Concomitant Medications Research Articles

A narrative review of risk mitigation strategies in the management of opioids for chronic pain and palliative care in older adults: interprofessional collaboration with the pharmacist.

The prevalence of chronic non-cancer pain (CNCP) in older adults is high. Opioids carry significant risk for harm in older adults. Yet, many older adults are established on long-term opioid therapy for the treatment of CNCP despite limited documented efficacy. Many of the non-opioid options to treat pain present challenges in this population. Since challenges with tapering patients off of opioids exist, older adults may remain established on long-term opioid therapy for CNCP. While opioid use is less scrutinized for older adults receiving palliative care, significant safety concerns exist. Therefore, efforts to mitigate risks for older adults receiving long-term opioids for CNCP and for palliative care are essential. Pharmacists as members of the interprofessional team are equipped to improve safety among older adults on chronic opioid therapy. Among patients receiving palliative care, collaboration with palliative care specialists is also key. The purpose of this narrative review is to describe risk mitigation strategies for opioid use among older adults with CNCP and those receiving palliative care. Data were identified by searching PubMed (January 1, 1990 to February 21, 2024) using the following search terms: older adults, opioids, chronic pain, palliative care, and pharmacist. The search was repeated using terms geriatric, elderly, opiates, narcotics, and controlled substances. Non-English articles and observational studies with fewer than 100 patients were excluded. Major North American and European guidelines were reviewed. Additional literature was obtained through review of relevant references of identified articles. A variety of risk mitigation strategies to improve safety for older adults using opioids exist. They include risk assessment, tapering opioids, reducing high-risk concomitant medications, utilizing non-opioid therapies, screening for and treatment of opioid use disorder (OUD), toxicology testing, co-prescribing naloxone, utilizing controlled substance agreements, reviewing prescription drug monitoring program data, prescriber and patient education, and collaboration with pharmacists and palliative care specialists. There are many opioid risk mitigation strategies for older adults. Collaboration with pharmacists and palliative care specialists can be an effective means for implementing strategies to optimize opioid safety for older adults with CNCP and those receiving palliative care.

Risk factors for hyponatremia associated with desmopressin use.

Nocturia is a urinary symptom that can significantly impact a patient's quality of life. Desmopressin is prescribed for adults with nocturia. However, desmopressin use is associated with hyponatremia. The objective of this study was to assess the rate of hyponatremia in patients prescribed desmopressin and associated risk factors. Study subjects were patients who were newly prescribed desmopressin 0.1 mg (tablet) between January 1, 2015 (the start of available data) and December 1, 2020. Factors such as patients' baseline characteristics, comorbidities, and concomitant medications were analyzed to compare risk factors for hyponatremia (≤135 mmol/dL). A total of 918 adults were included in this study. The rate of hyponatremia was 4.4 % in patients with desmopressin. The hyponatremia group was older than non-hyponatremia group (71.0 vs. 61.6 years, P<0.001). The hyponatremia group had a higher prevalence of hypertension as a comorbidity. Although hypertension was more common in males than in females, the difference was not statistically significant (4.6% in male vs. 3.5% in female, P=0.65). Patients with hyponatremia were more likely to be taking angiotensin receptor blockers or thiazides than those without hyponatremia. Hyponatremia occurred in 4.4% of patients with desmopressin. Risk factors of hyponatremia were age, comorbidities, concurrent medication and decreased estimated glomerular filtration rate (eGFR) level. Thus, care should be taken when administering desmopressin to these patients.

Frequency, Characteristics, and Preventability of Adverse Drug Reactions in Perioperative Neurosurgery: Analysis Over 11 Years

