealed bilateral stage 2 neurotrophic keratopathy with impaired corneal sensation which was previously resistant to conservative ulcer treatment. Following discontinuation of rosuvastatin therapy, there was dramatic bilateral improvement in corneal sensation, size of the corneal ulcers, and visual acuity.
CONCLUSION: Rosuvastatin may result in reversible trigeminal nerve impairment and neurotrophic keratopathy.

PMID: 31577084 [PubMed - in process]

PREPARING FOR VANESSA'S LAW: COLLABORATION BETWEEN THE MEDICAL RECORDS AND PHARMACY DEPARTMENTS AT A CANADIAN HOSPITAL CENTER.

J Popul Ther Clin Pharmacol. 2019 Jul 03;26(2):e5-e13

Authors: Rault P, Necsoiu D, Desjardins I, Lebel D, Bussières JF

Abstract
BACKGROUND AND OBJECTIVE: In the context of Vanessa's Law, the medical records department and the pharmacy team of a mother-child hospital collaborated to create a system for coding adverse drug reactions (ADRs). This study was conducted to validate the coding of ADRs by the medical records team.
MATERIAL AND METHODS: This retrospective descriptive study covered 12 months of coding of hospitalization data by the medical records team (November 1, 2017, to October 31, 2018). The pharmacy team performed twice-monthly analysis to validate the ADR data, based on coded information for drugs and associated clinical manifestations.
RESULTS: Over the 12-month study period, a total of 755 ADRs were coded by the medical records department (i.e., 2.1 ADRs per day, corresponding to 7.1% of admissions). For 34 (4.5%) of these ADRs, the pharmacy team made a change to the code originally assigned by the medical records department. Eighty-five (11.5%) of the coded ADRs were deemed serious, as defined by Health Canada, but only 13 (15%) of these serious ADRs were reported to the regulatory authority. The new process allowed clinical manifestation codes to be associated with individual drugs in the pharmacy's Med-Echo-Plus® software, which facilitated interpretation of the data. Following this study, coding practices were reviewed, a coding algorithm was developed, and the codes for 18 drugs were clarified.
CONCLUSION: This study highlights the feasibility of establishing a link between the medical records and pharmacy departments to validate the coding of ADRs. At the study hospital, this linkage has identified serious ADRs, for which reporting will soon be required by Health Canada.

PMID: 31577080 [PubMed - in process]

Evaluation of D1/D5 Partial Agonist PF-06412562 in Parkinson's Disease following Oral Administration.

Neurodegener Dis. 2018;18(5-6):262-269

Authors: Papapetropoulos S, Liu W, Duvvuri S, Thayer K, Gray DL

Abstract
BACKGROUND: PF-06412562 is a moderately potent, highly selective oral D1/D5 dopamine receptor partial agonist.
OBJECTIVE: To study the efficacy and safety of a single, oral, split dose of PF-06412562 in patients with Parkinson's disease.
METHODS: Following overnight levodopa (L-dopa, Sinemet®) washout, subjects received a single dose of levodopa in open-label period 1. Periods 2 and 3 had a double-blinded, sponsor-open, randomized, 2-way cross-over, placebo-controlled design, during which subjects were randomized to PF-06412562 30 mg (+ 20 mg 4 h later) or placebo. Maximum percent improvement from baseline in finger-tapping speed (measure of bradykinesia) measured using KinesiaTM technology (as the primary end point) and change from baseline in the Movement Disorder Society's Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS-III) motor section scores (the preferred exploratory end point) were evaluated.
RESULTS: Nineteen subjects received levodopa; 13 met the period 2/3 entry criteria and received PF-06412562, 30 + 20 mg, or placebo. The prespecified primary efficacy criterion for significant improvement in finger-tapping was not met due to inconsistencies in the task leading to large between-period fluctuations of within-patient baseline values. Change from baseline in MDS-UPDRS-III score with PF-06412562 resulted in a placebo-adjusted point estimate of -10.59 with a one-sided 90% upper CI of PF-06412562 versus placebo model-based contrast of (-inf, -7.44) at 1.5-2.5 h after the dose (p < 0.0001). All adverse events were mild-to-moderate.
CONCLUSIONS: We report the first evidence of potential anti-parkinsonian efficacy of the oral selective D1/D5 partial agonist PF-06412562 without the significant acute changes in cardiovascular parameters reported with previous D1 agonists.

