A systematic review and meta-analysis of the impacts of germline pharmacogenomics on severe toxicity and symptom burden in adult patients with cancer.

The clinical application of Pharmacogenomics (PGx) has improved patient safety. However, comprehensive PGx testing has not been widely adopted in clinical practice, and significant opportunities exist to further optimize PGx in cancer care. This systematic review and meta-analysis aim to evaluate the safety outcomes of reported PGx-guided strategies (Analysis 1) and identify well-studied emerging pharmacogenomic variants that predict severe toxicity and symptom burden (Analysis 2) in patients with cancer. We searched MEDLINE, EMBASE, CENTRAL, clinicaltrials.gov, and International Clinical Trials Registry Platform from inception to January 2023 for clinical trials or comparative studies evaluating PGx strategies or unconfirmed pharmacogenomic variants. The primary outcomes were severe adverse events (SAE; ≥ grade 3) or symptom burden with pain and vomiting as defined by trial protocols and assessed by trial investigators. We calculated pooled overall relative risk (RR) and 95% confidence interval (95%CI) using random effects models. PROSPERO, registration number CRD42023421277. Of 6811 records screened, six studies were included for Analysis 1, 55 studies for Analysis 2. Meta-analysis 1 (five trials, 1892 participants) showed a lower absolute incidence of SAEs with PGx-guided strategies compared to usual therapy, 16.1% versus 34.0% (RR = 0.72, 95%CI 0.57-0.91, p = 0.006, I2 = 34%). Meta-analyses 2 identified nine medicine(class)-variant pairs of interest across the TYMS, ABCB1, UGT1A1, HLA-DRB1, and OPRM1 genes. Application of PGx significantly reduced rates of SAEs in patients with cancer. Emergent medicine-variant pairs herald further research into the expansion and optimization of PGx to improve systemic anti-cancer and supportive care medicine safety and efficacy.

Exploring the role of ex vivo metabolism on blood and plasma measurements of oxytocin among women in the third stage of labour: A post hoc study.

AIMS: To examine the role of ex vivo oxytocin metabolism in post-dose peptide measurements. METHODS: The stability of oxytocin (Study 1) and oxytocinase activity (Study 2) in late-stage pregnancy blood was quantified using liquid-chromatography tandem mass-spectrometry (LC-MS/MS) and a fluorogenic assay, respectively. Analyses were conducted using blood from pregnant women (>36 weeks gestation) evaluated in lithium heparin (LH), ethylenediaminetetraacetic acid (EDTA) and BD P100 blood collection tubes with or without protease inhibitors. In addition, plasma oxytocin concentrations following administration of oxytocin 240 IU inhaled, 5 IU intravenous or 10 IU intramuscular in women in third stage of labour (TSL) were analysed using enzyme-linked immunosorbent assay (ELISA) and LC-MS/MS to understand how quantified peptide concentrations differ between these analytical methods (Study 3). RESULTS: Study 1: Oxytocin was stable in blood collected into EDTA tubes with or without protease inhibitors but not in LH tubes. Study 2: Blood collected into all EDTA-containing collection tubes led to near-complete inhibition of oxytocinase (≤100 min). In plasma, a 35% reduction in oxytocinase activity was observed in LH tubes with EDTA added. In plasma from late-stage pregnancy compared to nonpregnant participants, the oxytocinase activity was approximately 11-fold higher. Study 3: Plasma oxytocin concentrations from nonpregnant or women in TSL following exogenous oxytocin administration were ≤33 times higher when analysed using ELISA vs. LC-MS/MS methods. CONCLUSIONS: Collection of blood from late-stage pregnant women into tubes containing EDTA inhibits oxytocinase effectively stabilizing oxytocin, suggesting low concentrations of oxytocin after dose administration reflect rapid in vivo metabolism.

Incidence of Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease and Treatment with Defibrotide in Allogeneic Transplantation: A Multicenter Australasian Registry Study.

Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) is an established complication in patients undergoing allogeneic hemopoietic stem cell transplantation (HSCT). Defibrotide is an effective and safe pharmacologic option for treating diagnosed SOS/VOD. By exploring data provided to the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) by centers in Australia and New Zealand, this study aimed to describe the incidence of SOS/VOD and patterns of defibrotide use from 2016 to 2020. Patients who underwent allogeneic hemopoietic stem cell transplantation between 2016 and 2020 were identified from the ABMTRR. Data were extracted for a total of 3346 patients, 2692 from adult centers and 654 from pediatric centers, with a median follow-up of 21.5 months and 33.3 months, respectively. Descriptive statistics were used to describe the patient population, including the incidence of SOS/VOD and defibrotide use. Comparisons were made between patients without SOS/VOD and those with SOS/VOD, divided into defibrotide and no defibrotide cohorts. Associations with overall survival (OS) and day 100 survival with such variables as sex, age, disease at transplantation, stem cell source, conditioning agents, SOS/VOD diagnosis, and use of defibrotide, were determined. The reported incidence of SOS/VOD was 4.1% in adult centers and 11.5% in pediatric centers. Defibrotide was administered to 74.8% of adult patients and 97.3% of pediatric patients with SOS/VOD. Significant variability in the use, dosage, and duration of defibrotide was seen across the adult centers. The day 100 survival rate and median OS for patients managed with defibrotide was 51.8% and 103 days, respectively, for adult patients and 90.4% and not reached, respectively, for pediatric patients. In adults, older age at transplantation, an HLA-matched nonsibling relative donor, and a diagnosis of SOS/VOD treated with defibrotide were associated with reduced OS. In pediatric patients, the patient and transplantation characteristics associated with reduced OS were a diagnosis of SOS/VOD and a ≥2 HLA-mismatched related donor. A collaborative approach across Australasia to diagnosing and managing SOS/VOD, particularly with respect to consistent defibrotide use, is recommended.

Delineating gene-environment effects using virtual twins of patients treated with clozapine.

Studies that focus on individual covariates, while ignoring their interactions, may not be adequate for model-informed precision dosing (MIPD) in any given patient. Genetic variations that influence protein synthesis should be studied in conjunction with environmental covariates, such as cigarette smoking. The aim of this study was to build virtual twins (VTs) of real patients receiving clozapine with interacting covariates related to genetics and environment and to delineate the impact of interacting covariates on predicted clozapine plasma concentrations. Clozapine-treated patients with schizophrenia (N = 42) with observed clozapine plasma concentrations, demographic, environmental, and genotype data were used to construct VTs in Simcyp. The effect of increased covariate virtualization was assessed by performing simulations under three conditions: "low" (demographic), "medium" (demographic and environmental interaction), and "high" (demographic and environmental/genotype interaction) covariate virtualization. Increasing covariate virtualization with interaction improved the coefficient of variation (R2 ) from 0.07 in the low model to 0.391 and 0.368 in the medium and high models, respectively. Whereas R2 was similar between the medium and high models, the high covariate virtualization model had improved accuracy, with systematic bias of predicted clozapine plasma concentration improving from -138.48 ng/ml to -74.65 ng/ml. A high level of covariate virtualization (demographic, environmental, and genotype) may be required for MIPD using VTs.

Anakinra Pilot - a clinical trial to demonstrate safety, feasibility and pharmacokinetics of interleukin 1 receptor antagonist in preterm infants.