Despite the importance of adverse drug reactions (ADRs), little is known about their role in perioperative neurosurgery. This study aimed to determine the prevalence of ADRs in perioperative neurosurgery and clarify the characteristics, severity, preventability, and risk factors of ADRs. Data for all patients who underwent neurosurgical procedures over an 11-year period were analyzed. During the study period, 3648 surgical procedures were performed for 2695 patients. Demographic and clinical information documented included medical history, allergic history, diagnosis, surgical method, suspected drugs, concomitant medications, and drug details. Multivariate logistic regression analyses were performed to identify independent parameters that were correlated with ADRs. In total, 467 ADRs (18.3% ADRs/all neurosurgical procedures) were experienced by 401 patients. Anticonvulsants were associated with the highest number of ADRs (16.0%), followed by antibiotics (14.7%). Patients with ADRs were older than patients without ADRs (P < 0.01). The total number of drugs in patients with ADRs was 8.8 ± 3.6, compared to 5.2 ± 2.4 for patients without ADRs (P < 0.01). There were no significant differences in sex, allergic history, severe renal dysfunction (estimated glomerular filtration rate < 30ml/min/1.73 m2), hypertension, diabetes, urgency of surgery, and type of surgery. Multivariate analysis showed that a high total number of drugs (odds ratio=3.2; 95% confidence interval 1.9-5.1) and older age (odds ratio=2.1; 95% confidence interval 1.3-3.8) were independent risk factors for ADRs. The frequency of suspected and severe ADRs was higher than expected. Polypharmacy and older age were independent risk factors for ADRs in perioperative neurosurgery. To decrease ADRs during perioperative neurosurgery, polypharmacy must be discouraged, especially among older adult patients.

Data Flow Construction and Quality Evaluation of Electronic Source Data in Clinical Trials: Pilot Study Based on Hospital Electronic Medical Records in China.

The traditional clinical trial data collection process requires a clinical research coordinator who is authorized by the investigators to read from the hospital's electronic medical record. Using electronic source data opens a new path to extract patients' data from electronic health records (EHRs) and transfer them directly to an electronic data capture (EDC) system; this method is often referred to as eSource. eSource technology in a clinical trial data flow can improve data quality without compromising timeliness. At the same time, improved data collection efficiency reduces clinical trial costs. This study aims to explore how to extract clinical trial-related data from hospital EHR systems, transform the data into a format required by the EDC system, and transfer it into sponsors' environments, and to evaluate the transferred data sets to validate the availability, completeness, and accuracy of building an eSource dataflow. A prospective clinical trial study registered on the Drug Clinical Trial Registration and Information Disclosure Platform was selected, and the following data modules were extracted from the structured data of 4 case report forms: demographics, vital signs, local laboratory data, and concomitant medications. The extracted data was mapped and transformed, deidentified, and transferred to the sponsor's environment. Data validation was performed based on availability, completeness, and accuracy. In a secure and controlled data environment, clinical trial data was successfully transferred from a hospital EHR to the sponsor's environment with 100% transcriptional accuracy, but the availability and completeness of the data could be improved. Data availability was low due to some required fields in the EDC system not being available directly in the EHR. Some data is also still in an unstructured or paper-based format. The top-level design of the eSource technology and the construction of hospital electronic data standards should help lay a foundation for a full electronic data flow from EHRs to EDC systems in the future.

Proceedings of PRINCETON IV: PDE5 inhibitors and cardiac health symposium.

Prior consensus meetings have addressed the relationship between phosphodiesterase type 5 (PDE5) inhibition and cardiac health. Given significant accumulation of new data in the past decade, a fourth consensus conference on this topic was convened in Pasadena, California, on March 10 and 11, 2023. Our meeting aimed to update existing knowledge, assess current guidelines, and make recommendations for future research and practice in this area. An expert panel reviewed existing research and clinical practice guidelines. Key findings and clinical recommendations are the following: First, erectile dysfunction (ED) is a risk marker and enhancer for cardiovascular (CV) disease. For men with ED and intermediate levels of CV risk, coronary artery calcium (CAC) computed tomography should be considered in addition to previous management algorithms. Second, sexual activity is generally safe for men with ED, although stress testing should still be considered for men with reduced exercise tolerance or ischemia. Third, the safety of PDE5 inhibitor use with concomitant medications was reviewed in depth, particularly concomitant use with nitrates or alpha-blockers. With rare exceptions, PDE5 inhibitors can be safely used in men being treated for hypertension, lower urinary tract symptoms and other common male disorders. Fourth, for men unresponsive to oral therapy or with absolute contraindications for PDE5 inhibitor administration, multiple treatment options can be selected. These were reviewed in depth with clinical recommendations. Fifth, evidence from retrospective studies points strongly toward cardioprotective effects of chronic PDE5-inhibitor use in men. Decreased rates of adverse cardiac outcomes in men taking PDE-5 inhibitors has been consistently reported from multiple studies. Sixth, recommendations were made regarding over-the-counter access and potential risks of dietary supplement adulteration. Seventh, although limited data exist in women, PDE5 inhibitors are generally safe and are being tested for use in multiple new indications. Studies support the overall cardiovascular safety of the PDE5 inhibitors. New indications and applications were reviewed in depth.