PMID: 30453303 [PubMed - indexed for MEDLINE]

Toxicity-induced modification of treatment: what is in a name?

Eur J Cancer. 2018 11;104:145-150

Authors: Kok DE, Winkels RM, van Herpen CM, Kampman E

Abstract
Severe treatment-induced toxicities can have clinical consequences such as hospitalisation or treatment modifications, which in turn may deteriorate the prognosis of patients with cancer. Identification of determinants of treatment-induced toxicities is essential to develop strategies that promote therapy compliance and enhance the quality of life. Whereas toxicities are systematically recorded and graded per protocol in most clinical trials, observational studies often depend on retrospective data collection from medical records collected as standard care. Existing population-based or patient cohorts are a valuable source of information, even when relying on retrospective data collection, but comparisons across studies are hampered by a lack of a uniform definition for toxicity outcomes. We propose a new standardised approach to summarise toxicities in observational studies that rely on medical records for outcome assessment. We recommend the term 'toxicity-induced modification of treatment' (TIMT) to cover all toxicities that are responsible for changes in a planned treatment schedule. We define a TIMT as (i) a dose reduction, (ii) temporary interruption, (iii) discontinuation of therapy or (iv) an unanticipated switch to another regimen, as a result of treatment-induced toxicities and not because of progressive disease. This definition will provide clinically relevant information, especially when data on specific adverse events and Common Terminology Criteria for Adverse Events (CTCAE) grades are not uniformly available. Implementation of this definition empowers comparisons across studies, facilitates communication between clinicians and researchers and will allow new research questions in this active field of research.

PMID: 30352382 [PubMed - indexed for MEDLINE]

Oral Disease-Modifying Treatments for Relapsing Multiple Sclerosis: A Likelihood to Achieve No Evidence of Disease Activity or Harm Analysis.

CNS Drugs. 2018 11;32(11):1069-1078

Authors: Papadopoulos D, Mitsikostas DD

Abstract
BACKGROUND: The likelihood to help or harm (LHH) is an absolute measure of the benefit versus risk profile of a medication, which can be used to assess the potential for benefit versus harm of different disease-modifying treatments (DMTs) for relapsing multiple sclerosis (R-MS) and facilitate clinical decision-making.
OBJECTIVE: The objective of this study was to assess absolute differences in benefit:risk ratios of oral DMTs for R-MS, using LHH analysis with no evidence of disease activity (NEDA) as beneficial outcome.
DESIGN/METHODS: The number needed to treat for a paient to achieve NEDA (NNTBNEDA) was used as an effect size metric of efficacy and the number needed to treat for a patient  to experience  an adverse event (NNTHAE), a serious adverse event (NNTHSAE), or treatment discontinuation due to an adverse event (NNTHAE-D) were used as measures of risk. The LHH-which is the ratio of NNTH:NNTB-values were calculated from published phase III trial data for oral DMTs.
RESULTS: The values for likelihood to achieve NEDA than experience any AE ratio (LHH(AE/NEDA)) were 3.9, 6.8, 12.5 and 3.7, the likelihood to achieve NEDA than experience a SAE ratio (LHH(SAE/NEDA)) values were 3.5, 15, 23.5 and 2.8, and the likelihood to achieve NEDA versus discontinue treatment (LHH(AE-D/NEDA)) values were 20.3, 4.3, 3.9 and 3.1 for cladribine, dimethyl-fumarate, fingolimod, and teriflunomide, respectively.
CONCLUSIONS: With all of the oral DMTs examined, R-MS patients are more likely to achieve NEDA than experience any adverse event.

PMID: 30069684 [PubMed - indexed for MEDLINE]