Background: Bronchopulmonary dysplasia (BPD), its complication pulmonary hypertension (BPD-PH) and preterm brain and gut injury lead to significant morbidity and mortality in infants born extremely prematurely. There is extensive evidence that the pro-inflammatory cytokine interleukin 1 (IL-1) plays a key role in the pathophysiology of these illnesses. Two decades of clinical use in paediatric and adult medicine have established an excellent safety and efficacy record for IL-1 blockade with IL-1 receptor antagonist (IL-1Ra, medication name anakinra). Building on robust pre-clinical evidence, the Anakinra Pilot trial aims to demonstrate safety and feasibility of administering anakinra to preterm infants, and to establish pharmacokinetics in this population. Its ultimate goal is to facilitate large studies that will test whether anakinra can ameliorate early-life inflammation, thus alleviating multiple complications of prematurity. Methods and analysis: Anakinra Pilot is an investigator-initiated, single arm, safety and feasibility dose-escalation trial in extremely preterm infants born between 24 weeks 0 days (240) and 276 weeks of gestational age (GA). Enrolled infants will receive anakinra intravenously over the first 21 days after birth, starting in the first 24 h after birth. In the first phase, dosing is 1 mg/kg every 48 h, and dosage will increase to 1.5 mg/kg every 24 h in the second phase. Initial anakinra dosing was determined through population pharmacokinetic model simulations. During the study, there will be a interim analysis to confirm predictions before undertaking dose assessment. Anakinra therapy will be considered safe if the frequency of adverse outcomes/events does not exceed that expected in infants born at 240-276 weeks GA. Clinical Trial Registration: https://clinicaltrials.gov/, identifier NCT05280340.

A meta-analysis of palifermin efficacy for the management of oral mucositis in patients with solid tumours and haematological malignancy.

BACKGROUND: Palifermin, a recombinant keratinocyte growth factor promotes thickening of the mucosa, minimising severity of mucositis caused by chemotherapy and radiotherapy. OBJECTIVE: To synthesise published literature on palifermin for the management of oral mucositis, in patients receiving chemotherapy and/or radiotherapy, aiming to ascertain recommendations for practice. METHODS: Databases searched were Medline, Embase, IPA and CIANHL. A meta-analysis included randomised controlled trials (RCT) for palifermin compared to placebo or no palifermin, with the key data extracted being number of events of severe mucositis (defined by WHO criteria grade 3 or 4). RESULTS: The meta-analysis included 10 RCT. Patients were treated for solid and haematological malignancy. Analysis suggested benefit of palifermin decreasing the incidence of severe mucositis in solid tumours RR0.76 [95%CI 0.63-0.92;p = 0.004], haematological malignancy RR0.63 [95 %CI 0.48-0.82;p = 0.0007] and overall RR0.69 [95 %CI 0.59-0.81;p < 0.0001]. CONCLUSION: Palifermin reduces the incidence of severe mucositis up to 30 % in patients receiving treatment with chemotherapy and/or radiotherapy.

Quantifying the Impact of Phenoconversion on Medications With Actionable Pharmacogenomic Guideline Recommendations in an Acute Aged Persons Mental Health Setting.

Introduction: Polypharmacy and genetic variants that strongly influence medication response (pharmacogenomics, PGx) are two well-described risk factors for adverse drug reactions. Complexities arise in interpreting PGx results in the presence of co-administered medications that can cause cytochrome P450 enzyme phenoconversion. Aim: To quantify phenoconversion in a cohort of acute aged persons mental health patients and evaluate its impact on the reporting of medications with actionable PGx guideline recommendations (APRs). Methods: Acute aged persons mental health patients (N = 137) with PGx and medication data at admission and discharge were selected to describe phenoconversion frequencies for CYP2D6, CYP2C19 and CYP2C9 enzymes. The expected impact of phenoconversion was then assessed on the reporting of medications with APRs. Results: Post-phenoconversion, the predicted frequency at admission and discharge increased for CYP2D6 intermediate metabolisers (IMs) by 11.7 and 16.1%, respectively. Similarly, for CYP2C19 IMs, the predicted frequency at admission and discharge increased by 13.1 and 11.7%, respectively. Nineteen medications with APRs were prescribed 120 times at admission, of which 50 (42%) had APRs pre-phenoconversion, increasing to 60 prescriptions (50%) post-phenoconversion. At discharge, 18 medications with APRs were prescribed 122 times, of which 48 (39%) had APRs pre-phenoconversion, increasing to 57 prescriptions (47%) post-phenoconversion. Discussion: Aged persons mental health patients are commonly prescribed medications with APRs, but interpretation of these recommendations must consider the effects of phenoconversion. Adopting a collaborative care model between prescribers and clinical pharmacists should be considered to address phenoconversion and ensure the potential benefits of PGx are maximised.