Effect of concomitant medications on treatment response and survival in non-metastatic castrate resistant prostate cancer: Exploratory analysis of the SPARTAN trial

BackgroundWe performed an exploratory analysis of the SPARTAN trial to determine whether concomitant exposure to several classes of commonly prescribed medications influenced the effect of apalutamide on overall survival (OS) and metastasis-free survival (MFS) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Patients and methodsSPARTAN was a phase III randomized controlled trial in which nmCRPC patients were randomly assigned in a 2:1 ratio to receive androgen deprivation therapy with or without apalutamide. We focused on 5 commonly prescribed classes of medications: metformin, statins, angiotensin converting enzyme inhibitors (ACEI), acetylsalicylic acid (ASA), and proton pump inhibitors (PPI) based on a plausible biological and clinical rationale. To determine the potential effect modification, we applied multivariable Cox regression models for OS and MFS separately with additional interaction terms. To determine the independent association of concomitant medications with OS and MFS, we used IPTW-based log-rank test. A 2-sided p < 0.01 was considered statistically significant. ResultsWe did not find statistically significant differences in effect from apalutamide on OS across subgroups stratified by concomitant exposure to any of the medication classes. While there was some difference in the treatment effect from apalutamide on MFS between patients with concomitant statins (adjusted hazard ratio [aHR]: 0.20; 95 % CI: 0.15–0.28) versus without concomitant statins (aHR: 0.31 [0.24–0.39]), this did not reach the pre-specified threshold of statistical significance (p = 0.011). On IPTW-based analysis, patients treated concomitantly with metformin (median: not reached versus 31 months; p = 0.002), or ACEI (median: 37 versus 29 months, p = 0.006) had significantly improved MFS. ConclusionsIn this post-hoc exploratory analysis of SPARTAN, effects of apalutamide on MFS and OS were consistent across subgroups stratified by exposure to concomitant medications. Exposure to concomitant metformin and ACEI was independently associated with a significant improvement in MFS.

Overdosing of direct oral anticoagulants

Direct oral anticoagulants (DOAC) are increasingly used for prophylaxis and treatment of thromboembolic events. Incorrectly dosed DOAC treatment is associated with excess mortality. This article aims at raising awareness of DOAC overdosing and its causes as well as presenting adiagnostic and therapeutic work-up. Based on acase presentation, astructured review of the current literature on DOAC overdosing was performed and treatment recommendations were extracted. In addition to wittingly or unwittingly increased DOAC intake, common causes of overdose are inadequate dose adjustment for concomitant medication or comorbidities. Global coagulation testing should be supplemented with DOAC-specific testing. Severe bleeding and the need for invasive diagnostics or urgent surgery represent indications for treating DOAC overdoses. Based on the cause of an DOAC overdose, active charcoal, endoscopic pill rescue, antagonization with idarucizumab or andexanet alfa and the targeted substitution of coagulation factors represent treatment options. The sensitization of clinicians is important to ensure atimely diagnosis and adequate treatment of DOAC overdosing. This report provides an overview of current knowledge on diagnostics and treatment; however, further studies are necessary to improve the existing algorithms.

Clinical pharmacology considerations and drug-drug interactions with long-acting cabotegravir and rilpivirine relevant to sub-Saharan Africa.

Long-acting injectable (LAI) cabotegravir and rilpivirine for HIV treatment and LAI cabotegravir for pre-exposure HIV prophylaxis are being rolled out in a multitude of countries worldwide. Due to the prolonged exposure, it can be challenging to undertake 'traditional' pharmacokinetic studies and current guidance is derived from their oral equivalents or physiologically based pharmacokinetic studies. This review aims to consider pharmacokinetic characteristics of cabotegravir and rilpivirine and describe anticipated drug-drug interactions (DDIs) with frequent concomitant medications in African settings. Relevant co-medications were identified from the WHO 2021 List of Essential Medicines. All original human and physiologically based pharmacokinetic studies published in English on PubMed, discussing DDIs with LAI cabotegravir and rilpivirine prior to April 2023, were reviewed. The Liverpool HIV interaction database was also reviewed (https://www.hiv-druginteractions.org/checker). LAI cabotegravir and rilpivirine have half-lives of 6-12 and 13-28 weeks, respectively. Cabotegravir is primarily metabolized by UDP-glucuronyltransferase (UGT)-1A1 and rilpivirine by cytochrome P450 (CYP)-3A4. LAI cabotegravir and rilpivirine themselves exhibit low risk of perpetrating interactions with co-medications as they do not induce or inhibit the major drug metabolizing enzymes. However, they are victims of DDIs relating to the induction of their metabolizing enzymes by concomitantly administered medication. Noteworthy contraindicated co-medications include rifamycins, carbamazepine, phenytoin, flucloxacillin and griseofulvin, which induce CYP3A4 and/or UGT1A1, causing clinically significant reduced concentrations of rilpivirine and/or cabotegravir. In addition to virologic failure, subtherapeutic concentrations resulting from DDIs can lead to emergent drug resistance. Clinicians should be aware of potential DDIs and counsel people receiving LAI cabotegravir/rilpivirine appropriately to minimize risk.

