scholarly journals Foslevodopa/Foscarbidopa Is Well Tolerated and Maintains Stable Levodopa and Carbidopa Exposure Following Subcutaneous Infusion

2021 ◽  
pp. 1-8
Author(s):  
Matthew Rosebraugh ◽  
Wei Liu ◽  
Melina Neenan ◽  
Maurizio F. Facheris
Keyword(s):  
Steady State ◽  
Phase 1 ◽  
The United States ◽  
Therapeutic Window ◽  
Fixed Dose ◽  
Advanced Parkinson’S Disease ◽  
Subcutaneous Infusion ◽  
Study Results ◽  
Wide Range ◽  
Favorable Safety

Background: Foslevodopa/foscarbidopa, formerly known as ABBV-951, is a formulation of levodopa/carbidopa prodrugs with solubility that allows for subcutaneous (SC) infusion and is in development for the treatment of motor complications for patients with advanced Parkinson’s disease (aPD). Objective: The current work characterizes the levodopa (LD) and carbidopa (CD) pharmacokinetics (PK) following SC infusions of foslevodopa/foscarbidopa delivered at four different infusion rates in PD patients. Methods: This was a Phase 1, single ascending dose, single-blind study conducted in 28 adult male and female subjects at seven sites in the United States. Foslevodopa/foscarbidopa was administered via abdominal SC infusion in PD patients over 72 hours. Patients were stratified in 4 groups and received a fixed dose of foslevodopa/foscarbidopa based on their oral daily LD intake. Serial plasma PK samples were collected to assay for LD and CD concentrations. Safety and tolerability were assessed throughout the study. Results: LD exposure quickly reached steady state and remained stable with minimal fluctuations. Foslevodopa/foscarbidopa infusion provides stable LD and CD exposures compared to oral LD/CD dosing with the average steady-state exposure ranging from 747-4660 ng/mL for the different groups. Conclusion: Foslevodopa/foscarbidopa was able to provide stable LD and CD exposures in PD patients over 72 hours via SC route of delivery with very low fluctuation in LD concentration level across a wide range of clinically relevant exposures. Foslevodopa/foscarbidopa had a favorable safety profile. The low PK fluctuation following foslevodopa/foscarbidopa infusion is expected to maintain LD exposure to treat aPD patients within a narrow therapeutic window.

Does a plasma level of chlorpromazine help?

1981 ◽  
Vol 11 (4) ◽  
pp. 729-734 ◽  
Author(s):  
Theodore van Putten ◽  
Philip R. A. May ◽  
Donald J. Jenden
Keyword(s):  
Plasma Level ◽  
Plasma Levels ◽  
Internal Standard ◽  
Gas Chromatography Mass Spectrometry ◽  
Therapeutic Window ◽  
Fixed Dose ◽  
Speed Of Response ◽  
Wide Range ◽  
Dose Period ◽  
Schizophrenic Patients

SynopsisForty-eight newly admitted schizophrenic patients were treated with a fixed, conservative (6·6 mg/kg) dose of chlorpromazine (CPZ) for 28 days. CPZ plasma levels were measured by a gas chromatography mass spectrometry method (GCMS) using 2H6-chlorpromazine as an internal standard. At the end of the fixed-dose period, ‘responders’ had the same plasma levels as ‘non-responders’, suggesting that lack of response is primarily a matter of the illness' sensitivity to CPZ, not to a plasma level below some therapeutic window. After the fixed-dose period, the dosage of CPZ was increased in the ‘non-responders’ by physician's choice. Improvement occurred over a wide range of 10–225 picomoles (3–72 ng)/ml. Above 300 picomoles (95 ng/ml) 4 inaccessible patients eventually became much worse, suggesting psychotoxicity. It is in the inaccessible patient whose illness is only minimally, or not at all, sensitive to CPZ that a plasma level might be especially useful.Interpretation of plasma levels is complicated by the speed of response: some initial non-responders improved by the 56th day of treatment on very conservative plasma levels.