New Horizons in the impact of frailty on pharmacokinetics: latest developments.

Frail older people have a high prevalence of drug use and are susceptible to adverse drug reactions. The physiological changes of frailty are likely to affect pharmacokinetics and pharmacodynamics. We reviewed the methods and findings of published studies of pharmacokinetics in frailty. Nine studies describing pharmacokinetics and an additional three of pharmacokinetic pathways in frail older people were identified. Most pharmacokinetic studies investigated a single administration of a medication, dose or formulation, in small populations, often with limited representation of males or females, and applied variable definitions of frailty. Pharmacokinetic sampling designs generally utilised saturated sampling followed by analysis based on the trapezoidal rule for area under the curve, with more recent studies using sparser sampling and more sophisticated modelling to obtain individual and population values of all pharmacokinetic parameters. Overall, the pharmacokinetic studies reported only small changes in some parameters for some drugs with frailty, with the most consistent change reduced hepatic clearance in frail older people. Recommendations for future studies of pharmacokinetics in frailty include (i) standard objective definitions of frailty; (ii) larger studies including people with mild, moderate and severe frailty; (iii) population pharmacokinetic modelling to allow sparser sampling and consideration of multiple influences on pharmacokinetics; (iv) physiologically based modelling as the physiology of frailty emerges and (v) longitudinal pharmacokinetic studies of chronic drug therapy from middle to old age and from robust to pre-frail to frail, including pre-clinical studies. These data, accompanied by pharmacodynamics data in frailty, will inform safe, effective prescribing for frail older people.

Evaluation of Meropenem-Ciprofloxacin Combination Dosage Regimens for the Pharmacokinetics of Critically Ill Patients With Augmented Renal Clearance.

Augmented renal clearance (ARC, creatinine clearance > 130 mL/minute) makes difficult achievement of effective concentrations of renally cleared antibiotics in critically ill patients. This study examined the synergistic killing and resistance suppression for meropenem-ciprofloxacin combination dosage regimens against Pseudomonas aeruginosa isolates within the context of ARC. Clinically relevant meropenem and ciprofloxacin concentrations, alone and in combinations, were studied against three clinical isolates with a range of susceptibilities to each of the antibiotics. Isolate Pa1280 was susceptible to both meropenem and ciprofloxacin, Pa1284 had intermediate susceptibility to meropenem and was susceptible to ciprofloxacin, and CR380 was resistant to meropenem and had intermediate susceptibility to ciprofloxacin. Initially, isolates were studied in 72-hour static-concentration time-kill (SCTK) studies. Subsequently, the pharmacokinetic profiles expected in patients with ARC receiving dosage regimens, including at the highest approved daily doses (meropenem 6 g daily divided and administered as 0.5-hour infusions every 8 hours, or as a continuous infusion; ciprofloxacin 0.4 g as 1-hour infusions every 8 hours), were examined in a dynamic hollow-fiber infection model (HFIM) over 7-10 days. In both SCTK and HFIM, combination regimens were generally synergistic and suppressed growth of less-susceptible subpopulations, these effects being smaller for isolate CR380. The time-courses of total and less-susceptible bacterial populations in the HFIM were well-described by mechanism-based models, which enabled conduct of Monte Carlo simulations to predict likely effectiveness of approved dosage regimens at different creatinine clearances. Optimized meropenem-ciprofloxacin combination dosage regimens may be a viable consideration for P. aeruginosa infections in critically ill patients with ARC.

The role of medication advisory committees in residential aged care services.

BACKGROUND: There is increasing international interest in initiatives to reduce medication-related harm and preventable hospitalizations in residential aged care services (RACS). The Australian Government recommends that RACS establish multidisciplinary Medication Advisory Committees (MACs). No previous research has specifically investigated the structures and functioning of MACs. OBJECTIVES: To explore the current structures and functioning of MACs, and identify opportunities for MACs to better promote safe and effective medication use. METHODS: Semi-structured interviews and focus groups were conducted with a maximum variation sample of health professionals (n = 44) across four health services operating across 27 RACS in rural and regional Victoria, Australia. Qualitative data were analyzed using deductive and inductive content analyses. Results were presented to a multidisciplinary expert panel (n = 13) to identify opportunities for improvement. RESULTS: Deductively coded themes included composition and functioning of the MAC, education and information needs and support to better manage polypharmacy. Emergent inductively coded themes included general medical practitioner (GP) and pharmacist engagement, collaboration and effectiveness. Participation by GPs and pharmacists was variable, while no MACs involved residents or family carers. Aged care specific and multidisciplinary MACs were generally more proactive in addressing potential medication-related harm. Education to identify and report adverse drug events with high risk medications was identified as a priority. The multidisciplinary panel made 12 recommendations to promote safe and effective medication use. CONCLUSION: Despite all MACs having a strong commitment to medication safety, opportunities exist to improve the composition and structure, proactive identification and response to emerging issues, and systems for staff, resident and family carer training.

Nurse-initiated pre-prescribed antibiotic orders to facilitate prompt and appropriate antibiotic administration in febrile neutropenia.

PURPOSE: To assess the impact of a pathway allowing nurse initiation of first dose intravenous (IV) antibiotics on time to antibiotic administration (TTA) in adult inpatients with febrile neutropenia (FN). METHODS: This study evaluated the impact on TTA of a clinical pathway (November 2017 to April 2018) allowing nurse initiation of pre-prescribed antibiotics in adult haematology patients with FN, compared with a prior cohort (November 2016 to April 2017) in which antibiotics were only prescribed and administered after medical review. The primary endpoint for comparison was TTA, calculated as the time between the first recorded fever and IV antibiotic administration. Secondary endpoints included appropriateness of initial antibiotic choice, 30-day all-cause mortality and admission to intensive care unit (ICU). RESULTS: Forty-seven eligible FN episodes in 40 patients and 61 episodes in 52 patients were evaluated in the pre- and post-implementation groups, respectively. Baseline characteristics were comparable between groups. Median (IQR) TTA, in the pre-implementation group [66 min (40-100 min)] was significantly prolonged versus post-implementation group [29 min (20-41 min); p < 0.001]. A significantly higher proportion of episodes were administered appropriate initial antibiotics in the post-versus pre-implementation groups (100% vs. 89%, p = 0.03). There was no significant change in 30-day all-cause mortality (0% vs. 5%, p = 0.3) or ICU admission within 48 h of fever (0% vs. 2%, p > 0.99) between pre- and post-implementation groups, respectively. CONCLUSIONS: A pathway allowing nurse initiation of pre-prescribed antibiotic orders for FN significantly reduced TTA from first recorded fever and increased the proportion of appropriate initial antibiotic choices without significantly impacting on patient outcomes.

Effect of Perioperative Opioids on Cancer-Relevant Circulating Parameters: Mu Opioid Receptor and Toll-Like Receptor 4 Activation Potential, and Proteolytic Profile.