Immunological Drug-Drug Interactions Affect the Efficacy and Safety of Immune Checkpoint Inhibitor Therapies.

With the rapid expansion in the development and clinical utility of immune checkpoint inhibitors (ICIs) for oncology, the continual evaluation of the safety profile of such agents is imperative. The safety profile of ICIs as monotherapy is dominated by immune-related adverse events, which can be considered as an extension of the mechanism of action of these immunomodulatory drugs. Further to this, an emerging theme is that ICI treatment can significantly impact upon the tolerability of coadministered medications. Numerous reports in literature indicate that ICIs may alter the immunological perception of coadministered drugs, resulting in undesirable reactions to a variety of concomitant medications. These reactions can be severe in manifestation, including hepatotoxicity and Stevens-Johnson Syndrome (SJS)/toxic epidermal necrolysis (TEN), but may also have detrimental impact on malignancy control. To minimize the impact of such drug-drug interactions on patients, it is imperative to identify medications that may cause these reactions, understand the underlying mechanisms, consider the timing and dosing of comedication, and explore alternative medications with comparable efficacies. Improving our understanding of how concomitant medications affect the safety and efficacy of ICIs can allow for potential culprit drugs to be identified/removed/desensitized. This approach will allow the continuation of ICI therapy that may have been discontinued otherwise, thereby improving malignant control and patient and drug development outcomes.

Comprehensive signal detection of delirium-associated medication using the Food and Drug Administration Adverse Event Reporting System

ObjectiveSeveral medications are associated with delirium; however, studies with adequate statistical power are limited, and it is difficult to determine the effects of the various concomitant medications used in clinical practice. Therefore, in this study, we aimed to comprehensively evaluate the safety signals of delirium-associated drugs using a spontaneous adverse event reporting system. MethodThe JAPIC AERS (Food and Drug Administration Adverse Event Reporting System pre-processed by the Japan Pharmaceutical Information Center) was used for the analysis in this pharmacovigilance study. The reporting odds ratio (ROR) for delirium was adjusted for using multivariate logistic regression analysis with sex, age, indication, and melatonin receptor agonist use, and 22 drug categories were targeted as covariates. ResultsAfter excluding patients with missing information, 7,527,568 patients were included in the study. Delirium signals were detected even after adjusting for covariates in 17 drug categories, including benzodiazepines (adjusted ROR, 1.76; 95% confidence interval [CI], 1.64–1.89), opioids (adjusted ROR, 4.42; 95% CI, 4.21–4.64), and tricyclic antidepressants (adjusted ROR, 2.44; 95% CI, 2.20–2.71). ConclusionsThese findings suggest that many drug classes, such as benzodiazepines, are independent risk factors for delirium and strengthen the evidence of an association between delirium and medications.

Similar Efficacy of Mesalazine in Adult and Older Adult Ulcerative Colitis Patients: Post Hoc Analysis of a Randomized Noninferiority Trial of 1600mg vs 400mg Tablets.