Vorasidenib (VOR; AG-881), an inhibitor of mutant IDH1 and IDH2, in patients (pts) with recurrent/progressive glioma: Updated results from the phase I non-enhancing glioma population.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2504-2504 ◽  
Author(s):  
Ingo K. Mellinghoff ◽  
Katherine B. Peters ◽  
Timothy Francis Cloughesy ◽  
Howard A. Burris III ◽  
Elizabeth Anne Maher ◽  
...  
Keyword(s):  
Phase 1 ◽  
Objective Response ◽  
Low Grade ◽  
Isocitrate Dehydrogenase 1 ◽  
Eligibility Criteria ◽  
Dual Inhibitor ◽  
Study Results ◽  
Grade 3 ◽  
Mutant Idh1 ◽  
Favorable Safety

2504 Background: Isocitrate dehydrogenase 1 and 2 mutations (m IDH1/2) occur in approximately 70% and 4% of low-grade gliomas (LGGs), respectively, promoting oncogenesis via increased production of D-2-hydroxyglutarate. In this ongoing phase 1 trial, VOR, a potent, oral, reversible, brain-penetrant, first-in-class dual inhibitor of mIDH1/2, is being evaluated in advanced m IDH1/2 solid tumors, including gliomas. Safety and preliminary results were presented previously (Mellinghoff et al., J Clin Oncol 2018). Here, we report updated data for the non-enhancing glioma pt population. Methods: Pts with recurrent/progressive m IDH1/2 glioma received VOR daily (continuous 28-day cycles). Key eligibility criteria included: ≥18 years; histologically or cytologically confirmed glioma with documented m IDH1/2; ECOG 0-2; and evaluable disease by RANO-LGG criteria. Dose escalation cohorts enrolled using a Bayesian logistic regression model (BLRM) escalation guided by the overdose control (EWOC). Tumor response was evaluated by MRI every 8 weeks using RANO-LGG criteria by local assessment. Results: As of 28 Nov 2019, 22 pts with non-enhancing glioma had received VOR and 8 (36%) remain on treatment. M/F, 8/14; grade 2/3, 17/5; median age, 47 years; m IDH1/2, 20/1; 1p19q intact, 9/22; median (range) number of prior systemic therapies, 2 (1–4). Common (≥5 pts) treatment-emergent adverse events (AEs) of any grade and regardless of causality included increased ALT/AST (63.6%/59.1%), headache (45.5%), nausea (40.9%), neutropenia (31.8%), fatigue and hyperglycemia (27.3% each), and seizures and decreased white blood cell count (22.7% each). Transaminase elevations were grade 1 in severity at dose levels < 100mg and were less frequent (5 [38.5%] of 13 pts). Three subjects had related grade ≥3 AEs; 2 discontinued due to AEs. Objective response rate was 13.6% (1 partial response, 2 minor responses), and 17 (77.3%) pts achieved stable disease. 60.5% of pts were progression free and alive at 24 months. Conclusions: In this previously treated population with non-enhancing glioma, VOR was associated with a favorable safety profile. The study results also show encouraging preliminary activity within that population, with PFS duration extending to 24 months or longer in 60% of participants. A global randomized phase 3 study of VOR in grade 2 non-enhancing glioma pts who have had surgery only is currently enrolling (NCT04164901). Clinical trial information: NCT02481154 .

scholarly journals Dysphagia Management in Schools: A Survey of Speech-Language Pathologists

2020 ◽  
Vol 5 (2) ◽  
pp. 527-546
Author(s):  
Catherine Felicetti ◽  
Kelly Richardson ◽  
Angela Mansolillo
Keyword(s):  
Service Provision ◽  
Treatment Plan ◽  
The United States ◽  
Speech Language Pathologists ◽  
School Based ◽  
Study Results ◽  
Wide Range ◽  
Pediatric Feeding ◽  
Survey Responses