Purpose: The purpose of this study is to investigate the potential interplay between opioid analgesia and tumor metastasis through modulation of µ-opioid receptor (MOR), Toll-like receptor 4 (TLR4) activation, and matrix degradation potential.Experimental Design: Plasma samples were collected from 60 patients undergoing elective lower limb joint replacement preoperatively and at 3, 6, and 24 hours after surgery; pain scores were documented at the same time points. Opioid administration was recorded and converted into morphine IV equivalents. Plasma samples were also collected from 10 healthy volunteers. Alphascreen cyclic AMP assay and MOR-overexpressing cells were employed to quantify MOR activation. HEK-Blue hTLR4 were utilized to measure TLR4 activation. Circulating matrix metalloprotease and tissue inhibitor of matrix protease activities were assessed by gelatin zymography and reverse zymography, respectively.Results: Postoperative plasma samples displayed the ability to activate MOR and to inhibit lipopolysaccharide (LPS)-induced TLR4 activation. Linear mixed model analysis revealed that MOR activation had a significant effect on inhibition of LPS-induced TLR4 activation. Furthermore, TLR4 had a significant effect to explain pain scores. Postoperative samples also displayed altered circulating matrix-degrading enzymes activity potential, but this was correlated neither to opioid administration nor to MOR activation potential.Conclusions: Our results show for the first time that (i) opioids administered to surgery patients result in modulation of ligand-induced TLR4 activation and (ii) postoperative pain is associated with increased circulating TLR4 activation potential. Our study further promotes the use of MOR activation potential rather than opioid intake in clinical studies measuring opioid exposure at a given time point. Clin Cancer Res; 24(10); 2319-27. ©2018 AACR.

Defibrotide for the treatment of sinusoidal obstruction syndrome: evaluation of response to therapy and patient outcomes.

PURPOSE: Defibrotide is an agent used to treat sinusoidal obstruction syndrome (SOS/VOD) in patients undergoing haemopoietic stem cell transplantation. The aim of this study was to evaluate the effectiveness of defibrotide used within institutional guidelines for the treatment of SOS/VOD in patients undergoing haemopoietic stem cell transplantation (HSCT). METHODS: Data for 23 patients was retrospectively reviewed to evaluate the effectiveness of defibrotide and the utility of response criteria to direct therapy as specified within institution guidelines. Patients met institutional criteria for a diagnosis of SOS/VOD based on predominantly Baltimore criteria and received defibrotide. Stabilisation or improvement in symptoms and biochemical markers was required for continuation of therapy with defibrotide. RESULTS: Overall, 14 patients responded to therapy. Survival at day 100 post HSCT was 70%. Median serum (total) bilirubin concentrations in all evaluable patients had decreased at days 5 and 10 (p < 0.001). There was a proportional reduction in median weight of 4% by day 5 and 6.6% by day 10 (p < 0.001). On cessation of defibrotide, there was a decrease in the proportion of patients exhibiting hepatomegaly (p = 0.02), ascites (p < 0.01) and requiring oxygen supplementation (p < 0.01), with 70% survival at day 100 post HSCT. CONCLUSION: Defibrotide to treat SOS/VOD and continued based on attainment of early response was effective management of this condition. Defibrotide should be considered in any consensus protocol providing guidance on the management of SOS/VOD, with future studies considered to assess appropriate time points for response to therapy during treatment.

Prevalence and Variability in Medications Contributing to Polypharmacy in Long-Term Care Facilities.

BACKGROUND: Research into which medications contribute to polypharmacy and the variability in these medications across long-term care facilities (LTCFs) has been minimal. OBJECTIVE: Our objective was to investigate which medications were more prevalent among residents with polypharmacy and to determine the variability in prescribing of these medications across LTCFs. METHODS: This was a cross-sectional study of 27 LTCFs in regional and rural Victoria, Australia. An audit of the medication charts and medical records of 754 residents was performed in May 2015. Polypharmacy was defined as nine or more regular medications. Logistic regression was performed to determine the association between medications and resident characteristics with polypharmacy. Analyses were adjusted for age, sex and Charlson's comorbidity index. Variability in the use of the ten most prevalent medication classes was explored using funnel plots. Characteristics of LTCFs with low (< 30%), moderate (30-49%) and high (≥ 50%) polypharmacy prevalence were compared. RESULTS: Polypharmacy was observed in 272 (36%) residents. In adjusted analyses, each of the top ten most prevalent medication classes, with the exception of antipsychotics, were associated with polypharmacy. Between 7 and 23% of LTCFs fell outside the 95% control limits for each of the ten most prevalent medications. LTCFs with ≥ 50% polypharmacy prevalence were predominately smaller. CONCLUSION: Polypharmacy was associated with nine of the ten most prevalent medication classes. There was greater than fourfold variability in nine of the ten most prevalent medications across LTCFs. Further studies are needed to investigate the clinical appropriateness of the variability in polypharmacy.