The efficacy data on treatment in older adults are scarce, while the greatest increase in ulcerative colitis (UC) prevalence is observed in age groups of individuals 40 to 65 years of age and ≥65 years of age. We assessed the difference in rates of clinical and endoscopic response and remission in UC adults (≤60 years) and older adults (>60 years) treated with mesalazine. We performed a post hoc analysis of data from a phase 3 noninferiority trial of 817 UC patients treated with mesalazine for 8 and additional 26 weeks in a double-blind and open-label study, respectively. We used Wilcoxon rank sum or chi-square test to analyze differences between groups and multivariable logistic regression to determine the associations between endoscopic remission as outcome (Mayo endoscopic subscore [MES] = 0 or ≤1) and independent variables including disease duration, baseline MES, age, sex, comedications, and comorbidities. Older adults had a longer disease duration, a higher number of comorbidities, concomitant medications, and higher baseline MES (2.38 ± 0.486 in older adults vs 2.26 ± 0.439 in adults; P = .008) compared with adults. We observed no difference in rates of combined clinical and endoscopic remission, clinical remission and response, and endoscopic remission and response at week 8 and 38 post-treatment. In addition to other well-known predictors of worse outcome, patients with ≥3 comedications were less likely to achieve an MES = 0 at week 8 and 38 and an MES ≤1 at week 38. We observed similar efficacy of mesalazine in adult and older adult UC patients. The increased comedication number rather than age may decrease effectiveness of UC medications, highlighting the importance of healthy aging.

Perampanel in post-stroke epilepsy: Clinical practice data from the PERampanel as Only Concomitant antiseizure medication (PEROC) study

IntroductionPost-stroke epilepsy (PSE) is one of the most common causes of acquired epilepsy. Nevertheless, there is limited evidence regarding the clinical profile of antiseizure medications (ASMs) in PSE. This study aims to evaluate the 12-month effectiveness and tolerability of perampanel (PER) used as only add-on treatment in patients with PSE in a real-world setting. MethodsWe performed a subgroup analysis of PSE patients included in a previous retrospective, longitudinal, multicentre observational study on adults. Treatment discontinuation, seizure frequency and adverse events were collected at 3, 6 and 12 months. Sub-analyses by early (≤1 previous ASM) or late PER add-on were also conducted. ResultsOur analysis included 56 individuals with PSE, characterized by varying initial treatment modalities and timeframes relative to disease onset. We found notable retention rates (92.8%, 83.7%, and 69% at 3, 6, and 12 months), with treatment withdrawal mainly due to poor tolerability. One year after PER introduction, seizure frequency significantly reduced, with a responder rate (≥50% reduction) of 83.9% and a seizure-free rate of 51.6%. Adverse events occurred in 25 (46.3%) patients, mainly dizziness, irritability, and behavioural disorders. No major statistical differences were found between early (30 patients, 53.6%) and late add-on groups, except for a higher 6-month responder rate in the early add-on group. ConclusionAdjunctive PER was effective and well-tolerated in patients with PSE in a real-world setting. Perampanel demonstrated good efficacy and safety as both early and late add-on treatment, making it a compelling option for this unique patient population.

Trends in Pediatric Attention-Deficit Hyperactive Disorder Diagnoses and Prescription Utilization: 2016 to 2019.

Attention-deficit hyperactive disorder (ADHD) is one of the most common psychiatric disorders among children, with estimated prevalence of 7% to 15% worldwide. The aim of this analysis was to update and summarize trends in diagnosis, demographics, and drug utilization of pediatric patients with ADHD. We used the Agency for Health care Research and Quality Medical Expenditure Panel Survey (MEPS), a survey of US individuals, families, their medical providers, and employers, using datasets from 2016 to 2019. The data sources from the MEPS database included the full-year consolidated files, medical conditions files, prescribed-medicines files, and condition-event link files for each year. We summarized trends in the proportion of children, ages 17 years and younger, with a diagnosis of ADHD, demographic information and a prescription for medication known to treat ADHD. In addition, we further stratified ADHD medication use by stimulant/nonstimulant categories. There was a 1.6% and 4.7% absolute increase in children with an ADHD diagnosis and those prescribed ADHD medications, respectively, from 2016 to 2019. Most of these children were male, non-Hispanic, and on public insurance. Of the children prescribed an ADHD medication and concomitant behavioral medications, stimulants-only use was the highest (60%-67%), followed by stimulants/nonstimulants (13%-15%), stimulant/antidepressants (6%-9%), and nonstimulants only (5%-9%). The proportion of patients with ADHD in the high-income and near-poor categories increased by 4% from 2016 to 2019. Diagnosis of ADHD among children is trending upward in the United States. Central nervous system stimulants, especially methylphenidate formulations, are the most prescribed ADHD medications for children 17 years and younger.

Prevalence and Factors Associated with De-escalation of Anti-TNFs in Older Adults with Rheumatoid Arthritis: A Medicare Claims-Based Observational Study.

The aim was to evaluate prevalence and factors associated with anti-tumor necrosis factor (anti-TNF) de-escalation in older adults with rheumatoid arthritis (RA). We identified adults ≥66 years of age with RA on anti-TNF therapy within 6 months after RA diagnosis with at least 6-7 months duration of use (proxy for stable use), using 20% Medicare data from 2008-2017. Patient demographic and clinical characteristics, including concomitant use of glucocorticoid (GC), were collected. Anti-TNF use was categorized as either de-escalation (identified by dosing interval increase, dose reduction, or cessation of use) or continuation. We used (1) an observational cohort design with Cox regression to assess patient characteristics associated with de-escalation and (2) a case-control design with propensity score-adjusted logistic regression to assess the association of de-escalation with different clinical conditions and concomitant medication use. We identified 5106 Medicare beneficiaries with RA on anti-TNF, 65.5% of whom had de-escalation. De-escalation was more likely with older age (hazard ratio [HR] 1.01, 95% confidence interval [CI] 1.01-1.02) or greater comorbidity (HR 1.07, 95% CI 1.05-1.09), but was less likely with low-income subsidy status (HR 0.85, 95% CI 0.78-0.92), adjusting for patient sex and race/ethnicity. Lower odds of de-escalation were associated with serious infection (odds ratio [OR] 0.79, 95% CI 0.66-0.94), new heart failure diagnosis (OR 0.70, 95% CI 0.52-0.95), and long-term GC use (OR 0.84, 95% CI 0.74-0.95), whereas higher odds were associated with concomitant methotrexate use (OR 1.16, 95% CI 1.03-1.31). Anti-TNFs are de-escalated in two-thirds of older adults with RA in usual care. Further study is needed on RA outcomes after anti-TNF de-escalation.

DIPG-31. IS RE-IRRADIATION A POTENTIAL SURVIVAL BENEFIT FOR PATIENTS WITH DIFFUSE INTRINSIC PONTINE GLIOMA?

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is an aggressive infiltrative glioma with dismal prognosis. Radiation therapy (RT) offers a transient benefit and re-irradiation (reRT) may be an option at disease progression. OBJECTIVE To evaluate the outcome of patients with DIPG at progression in a single institution. METHODS Between 2010-2023, 55 patients were evaluated, retrospectively, in respect of their treatment-one RT course versus re-RT) and concomitant medications. Overall survival (OS) was measured from diagnosis to date of death and from reRT to death using Kaplan–Meier and log-rank test. RESULTS Median age was 7.1 years (range 2.9-16.2y). Twenty-two patients underwent biopsy with 11 performing immunohistochemistry for H3K27M (9 mutated). In nine cases molecular analyses was evaluated: 6 H3.3K27M-mutant (2 simultaneously TP53 + 1PTPRZ1-MET fusion), 1 H3.1K27M-mutant, 1 H3C2-mutant + ACVR1 mutation and 1 PDGFRA + KIT amplifications. Thirty-five patients completed the initial course of RT (54Gy- 13-33 daily fraction), 30/35 also received valproic acid (VA), 5/35 bevacizumab, 3/35 nimotuzumab and 1/35 nivolumab+ipilimumab. Twenty patients underwent re-RT at first progression, four with 54 Gy (30x 180Gy), nine with 50Gy (25x 200Gy) and seven with median dose of 30Gy (26-39Gy), depending on their clinical status. These group also received valproic acid(8/20), bevacizumab(8/20), nivolumab(1/20) and ONC 201(1/20). Patients who received reRT showed prolonged OS compared to no reRT (median 524 vs 351 days; p=0.013). ReRT was well tolerated with 15(75%) patients experiencing stable to improved neurologic function. Patients with better clinical status and 50-54Gy reRT doses, showed prolonged OS (median 238 vs 135 days; p=0.1). Median OS from re-RT to death was 174 days (range, 14-218 days) with eight patients alive to date. CONCLUSIONS Re-irradiation with 50-54Gy seems safe and feasible for DIPG patients after disease progression from the first treatment, with mostly patients experiencing neurological improvement and prolonged life period.

A Genome-Wide Association Study of Oxypurinol Concentrations in Patients Treated with Allopurinol.