Purpose To date, few studies have examined school-based pediatric feeding and swallowing practices across the United States. This study aims to (a) identify barriers to feeding and swallowing service provision in an educational setting and (b) identify the types of service suggested by school-based speech-language pathologists in response to a fictional case study. Method School-based speech-language pathologists and clinical fellows were invited to participate in a 15-min web-based survey. The survey questions addressed demographic and vocational information and perceived barriers to service provision. Survey respondents were also asked to develop a treatment plan in response to a fictional case study. In total, 200 anonymous survey responses were coded and analyzed using qualitative analysis methods. Results A number of barriers to practice were identified, which include academic and/or clinical preparedness and concerns related to the educational relevance of service. Analysis of the case study results indicated a wide range of treatment plans. The most common type of direct intervention suggested was an oral motor exercise regime, followed by diet modifications, and the implementation of safe swallow strategies. Conclusions Information gained in this study may be used to support policies and protocols related to the assessment and treatment of pediatric feeding and swallowing impairment in school settings.

Results and Recommendations From a National Public Health Workforce Development Systems Assessment Conducted in the United States

2020 ◽  
pp. 237337992090764
Author(s):  
Christina R. Welter ◽  
Betty Bekemeier ◽  
Jennifer McKeever
Keyword(s):  
Public Health ◽  
United States ◽  
Workforce Development ◽  
Health Workforce ◽  
Phase 1 ◽  
The United States ◽  
Public Health Workforce ◽  
Public Health Training ◽  
Wide Range ◽  
Health Workforce Development

Multiple public health workforce development assessments report individual worker knowledge and skill-based training needs. These assessments do not capture practitioners’ in-depth perceptions of complex public health challenges and whether workforce development approaches address these issues. To address this gap, the Public Health Learning Network—a national coalition of 10 Regional Public Health Training Centers located at United States accredited schools of public health, their partners, and the National Network of Public Health Institutes—conducted a public health workforce development assessment using a two-phased mixed-method design to explore systems-level gaps and opportunities for improving workforce development effectiveness. Phase 1 included a content analysis of major public health workforce development reports and peer-reviewed literature. Phase 2 included primary qualitative data collection of key informant interviews and focus groups via conference call with 43 participants representing 41 public health organizations at the local, state, and national levels. Results included a wide range of challenges with an emphasis on major systems changes, the shift in public health’s role to more effectively build community collective capacity, limited staff capacity and capability, and the need for more flexible and integrated training funding. Public health workforce development approaches recommended to address these challenges included improving pedagogical approaches toward more integrated, multimodal training delivered over time; increasing workforce capacity to address complex challenges such as racism and housing; and facilitating public health workforce development system coordination and alignment. Public Health Learning Network’s workforce assessment also identified opportunities for conceptualizing the definition and delivery of training toward ongoing learning.

scholarly journals 734. Modeling the Pharmacokinetics and Pharmacodynamics of Intravenous and Oral Omadacycline with and without a Loading Dose

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S329-S329
Author(s):  
Lawrence Friedrich ◽  
Marla Curran ◽  
Surya Chitra ◽  
Amy Manley ◽  
Stephen Bai ◽  
...  
Keyword(s):  
Steady State ◽  
Bacterial Pneumonia ◽  
Phase 1 ◽  
The United States ◽  
Clinical Impact ◽  
Loading Dose ◽  
Pharmacokinetics And Pharmacodynamics ◽  
Dosing Regimens ◽  
The Impact

Abstract Background Omadacycline (OMC) is an intravenous (IV) and oral aminomethylcycline antibiotic in the tetracycline class approved in the United States to treat acute bacterial skin and skin structure infections (ABSSSI) and community-acquired bacterial pneumonia (CABP) in adults. The approved dosing regimens of OMC include a loading dose designed to achieve steady-state exposures early in the course of therapy. We assessed the impact on OMC exposure and subsequent pharmacodynamics (PD) on Day 2 and at steady state (Day 5) in the situation where a loading dose may not be given. Methods Phase 1 pharmacokinetic (PK) data were used to determine OMC exposure on Day 2 and at steady state (Day 5) for the following: IV regimens 100 mg IV q12h on Day 1 then 100 mg IV QD (load), 100 mg IV QD (no load); and oral regimens 450 mg oral QD on Days 1 and 2 then 300 mg QD (load) and 300 mg oral QD (no load). AUCs on Day 2 and Day 5 for no-load regimens were compared with the regimens with loading doses. