Effect of dulaglutide on liver fat in patients with type 2 diabetes and NAFLD: randomised controlled trial (D-LIFT trial).

Diabetologia. 2020 Aug 31;:

Authors: Kuchay MS, Krishan S, Mishra SK, Choudhary NS, Singh MK, Wasir JS, Kaur P, Gill HK, Bano T, Farooqui KJ, Mithal A

Abstract
AIMS/HYPOTHESIS: Liraglutide, a daily injectable glucagon-like peptide-1 receptor (GLP-1r) agonist, has been shown to reduce liver fat content (LFC) in humans. Data regarding the effect of dulaglutide, a once-weekly GLP-1r agonist, on human LFC are scarce. This study examined the effect of dulaglutide on LFC in individuals with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD).
METHODS: Effect of dulaglutide on liver fat (D-LIFT) was a 24 week, open-label, parallel-group, randomised controlled trial to determine the effect of dulaglutide on liver fat at a tertiary care centre in India. Adults (n = 64), who had type 2 diabetes and MRI-derived proton density fat fraction-assessed LFC of ≥6.0% at baseline, were randomly assigned to receive dulaglutide weekly for 24 weeks (add-on to usual care) or usual care, based on a predefined computer-generated number with a 1:1 allocation that was concealed using serially numbered, opaque, sealed envelopes. The primary endpoint was the difference of the change in LFC from 0 (baseline) to 24 weeks between groups. The secondary outcome measures included the difference of the change in pancreatic fat content (PFC), change in liver stiffness measurement (LSM in kPa) measured by vibration-controlled transient elastography, and change in liver enzymes.
RESULTS: Eighty-eight patients were screened; 32 were randomly assigned to the dulaglutide group and 32 to the control group. Overall, 52 participants were included for per-protocol analysis: those who had MRI-PDFF data at baseline and week 24. Dulaglutide treatment resulted in a control-corrected absolute change in LFC of -3.5% (95% CI -6.6, -0.4; p = 0.025) and relative change of -26.4% (-44.2, -8.6; p = 0.004), corresponding to a 2.6-fold greater reduction. Dulaglutide-treated participants also showed a significant reduction in γ-glutamyl transpeptidase (GGT) levels (mean between-group difference -13.1 U/l [95% CI -24.4, -1.8]; p = 0.025) and non-significant reductions in aspartate aminotransferase (AST) (-9.3 U/l [-19.5, 1.0]; p = 0.075) and alanine aminotransferase (ALT) levels (-13.1 U/l [-24.4, 2.5]; p = 0.10). Absolute changes in PFC (-1.4% [-3.2, 0.3]; p = 0.106) and LSM (-1.31 kPa [-2.99, 0.37]; p = 0.123) were not significant when comparing the two groups. There were no serious drug-related adverse events.
CONCLUSIONS/INTERPRETATION: When included in the standard treatment for type 2 diabetes, dulaglutide significantly reduces LFC and improves GGT levels in participants with NAFLD. There were non-significant reductions in PFC, liver stiffness, serum AST and serum ALT levels. Dulaglutide could be considered for the early treatment of NAFLD in patients with type 2 diabetes.
TRIAL REGISTRATION: ClinicalTrials.gov NCT03590626 FUNDING: The current study was supported by an investigator-initiated study grant from Medanta-The Medicity's departmental research fund and a grant from the Endocrine and Diabetes Foundation (EDF), India. Graphical abstract.

PMID: 32865597 [PubMed - as supplied by publisher]

Drug-associated adverse events in the treatment of multidrug-resistant tuberculosis: an individual patient data meta-analysis.

Lancet Respir Med. 2020 04;8(4):383-394

Authors: Lan Z, Ahmad N, Baghaei P, Barkane L, Benedetti A, Brode SK, Brust JCM, Campbell JR, Chang VWL, Falzon D, Guglielmetti L, Isaakidis P, Kempker RR, Kipiani M, Kuksa L, Lange C, Laniado-Laborín R, Nahid P, Rodrigues D, Singla R, Udwadia ZF, Menzies D, Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB treatment 2017