Cohort studies have identified several genetic determinants that could predict the clinical response to allopurinol. However, they have not been commonly used for genome-wide investigations to identify genetic determinants on allopurinol metabolism and concentrations. We conducted a genome-wide association study of a prior cross-sectional investigation of patients from the Montreal Heart Institute Biobank undergoing allopurinol therapy. Four endpoints were investigated, namely plasma concentrations of oxypurinol, the active metabolite of allopurinol, allopurinol, and allopurinol-riboside, as well as allopurinol daily dosing. A total of 439 participants (mean age 69.4 years; 86.4% male) taking allopurinol (mean daily dose 194.5 mg) and who had quantifiable oxypurinol concentrations were included in the genome-wide analyses. Participants presented with multiple comorbidities and received concomitant cardiovascular medications. No association achieved the predefined genome-wide threshold values for any of the endpoints (all p > 5 × 10-8). Our results are consistent with prior findings regarding the difficulty in identifying genetic determinants of drug concentrations or pharmacokinetics of allopurinol and its metabolites, as well as allopurinol daily dosing. Given the size of this genome-wide study, collaborative investigations involving larger and diverse cohorts may be required to further identify pharmacogenomic determinants of allopurinol and measure their clinical relevance to personalize allopurinol therapy.

Drug-drug interaction and initial dosage optimization of aripiprazole in patients with schizophrenia based on population pharmacokinetics.

The present study aimed to investigate the drug-drug interaction and initial dosage optimization of aripiprazole in patients with schizophrenia based on population pharmacokinetics. A total of 119 patients with schizophrenia treated with aripiprazole were included to build an aripiprazole population pharmacokinetic model using nonlinear mixed effects. The weight and concomitant medication of fluoxetine influenced aripiprazole clearance. Under the same weight, the aripiprazole clearance rates were 0.714:1 in patients with or without fluoxetine, respectively. In addition, without fluoxetine, for the once-daily aripiprazole regimen, dosages of 0.3 and 0.2 mg kg-1 day-1 were recommended for patients with schizophrenia weighing 40-95 and 95-120 kg, respectively, while for the twice-daily aripiprazole regimen, 0.3 mg kg-1 day-1 was recommended for those weighing 40-120 kg. With fluoxetine, for the once-daily aripiprazole regimen, a dosage of 0.2 mg kg-1 day-1 was recommended for patients with schizophrenia weighing 40-120 kg, while for the twice-daily aripiprazole regimen, 0.3 and 0.2 mg kg-1 day-1 were recommended for those weighing 40-60 and 60-120 kg, respectively. This is the first investigation of the effects of fluoxetine on aripiprazole via drug-drug interaction. The optimal aripiprazole initial dosage is recommended in patients with schizophrenia.

Effects of catheter-based renal denervation in hypertension: a systematic review and meta-analysis.

Several sham-controlled trials have investigated the efficacy and safety of catheter-based renal denervation (RDN) with mixed outcomes. To perform a comprehensive meta-analysis of all randomized, sham-controlled trials investigating RDN with first- and second-generation devices in hypertension. We searched MEDLINE and Cochrane Library for eligible trials. Outcomes included both efficacy (24-hour and office systolic [SBP] and diastolic blood pressure [DBP]) and safety (all-cause death, vascular complication, renal artery stenosis >70%, hypertensive crisis) of RDN. We performed a study-level, pairwise, random-effects meta-analysis of the summary data. Ten trials comprising 2,478 patients with hypertension while being either off- or on-treatment were included. Compared with sham, RDN reduced 24-hour and office systolic BP by 4.4 mmHg (95%CI -6.1, -2.7, p<0.00001) and 6.6 mmHg (95%CI -9.7, -3.6, p<0.0001), respectively. The 24-hour and office diastolic BP paralleled these findings (-2.6 mmHg, 95%CI - 3.6, -1.5, p<0.00001; -3.5 mmHg, 95%CI -5.4, -1.6, p=0.0003). There was no difference in 24-hour and office SBP reduction between trials with and without concomitant antihypertensive medication (p for interaction 0.62 and 0.73, respectively). There was no relevant difference concerning vascular complications (OR 1.69, 95%CI 0.57-5.0, p=0.34), renal artery stenosis (OR 1.50, 95%CI 0.06-36.97, p=0.80), hypertensive crisis (OR 0.65, 95%CI 0.30-1.38, p=0.26) and all-cause death (OR 1.76, 95%CI 0.34-9.20, p=0.50) between RDN and sham groups. Change of renal function based on eGFR was comparable between groups (p for interaction 0.84). There was significant heterogeneity between trials. RDN safely reduces ambulatory and office SBP/DBP vs. a sham procedure in the presence and absence of antihypertensive medication. What is new?Several sham-controlled trials have investigated the efficacy and safety of catheter-based renal denervation (RDN) with mixed outcomes.This comprehensive meta-analysis comprising 2,478 patients shows that irrespective of the utilized method (radiofrequency-, ultrasound-or alcohol-mediated), renal denervation effectively reduced ambulatory and office systolic blood pressure.Renal denervation exhibited no additional risk concerning vascular injury or renal function impairment.What are the clinical implications?This meta-analysis supports current guidelines/consensus statements that renal denervation represents an additive treatment option in carefully selected patients with uncontrolled hypertension.

Real-life effectiveness of sacubitril/valsartan in older Belgians with heart failure, reduced ejection fraction and most severe symptoms

We assessed the real-world effectiveness of sacubitril/valsartan in patients with chronic heart failure (HF) and reduced ejection fraction (HFrEF) with an emphasis on those with older age (≥ 75 years) or with New York Heart Association (NYHA) class IV, for whom greater uncertainty existed regarding clinical outcomes. We conducted a retrospective cohort study based on patient-level linkage of electronic healthcare datasets. Data from all adults with HFrEF in Belgium receiving a prescription for sacubitril/valsartan between 01-November-2016 and 31-December-2018 were collected, with a follow-up of > 6 years. The total study population comprised 5446 patients, older than the PARADIGM-HF trial participants, and with higher NYHA class (all P < 0.0001). NYHA class improved following sacubitril/valsartan initiation (P < 0.0001 baseline vs. reassessment). Most concomitant medications were reduced. Remarkably, the risk of hospitalization for a cardiovascular reason and for HF was reduced by > 26% in the overall cohort, and in subgroups of patients ≥ 75 years, with NYHA class III/IV (all P < 0.0001) or with NYHA class IV (P < 0.05), vs. baseline. All-cause mortality did not increase in real-world patients with NYHA class III/IV. The results support the long-term beneficial effects of sacubitril/valsartan in older patients and in those experiencing the most severe symptoms.

Evaluation of PET/CT imaging with [89Zr]Zr-DFO-girentuximab: a phase 1 clinical study in Japanese patients with renal cell carcinoma (Zirdac-JP).

PET/CT imaging with Zirconium-89 labeled [89Zr]Zr-DFO-girentuximab, which targets tumor antigen CAIX, may aid in the differentiation and characterization of clear cell renal cell carcinomas (RCC) and other renal and extrarenal lesions, and has been studied in European and American cohorts. We report results from a phase I study that evaluated the safety profile, biodistribution, and dosimetry of [89Zr]Zr-DFO-girentuximab in Japanese patients with suspected RCC. Eligible adult patients received 37MBq (± 10%; 10mg mass dose) of intravenous [89Zr]Zr-DFO-girentuximab. Safety and tolerability profile was assessed based on adverse events, concomitant medications, physical examination, vital signs, hematology, serum chemistry, urinalysis, human anti-chimeric antibody measurement, and 12-lead electrocardiograms at predefined intervals. Biodistribution and normal organ and tumor dosimetry were evaluated with PET/CT images acquired at 0.5, 4, 24, 72h and Day 5±2d after administration. [89Zr]Zr-DFO-girentuximab was administered in six patients as per protocol. No treatment-emergent adverse events were reported. Dosimetry analysis showed that radioactivity was widely distributed in the body, and that the absorbed dose in healthy organs was highest in the liver (mean±standard deviation) (1.365±0.245mGy/MBq), kidney (1.126±0.190mGy/MBq), heart wall (1.096±0.232mGy/MBq), and spleen (1.072±0.466mGy/MBq). The mean effective dose, adjusted by the radioactive dose administered, was 0.470mSv/MBq. The radiation dose was highly accumulated in the targeted tumor, while any abnormal accumulation in other organs was not reported. This study demonstrates that [89Zr]Zr-DFO-girentuximab administered to Japanese patients with suspected RCC has a favorable safety profile and is well tolerated and has a similar dosimetry profile to previously studied populations.