Medication Use and Fall-Related Hospital Admissions from Long-Term Care Facilities: A Hospital-Based Case-Control Study.

BACKGROUND: Falls are a leading cause of preventable hospitalizations from long-term care facilities (LTCFs). Polypharmacy and falls-risk medications are potentially modifiable risk factors for falling. OBJECTIVE: This study investigated whether polypharmacy and falls-risk medications are associated with fall-related hospital admissions from LTCFs compared with hospital admissions for other causes. METHODS: This was a hospital-based, case-control study of patients aged ≥65 years hospitalized from LTCFs. Cases were patients with falls and fall-related injuries, and controls were patients admitted for infections. Conditional logistic regression was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between polypharmacy (defined as the use of nine or more regular pre-admission medications) and falls-risk medications (categorized as psychotropic medications and those that can cause orthostatic hypotension) with fall-related hospital admissions. RESULTS: There was no association between polypharmacy and fall-related hospital admissions (adjusted OR 0.97, 95% CI 0.63-1.48); however, the adjusted odds of fall-related hospital admissions increased by 16% (95% CI 3-30%) for each additional falls-risk medication. Medications that can cause orthostatic hypotension (adjusted OR 1.25, 95% CI 1.06-1.46), but not psychotropic falls-risk medications (adjusted OR 1.02, 95% CI 0.88-1.18) were associated with fall-related hospital admissions. The association between medications that can cause orthostatic hypotension and fall-related hospital admissions was strongest among residents with polypharmacy (adjusted OR 1.44, 95% CI 1.08-1.92). CONCLUSION: Polypharmacy was not an independent risk factor for fall-related hospital admissions; however, medications that can cause orthostatic hypotension were associated with fall-related hospital admissions, particularly among residents with polypharmacy. Falls-risk should be considered when prescribing medications that can cause orthostatic hypotension.

Prioritizing interventions to manage polypharmacy in Australian aged care facilities.

BACKGROUND: Polypharmacy is highly prevalent in residential aged care facilities (RACFs). Although polypharmacy is sometimes unavoidable, polypharmacy has been associated with increased morbidity and mortality. OBJECTIVE: To identify and prioritize a range of potential interventions to manage polypharmacy in RACFs from the perspectives of health care professionals, health policy and consumer representatives. METHODS: Two nominal group technique (NGT) sessions were convened in August 2015. A purposive sample (n = 19) of clinicians, researchers, managers and representatives of consumer, professional and health policy organizations were asked to nominate interventions to address the prevalence and appropriateness of medication use. Participants were then asked to prioritize five interventions suitable for possible implementation at the system level. RESULTS: Six of 16 potential interventions were prioritized highest for possible implementation in clinical practice, with two interventions prioritized as second highest. The top interventions in rank order were 'implementation of a pharmacist-led medication reconciliation service for new residents,' 'conduct facility-level audits and feedback to staff and health care professionals,' 'develop deprescribing scripts to assist clinician-resident discussion,' 'develop or revise prescribing guidelines specific to older people with multimorbidity in RACFs,' 'implement electronic medication charts and records' and 'better support Medication Advisory Committees (MACs) to address medication appropriateness.' CONCLUSION: This study prioritized a range of potential interventions that may be used to assist clinicians and policy makers develop a comprehensive strategy to manage polypharmacy in RACFs.

Defibrotide for the management of sinusoidal obstruction syndrome in patients who undergo haemopoietic stem cell transplantation.

Sinusoidal obstruction syndrome, previously known as veno-occlusive disease (VOD/SOS), is a complication in patients undergoing haemopoietic stem cell transplantation (HSCT). Severe VOD/SOS, including progression to multi-organ failure, has resulted in a mortality of greater than 80%. Defibrotide's varying pharmacological actions, particularly on endothelial cells, make it is a useful agent to consider for prophylaxis and treatment of VOD/SOS. Barriers to its routine use include the high acquisition cost and the fact that neither the oral or parenteral formulations are licensed products in many countries at this time. This review summarises available literature on the use of defibrotide in the management of VOD/SOS. Publications consist predominantly of single centre cohort studies and case series. Available evidence indicates that defibrotide is effective in the management of VOD/SOS. Using defibrotide prophylaxis should also be considered, especially in the paediatric setting, where there are available results from a large, open label, randomized controlled trial. Patient outcome data from the larger studies and compassionate programs can inform consensus recommendations on dosing regimen and criteria for the treatment of VOD/SOS with defibrotide in the adult population. The reviewed literature indicates an effective and safe dose for treatment is 25mg/kg/day, continued for at least 14days or until complete response is achieved. Further studies are required to determine the optimal dose and duration of treatment in both paediatric patients and adults. Recent recommendations and a phase 3 trial using historical controls indicate that defibrotide should be included as a pharmacotherapy option in protocols guiding management of VOD/SOS.

Why is polypharmacy increasing in aged care facilities? The views of Australian health care professionals.

RATIONALE, AIMS AND OBJECTIVES: The prevalence of polypharmacy in residential aged care facilities (RACFs) is high and increasing. Although not necessarily inappropriate, polypharmacy has been associated with drug interactions, adverse drug events, geriatric syndromes and hospital admissions. The aim of this study was to identify and prioritize factors contributing to the increasing prevalence of polypharmacy in RACFs. METHODS: Seventeen health care professionals from metropolitan and regional Victoria and South Australia identified and prioritized factors using a modified nominal group technique. RESULTS: The top five factors ranked from most important to fifth most important were 'changes in resident mix', 'increasing numbers of prescribers and the reluctance of one prescriber to discontinue a medicine commenced by another prescriber', 'better adherence to clinical practice guidelines', 'increasing reliance on locums' and 'greater recognition and pharmacological management of pain'. CONCLUSIONS: Reasons for the increase in polypharmacy are multifactorial. Understanding the factors contributing to polypharmacy may help to guide future research and develop interventions to manage polypharmacy in RACFs.

Primary antifungal prophylaxis in adult patients with acute lymphoblastic leukaemia: a multicentre audit.

OBJECTIVES: The primary objectives were to investigate the prescribing practices of primary antifungal prophylaxis (PAP) and incidence of invasive fungal disease (IFD) in adult patients with ALL receiving induction-consolidation chemotherapy. Secondary objectives were to determine risk factors for IFD and resource utilization associated with IFD. METHODS: A retrospective chart review of adult patients with ALL from commencement of induction until completion of consolidation chemotherapy was undertaken from January 2008 to June 2013 in four hospitals in Melbourne, Australia. IFD was classified according to the revised European Organisation for Research and Treatment of Cancer criteria. Cost analysis was performed from an Australian public hospital perspective. RESULTS: Ninety-eight patients were included in the audit; 83 (85%) received PAP. Most patients (49/83, 59%) switched between two different antifungal agents, predominantly between liposomal amphotericin B and an azole. Five proven/probable and six possible IFD cases were identified. Proven/probable IFD was most common in patients receiving the BFM95 chemotherapy protocol. The incidence of proven/probable IFD was significantly lower in patients receiving PAP compared with those who did not (2/78, 2.6% versus 3/14, 21.4%; P = 0.024). For every five patients receiving PAP, one proven/probable IFD case would be prevented. Proven/probable IFD was associated with an additional median cost of 121,520 Australian dollars (95% CI: 90,781-180,141 Australian dollars; P < 0.001) compared with patients without IFD. CONCLUSIONS: This is the first multicentre study evaluating PAP use in patients with ALL. With the caveats of interpretation of retrospective, non-randomized data, PAP was associated with a reduced IFD risk.