Abstract
BACKGROUND: Treatment of multidrug-resistant tuberculosis requires long-term therapy with a combination of multiple second-line drugs. These drugs are associated with numerous adverse events that can cause severe morbidity, such as deafness, and in some instances can lead to death. Our aim was to estimate the absolute and relative frequency of adverse events associated with different tuberculosis drugs to provide useful information for clinicians and tuberculosis programmes in selecting optimal treatment regimens.
METHODS: We did a meta-analysis using individual-level patient data that were obtained from studies that reported adverse events that resulted in permanent discontinuation of anti-tuberculosis medications. We used a database created for our previous meta-analysis of multidrug-resistant tuberculosis treatment and outcomes, for which we did a systematic review of literature published between Jan 1, 2009, and Aug 31, 2015 (updated April 15, 2016), and requested individual patient-level information from authors. We also considered for this analysis studies contributing patient-level data in response to a public call made by WHO in 2018. Meta-analysis for proportions and arm-based network meta-analysis were done to estimate the incidence of adverse events for each tuberculosis drug.
FINDINGS: 58 studies were identified, including 50 studies from the updated individual patient data meta-analysis for multidrug-resistant tuberculosis treatment. 35 of these studies, with 9178 patients, were included in our analysis. Using meta-analysis of proportions, drugs with low risks of adverse event occurrence leading to permanent discontinuation included levofloxacin (1·3% [95% CI 0·3-5·0]), moxifloxacin (2·9% [1·6-5·0]), bedaquiline (1·7% [0·7-4·2]), and clofazimine (1·6% [0·5-5·3]). Relatively high incidence of adverse events leading to permanent discontinuation was seen with three second-line injectable drugs (amikacin: 10·2% [6·3-16·0]; kanamycin: 7·5% [4·6-11·9]; capreomycin: 8·2% [6·3-10·7]), aminosalicylic acid (11·6% [7·1-18·3]), and linezolid (14·1% [9·9-19·6]). Risk of bias in selection of studies was judged to be low because there were no important differences between included and excluded studies. Variability between studies was significant for most outcomes analysed.
INTERPRETATION: Fluoroquinolones, clofazimine, and bedaquiline had the lowest incidence of adverse events leading to permanent drug discontinuation, whereas second-line injectable drugs, aminosalicylic acid, and linezolid had the highest incidence. These results suggest that close monitoring of adverse events is important for patients being treated for multidrug-resistant tuberculosis. Our results also underscore the urgent need for safer and better-tolerated drugs to reduce morbidity from treatment itself for patients with multidrug-resistant tuberculosis.
FUNDING: Canadian Institutes of Health Research, Centers for Disease Control and Prevention (USA), American Thoracic Society, European Respiratory Society, and Infectious Diseases Society of America.

PMID: 32192585 [PubMed - indexed for MEDLINE]

A qualitative study on reasons for early removal of Implanon among users in Arba Minch town, Gamo Goffa zone, South Ethiopia: a phenomenological approach.

BMC Womens Health. 2020 01 02;20(1):2

Authors: Utaile MM, Debere MK, Nida ET, Boneya DJ, Ergano AT

Abstract
BACKGROUND: Implanon is one of the cost - effective long acting reversible contraceptive methods used for spacing and limiting births in Ethiopia. Despite the scaling up initiative undertaken by the Ethiopian Government, Implanon uptake is very low compared to short acting contraceptive methods. There is low utilization of Implanon with high level of discontinuation in Ethiopia. Therefore, this study was conducted to explore the reasons for early removal of Implanon among users in Arba Minch town, South Ethiopia.
METHODS: A community-based qualitative exploratory study using phenomenological approach was conducted. In-depth and key informant interviews were used to collect data from April 20-27, 2018 in Arba Minch town. Convenient sampling was employed to recruit participants from the households of targeted villages. A total of 10 in-depth interviews with women who recently removed Implanon and 5 key informant interviews with health extension workers were conducted. The sample size was determined based on the concept of saturation. The collected data were analyzed using thematic content analysis technique. Data coding and analysis were facilitated by using Open code version 4.0 software.
RESULTS: This study revealed that majority of participants were able to mention at least three types of contraceptive methods available in the nearby health facilities. The study underlined that side effect of the method, husband opposition, seeking more children, and method failure were the common reasons for early removal of Implanon, in which side effect of the method was the main reason. Among various forms of side effects of Implanon identified by users, heavy and irregular bleeding was mentioned as the most frequently occurring side effect.
CONCLUSION: Our result indicated that heavy and irregular bleeding was the main reason for early removal of Implanon. Therefore it suggests improvement in the service delivery system. Improving client's education and counseling service program could contribute much to avoid unreasonable and untimely removal of Implanon.

PMID: 31896349 [PubMed - indexed for MEDLINE]

New horizons in deprescribing for older people.

Age Ageing. 2019 11 01;48(6):768-775

Authors: Woodford HJ, Fisher J

Abstract
Deprescribing has gained interest recently, driven by an ageing population seeing an increasing number living with multiple long-term conditions. This, coupled with disease-specific guidelines derived from clinical trials in younger people, has led to an increase in exposure to polypharmacy and the associated therapeutic burden. Older people, especially those living with frailty, tend to experience lower efficacy of these medications along with a higher risk of drug adverse effects. Explanations for these differences include the physiological effects of frailty, drug-drug interactions, drug-disease interactions and reduced medication adherence. Adverse drug reactions often go unnoticed and can trigger further prescribing. Certain medications have been recognised as potentially inappropriate for people with frailty, yet their use remains common. Evidence suggests that many older people are open to the concept of reducing medications. Deprescribing should be based around a shared decision-making approach. Trials to date have suggested that it can often be achieved without harm. To date, there are few data to support improvements in hospitalisation or mortality rates. However, there is some evidence that it may reduce polypharmacy, improve medication adherence, reduce financial costs and improve quality of life. In the future, it will be necessary to grow the evidence base and improve public and clinician awareness of the potential benefits of deprescribing. It will require excellent team working and communication between all of those involved in the prescribing and administration of medications, also supported by improved healthcare informatics. Non-pharmacological approaches will need to be promoted. Fewer drugs is not less care.

PMID: 31595290 [PubMed - indexed for MEDLINE]

Long-term effects and significant Adverse Drug Reactions (ADRs) associated with the use of Gonadotropin-Releasing Hormone analogs (GnRHa) for central precocious puberty: a brief review of literature.

Acta Biomed. 2019 09 06;90(3):345-359

Authors: De Sanctis V, Soliman AT, Di Maio S, Soliman N, Elsedfy H

Abstract
Central precocious puberty (CPP) is defined as an early pubertal development that occurs before the age of 9 years in boys and 8 years in girls. It results from premature activation of the hypothalamic-pituitary-gonadal axis. Gonadotropin-releasing hormone agonists (GnRHa) have been the gold standard therapy for CPP for more than 30 years. These compounds have a high affinity for the pituitary LHRH receptor and are resistant to enzymatic degradation. Through continuous stimulation, GnRHa inhibit the pulsatile secretion of gonadotropin, resulting in hormonal suppression, cessation of pubertal development, and normalization of growth and skeletal maturation rates. The goal of therapy is to halt pubertal progression and delay epiphyseal maturation that leads to improvement of final adult height. There are no widely accepted guidelines for how long to continue treatment with a GnRHa for CPP, and individual practice varies widely. Furthermore, conflicting results have been published on the long-term effects of GnRHa therapy in patients with CPP. Therefore, we reviewed the current literature focusing our attention on the long-term effects and the significant adverse drug reactions (ADRs) observed during treatment with GnRHa in patients with CPP. Our review may provide the necessary data to enable clinicians to administer GnRHa in the safest and most appropriate way. Further studies are necessary to identify the mechanisms of development of potential adverse drug reactions related to GnRHa therapy in CPP.

PMID: 31580327 [PubMed - indexed for MEDLINE]

Potentially serious alcohol-medication interactions and falls in community-dwelling older adults: a prospective cohort study.

Age Ageing. 2019 11 01;48(6):824-831

Authors: Holton A, Boland F, Gallagher P, Fahey T, Moriarty F, Kenny RA, Cousins G

Abstract
OBJECTIVE: To investigate the association between potentially serious alcohol-medication interactions (POSAMINO criteria), hypothesised to increase the risk of falls in older adults, and falls in community-dwelling older adults at two and 4 years follow-up.
DESIGN: A prospective cohort study.
SETTING: The Irish Longitudinal Study on Ageing.
SUBJECTS: A total of 1,457 community-dwelling older adults aged ≥65 years, with a complete alcohol and regular medication data to allow for the application of the POSAMINO criteria.
OUTCOMES: Self-reported falls at 2 and 4 years follow-up, any falls (yes/no), injurious falls (yes/no) and number of falls (count variable).
RESULTS: The number of participants who reported falling since their baseline interview at 2 and 4 years were 357 (24%) and 608 (41.8%), respectively; 145 (10%) reported an injurious fall at 2 years and 268 (18%) at 4 years. Median (IQR) number of falls was 1 (1-2) at 2 years and 2 (1-3) at 4 years. Exposure to CNS POSAMINO criteria, hypothesised to increase the risk of falls due primarily to increased sedation, was associated with a significantly increased risk for falling (adjusted relative risk (RR) 1.50, 95% confidence interval (CI) 1.21-1.88) and for injurious falls (adjusted RR 1.62, 95% CI: 1.03-2.55) at 4 years. These equate to an absolute risk of 19% for falling (95% CI: 5-33%) and 8% for injurious falls (95% CI, 4-20%) at 4 years.
CONCLUSIONS: Assessment and management strategies to prevent falls in community-dwelling older adults should consider patients' alcohol consumption alongside their assessment of patient medications, particularly among those receiving CNS agents.

PMID: 31579905 [PubMed - indexed for MEDLINE]

[Use of cannabidiol oil in children].

Ned Tijdschr Geneeskd. 2019 05 03;163:

Authors: Wolff D, Reijneveld SA

Abstract
Useof cannabidiol oil in children The use of cannabidioloil (CBD oil), a cannabis-derived chemical, is increasing. CBD oil is freely available in the Netherlands, but its composition and quality are not monitored. However, the alternative, pharmacist-prepared oil, is more expensive and difficult to acquire. Common reasons for CBD oil use in children include impulsive behaviour, itch, epilepsy, stress, pain and sleeping problems. However, evidence of its effectiveness is scarce and focuses primarily on the effectiveness of the oil in reducing epileptic seizures. Known side-effects are vomiting, diarrhoea, fever, sleepiness, and abnormal liver function test results. We advise medical professionals who encounter young patients who may potentially be using CBD oil, to discuss its questionable quality and potential side effects and interactions. If a patient presents with poorly-understood fever, diarrhoea, vomiting or drowsiness, then the side effects of CBD oil should be considered. Finally, CBD should be differentiated from delta-THC, a cannabis-derived chemical with a psychoactive effect, the use of which should be discouraged in children.

PMID: 31120211 [PubMed - indexed for MEDLINE]

Drugs-Induced Pathological Gambling: An Analysis of Italian Spontaneous Reporting System.

J Gambl Stud. 2020 Mar;36(1):85-96

Authors: Scavone C, Stelitano B, Rafaniello C, Rossi F, Sportiello L, Capuano A

Abstract
Pathological gambling has been reported as a direct complication of Parkinson's disease and its pharmacological treatment based on dopamine agonists. Moreover, further medications (not dopamine agonists) were associated to the occurrence of gambling disorder. We aim to analyze the spontaneous reports of gambling disorder on the whole Italian territory with a focus on Campania Region (Southern Italy) from January 1st 2002 to July 31st 2018. We analyzed gambling disorder's reports across the 2002-2018 period in the Italian spontaneous reporting database (Rete Nazionale di Farmacovigilanza-RNF), with a focus on Campania region. 94 suspected cases of gambling disorder associated to apomorphine, aripiprazole, cabergoline, levodopa, levodopa and derivatives in association with entacapone/benserazide and carbidopa, pergolide, pramipexole, ropinirole, and rotigotine were reported into the RNF. Of these cases, two related to pramipexole and one to aripiprazole were sent to Campania Pharmacovigilance Regional Centre. Although it is widely recognized that dopamine agonists may induce behavioral disorders, Parkinson's disease is itself associated to pathological gambling, compulsive shopping and eating. Since our results could not clarify the correlation between Parkinson's disease, its pharmacological treatment and pathological gambling, in order to better define this correlation there is a need to conduct further ad hoc observational studies.

PMID: 30671764 [PubMed - indexed for MEDLINE]

Stevens-Johnson Syndrome Due to Influenza Vaccination.

Cureus. 2020 Jul 26;12(7):e9405

Authors: Tong J, Chan J

Abstract
Influenza is a common virus that affects millions of people every year. The influenza vaccine decreases morbidity and mortality associated with influenza and is generally well tolerated. Stevens-Johnson syndrome (SJS) is a rare disorder of the skin and mucous membranes. We report the second known case of SJS occurring after an influenza vaccination alone without any other associated drug exposure. This corroborates the possibility of the influenza vaccine alone causing SJS. Despite the initial adverse reaction, the patient made a full recovery. Although the disease can be associated with vaccinations, the benefits of receiving the vaccinations outweigh the potential harms.

PMID: 32864234 [PubMed]

Veliparib with carboplatin and paclitaxel in BRCA-mutated advanced breast cancer (BROCADE3): a randomised, double-blind, placebo-controlled, phase 3 trial.

Lancet Oncol. 2020 Aug 27;:

Authors: Diéras V, Han HS, Kaufman B, Wildiers H, Friedlander M, Ayoub JP, Puhalla SL, Bondarenko I, Campone M, Jakobsen EH, Jalving M, Oprean C, Palácová M, Park YH, Shparyk Y, Yañez E, Khandelwal N, Kundu MG, Dudley M, Ratajczak CK, Maag D, Arun BK

Abstract
BACKGROUND: BRCA1 or BRCA2-mutated breast cancers are sensitive to poly(ADP-ribose) polymerase (PARP) inhibitors and platinum agents owing to deficiency in homologous recombination repair of DNA damage. In this trial, we compared veliparib versus placebo in combination with carboplatin and paclitaxel, and continued as monotherapy if carboplatin and paclitaxel were discontinued before progression, in patients with HER2-negative advanced breast cancer and a germline BRCA1 or BRCA2 mutation.
METHODS: BROCADE3 was a randomised, double-blind, placebo-controlled, phase 3 trial done at 147 hospitals in 36 countries. Eligible patients (aged ≥18 years) had deleterious germline BRCA1 or BRCA2 mutation-associated, histologically or cytologically confirmed advanced HER2-negative breast cancer, an Eastern Cooperative Oncology Group performance status of 0-2, and had received up to two previous lines of chemotherapy for metastatic disease. Patients were randomly assigned (2:1) by interactive response technology by means of permuted blocks within strata (block size of 3 or 6) to carboplatin (area under the concentration curve 6 mg/mL per min intravenously) on day 1 and paclitaxel (80 mg/m2 intravenously) on days 1, 8, and 15 of 21-day cycles combined with either veliparib (120 mg orally twice daily, on days -2 to 5) or matching placebo. If patients discontinued carboplatin and paclitaxel before progression, they could continue veliparib or placebo at an intensified dose (300 mg twice daily continuously, escalating to 400 mg twice daily if tolerated) until disease progression. Patients in the control group could receive open-label veliparib monotherapy after disease progression. Randomisation was stratified by previous platinum use, history of CNS metastases, and oestrogen and progesterone receptor status. The primary endpoint was investigator-assessed progression-free survival per Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy analyses were done by intention to treat, which included all randomly assigned patients with a centrally confirmed BRCA mutation, and safety analyses included all patients who received at least one dose of velilparib or placebo. This study is ongoing and is registered with ClinicalTrials.gov, NCT02163694.
FINDINGS: Between July 30, 2014, and Jan 17, 2018, 2202 patients were screened, of whom 513 eligible patients were enrolled and randomly assigned. In the intention-to-treat population (n=509), 337 patients were assigned to receive veliparib plus carboplatin-paclitaxel (veliparib group) and 172 were assigned to receive placebo plus carboplatin-paclitaxel (control group). Median follow-up at data cutoff (April 5, 2019) was 35·7 months (IQR 24·9-43·6) in the veliparib group and 35·5 months (23·1-45·9) in the control group. Median progression-free survival was 14·5 months (95% CI 12·5-17·7) in the veliparib group versus 12·6 months (10·6-14·4) in the control group (hazard ratio 0·71 [95% CI 0·57-0·88], p=0·0016). The most common grade 3 or worse adverse events were neutropenia (272 [81%] of 336 patients in the veliparib group vs 143 [84%] of 171 patients in the control group), anaemia (142 [42%] vs 68 [40%]), and thrombocytopenia (134 [40%] vs 48 [28%]). Serious adverse events occurred in 115 (34%) patients in the veliparib group versus 49 (29%) patients in the control group. There were no study drug-related deaths.
INTERPRETATION: The addition of veliparib to a highly active platinum doublet, with continuation as monotherapy if the doublet were discontinued, resulted in significant and durable improvement in progression-free survival in patients with germline BRCA mutation-associated advanced breast cancer. These data indicate the utility of combining platinum and PARP inhibitors in this patient population.
FUNDING: AbbVie.

PMID: 32861273 [PubMed - as supplied by publisher]

Linezolid as salvage therapy for central nervous system infections due to methicillin-resistant Staphylococcus aureus at two medical centers in Taiwan.

J Microbiol Immunol Infect. 2020 Aug 14;:

Authors: Chen HA, Yang CJ, Tsai MS, Liao CH, Lee CH

Abstract
BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA)-associated central nervous system infections are potentially devastating. Linezolid has good penetration into cerebrospinal fluid and brain tissue. In clinical practice, linezolid may be used to treat central nervous system infections caused by MRSA resulting from glycopeptide intolerance or treatment failure. However, the clinical experience of linezolid in treating MRSA related central nervous system infections is scarce.
METHODS: From 2006 to 2016, patients aged ≥20 years who had central nervous system infections caused by MRSA treated with linezolid for more than 24 hours were retrospectively included from two medical centers. The demographic details, treatment response, side effects, and relapse of infection were reviewed.
RESULTS: Sixty-six patients with proven CNS infection caused by MRSA were treated with linezolid. The mean age was 53.3 years. The diagnoses in this cohort consisted of brain abscesses (n = 19, 28.8%), spinal epidural abscess (n = 18, 27.3%), meningitis only (n = 12, 18.2%), meningitis with brain epidural abscess (n = 9, 13.6%), and spine device-related infection (n = 5, 7.6%). The main reasons to prescribe linezolid were glycopeptide treatment failure (51.5%) and glycopeptide allergy (48.5%). Ninety-one percent of patients were treated with linezolid for more than 14 days. The in-hospital mortality rate was 13.6%. The relapse rate after treatment was 16.7%. Drug-related adverse events (mainly cytopenia) were observed in 27.3% of patients, but none of the adverse events was fatal.
CONCLUSIONS: In our retrospective study, linezolid demonstrated promising effect as a salvage therapy for central nervous system infection caused by MRSA, whether due to drug allergy or glycopeptide treatment failure.

PMID: 32859532 [PubMed - as supplied by publisher]

Making medicines safer?

Drug Ther Bull. 2020 Aug 27;:

Authors: Phizackerley D

PMID: 32855196 [PubMed - as supplied by publisher]

Prognostic prediction models and clinical tools based on consensus to support patient prioritization for clinical pharmacy services in hospitals: A scoping review.

Res Social Adm Pharm. 2020 Aug 25;:

Authors: Botelho SF, Neiva Pantuzza LL, Marinho CP, Moreira Reis AM

Abstract
BACKGROUND: Identifying patients at high risk of adverse medication-related outcomes for targeted clinical pharmacy services is essential in hospital pharmacy. Models and predictive tools to prioritize patients are available to the clinical pharmacy services for hospital use.
OBJECTIVE: To describe and assess prognostic models and predictive tools used to identify inpatients at risk of adverse medication-related outcomes.
METHODS: We searched in Medline, Lilacs, Cochrane, CINAHL, Embase, Scopus and Web of Science, databases of theses and dissertations, and the references of the selected studies. The screening was carried out by two independent researchers. Cross-sectional studies, prospective or retrospective cohort studies, and case-control studies were eligible for inclusion. The studies addressed the development or validation of predictive models and clinical prioritization tools based on expert opinion to identify inpatients at risk of adverse medication-related outcomes.
RESULTS: 25 studies were included, 13 of which were prognostic prediction models, seven were instrument development using the consensus method, and five were validation. The outcome events were drug-related problems (9), adverse drug reactions (8), adverse drug events (6), and medication errors (2). Most studies targeted adult patients (14), eight had older adult patients, one had obstetric patients, and others had pediatric patients. External validation was performed after the development study in three studies. The predictive model with a low risk of bias was the Medicines Optimisation Assessment Tool. Limited details on the method of expert involvement and the number of experts were identified in four studies.
CONCLUSION: The development of patient prioritization tools to optimize pharmacotherapy by clinical pharmacy services is a complex process. The predictive models and tools analyzed are limited in their development and validation process, hindering their effective use in prioritizing patients by the clinical pharmacy services. The development of additional prognostic prediction models for drug-related problems is a priority.

PMID: 32855080 [PubMed - as supplied by publisher]

Prevention of allopurinol-associated adverse cutaneous drug reactions in high-risk patient groups in Canada.

CMAJ. 2020 02 18;192(7):E168

Authors: Ponzo M, Dutz J

PMID: 32071111 [PubMed - indexed for MEDLINE]

Systematic review: hepatosplenic T-cell lymphoma on biologic therapy for inflammatory bowel disease, including data from the Food and Drug Administration Adverse Event Reporting System.

Aliment Pharmacol Ther. 2020 03;51(5):527-533

Authors: Shah ED, Coburn ES, Nayyar A, Lee KJ, Koliani-Pace JL, Siegel CA

Abstract
BACKGROUND: Hepatosplenic T-cell lymphoma (HSTCL) is a rare, poorly treatable malignancy associated with therapy for IBD. Current knowledge of HSTCL risk in IBD comes from an era of step-up therapy, before earlier use of biologics or combination therapy was advocated to achieve deep mucosal healing. HSTCL risk among newer biologic classes has also not been evaluated.
AIMS: To systematically characterise the association of HSTCL with biologic therapy for IBD.
METHODS: We conducted a literature search and query of the Food and Drug Administration Adverse Event Reporting System to summarise HSTCL cases among IBD patients with prior biologic exposure. Demographics and immunosuppression exposure were extracted. Patients were stratified by current regimen (combination therapy, biologic monotherapy or no biologic), and biologic class (anti-TNF, anti-integrin, anti-interleukin 12/23).
RESULTS: Sixty-two cases of HSTCL were identified from 2486 abstracts and 181 FDA Adverse Events Reporting System reports. The median age of affected patients was 28 years (range 12-81), and 83.6% were male, 84.7% had Crohn's disease. Five of 62 patients had no reported azathioprine/mercaptopurine exposure. Three patients within the cohort developed HSTCL after exposure to natalizumab, vedolizumab or ustekinumab; all three also had anti-TNF and azathioprine/mercaptopurine exposure. Forty-three of 49 (87.8%) patients with known outcomes died with a median survival of 5 months.
CONCLUSIONS: Consistent with existing data, almost all identified HSTCL cases among IBD patients on biologic therapy had azathioprine/mercaptopurine exposure, and all cases on patients exposed to biologics had anti-TNF exposure. These data suggest initiating a patient-centred discussion before starting anti-TNF therapy or other biologics.

PMID: 31990422 [PubMed - indexed for MEDLINE]

Risk of drug interactions and prescription appropriateness in elderly patients.

Ir J Med Sci. 2020 Aug;189(3):953-959

Authors: Petrini E, Caviglia GP, Pellicano R, Saracco GM, Morino M, Ribaldone DG

Abstract
BACKGROUND: In Europe, adverse drug reactions and drug interactions are the cause of considerable morbidity and mortality. In over 75s, hospital access due to adverse drug reactions can be as high as 1 in every 3.
AIMS: To assess the quality of the prescribed polytherapies in the territory, in terms of the risk of drug interactions and of prescription appropriateness, in over 75s.
METHODS: Randomly selected patients, over 75s, were analysed among the patients of 3 general practitioners. Their data were analysed with the INTERCheck® software. This software provided the list of drug interactions deriving from the chronic therapies. The program also provided the Beers criteria and the STOPP criteria related to the drugs, highlighting potentially inappropriate drugs.
RESULTS: A total of 188 patients were included in the study. A total of 216 serious or very serious drug interactions have been identified. A total of 92 patients (48.9%) were at risk of at least one serious or very serious interaction. The cut-off of the correlation between the number of drugs taken and the risk of incurring a serious or very serious interaction was found to be 5 (AUC = 0.833, sensitivity = 87%, p < 0.001). Patients on ≥ 4 drugs were at risk of prescriptive inappropriateness with a sensitivity of 84% (AUC = 0.781, p < 0.0001).
CONCLUSIONS: Focusing on patients with at least 4 drugs in therapy is the right strategy to reduce the risks associated with polypharmacy.

PMID: 31786720 [PubMed - indexed for MEDLINE]

Concurrent therapy with immune checkpoint inhibitors and TNFα blockade in patients with gastrointestinal immune-related adverse events.

J Immunother Cancer. 2019 08 22;7(1):226

Authors: Badran YR, Cohen JV, Brastianos PK, Parikh AR, Hong TS, Dougan M

Abstract
BACKGROUND: Immune checkpoint inhibitors (ICI) have demonstrated remarkable efficacy as cancer therapeutics, however, their use remains limited due to the development of immune related adverse events (irAEs). Immune related enterocolitis (irEC) is among the most common severe irAEs leading to the discontinuation of ICIs. Inhibitors of tumor necrosis factor alpha (anti-TNFα) have been used to treat irEC. Recent animal studies have shown that concurrent treatment with anti-TNFα and ICIs improves tumor responses and decreases colitis severity. This approach has not yet been studied in prospective trials in humans. Here we describe, for the first time, the outcomes of patients who were treated concurrently with anti-TNFα and one or two ICIs.
CASE PRESENTATIONS: Five patients with different primary malignancies were treated with ipilimumab/nivolumab (2 patients), pembrolizumab (1 patient), ipilimumab (1 patient), or cemiplimab (1 patient). All patients developed irEC within 40 days of their first ICI dose. The patients presented with a combination of upper and lower gastrointestinal symptoms and subsequently underwent upper endoscopy and/or lower endoscopy. Endoscopy results demonstrated a spectrum of acute inflammatory changes across the gastrointestinal tract. Steroid therapy was used as first line treatment. To prevent prolonged steroid use and recurrence of gastrointestinal inflammation after resumption of cancer therapy, patients were treated concurrently with infliximab and ICI. Patients tolerated further ICI therapy with no recurrence of symptoms. Repeat endoscopies showed resolution of acute inflammation and restaging imaging showed no cancer progression.
CONCLUSIONS: Concurrent treatment with anti-TNFα and ICI appears to be safe, facilitates steroid tapering, and prevents irEC. Prospective clinical trials are needed to assess the outcomes of this treatment modality.

PMID: 31439050 [PubMed - indexed for MEDLINE]

Comparative assessment of docetaxel for safety and efficacy between hormone-sensitive and castration-resistant metastatic prostate cancer.

Urol Oncol. 2019 12;37(12):999-1005

Authors: Mager R, Savko O, Böhm K, Thomas A, Dotzauer R, Borgmann H, Jäger W, Thomas C, Haferkamp A, Höfner T, Tsaur I

Abstract
OBJECTIVE: To compare toxicity and response of docetaxel chemotherapy between metastatic hormone-sensitive prostate cancer (mHSPC) and castration-resistant metastatic prostate cancer (mCRPC) patients of the same therapeutic era for assessing of upfront docetaxel against the benchmark of docetaxel in the castrate resistant stage in the setting outside of clinical trials.
METHODS: A prospectively collected database of real-world prostate cancer patients receiving docetaxel was divided in mHSPC and mCRPC cases and retrospectively analyzed. Principal objectives were toxicity measured by the common criteria of adverse events terminology and response characterized by Prostate specific antigen decline and radiographic progression-free disease at restaging. The prognostic value of suspected variables for grade 3 to 5 toxicity and response was investigated by logistic regression analysis.
RESULTS: Of 72 patients 34 (47%) were treated for mHSPC and 38 (53%) for mCRPC. Patients with mCRPC were older and had worse performance status (P< 0.01). In mHSPC total number of grade 3 to 5 adverse events (24, median 0, interquartile range 0-1) was significantly less than in mCRPC (46, median 1, interquartile range 1-2) (P = 0.01). Multivariable analysis revealed age as independent predictive variable for grade 3 to 5 toxicity (P = 0.03) but not disease stage, Prostate specific antigen predocetaxel, volume of disease, and Eastern Cooperative Oncology Group performance status (P > 0.05). Objective response was significantly higher in mHSPC compared to mCRPC patients (P < 0.01). Multivariable analysis confirmed mHSPC stage as independent prognostic factor for radiographic progression free disease at restaging (P < 0.01).
CONCLUSIONS: The association of age with toxicity and of mHSPC stage with response resulted in significantly fewer grade 3 to 5 adverse events but higher response rates for upfront docetaxel in mHSPC compared with docetaxel in the later mCRPC stage.

PMID: 31377168 [PubMed - indexed for MEDLINE]

Rapid disease progression following discontinuation of ibrutinib in patients with chronic lymphocytic leukemia treated in routine clinical practice.

Leuk Lymphoma. 2019 11;60(11):2712-2719

Authors: Hampel PJ, Ding W, Call TG, Rabe KG, Kenderian SS, Witzig TE, Muchtar E, Leis JF, Chanan-Khan AA, Koehler AB, Fonder AL, Schwager SM, Slager SL, Shanafelt TD, Kay NE, Parikh SA

Abstract
We identified all patients with chronic lymphocytic leukemia at Mayo Clinic treated with ibrutinib outside the context of a clinical trial; timing and reasons for discontinuation were ascertained, as were symptoms, exam and radiographic findings, and laboratory changes following discontinuation. Of 202 patients who received ibrutinib, 52 discontinued therapy (estimated 1- and 2-year risk of discontinuation 18% and 28%, respectively). The most common reasons for discontinuation were toxicity (56%) and progression of disease (32%, including Richter's transformation in 15%). Rapid progression of disease within 4 weeks after discontinuation was observed in 9/36 (25%) patients with adequate records for review, mostly in those stopping ibrutinib for disease progression (n = 8) rather than toxicity (n = 1). This was evident by sudden worsening of disease-related symptoms (n = 9), exam/radiographic changes (n = 7), and laboratory changes (n = 8). An estimated one in every three patients discontinued ibrutinib by 2 years, with 25% developing rapid disease progression afterwards.

PMID: 31014142 [PubMed - indexed for MEDLINE]

Feasibility of a Symptom Management Intervention for Honduran Adults Undergoing Chemotherapy.

West J Nurs Res. 2019 10;41(10):1517-1539

Authors: Bejarano S, Freed ME, Zeron D, Medina R, Zuniga-Moya JC, Kennedy L, Bruce ML, Zubkoff L, Bakitas MA, Lyons KD

Abstract
Evidence-based interventions often need to be adapted to maximize their implementation potential in low-to middle-income countries. A single-arm feasibility study was conducted to determine the feasibility and acceptability of a telephone-delivered, nurse-led, symptom management intervention for adults undergoing chemotherapy in Honduras. Over the course of 6 months, nurses engaged 25 patients undergoing chemotherapy in the intervention. Each participant received an average of 16.2 attempts to contact them for telephone sessions (SD = 8.0, range = 2-28). Collectively, the participants discussed 24 different types of symptoms. The most commonly discussed symptoms were pain (12%), nausea (7%), and constipation (5%). Qualitative and quantitative data were used to identify treatment manual modifications (i.e., adding content about different symptoms and addressing scheduling of treatment) and workplace modifications (i.e., dedicated nurse time and space) that are needed to optimize implementation of the intervention.

PMID: 30755109 [PubMed - indexed for MEDLINE]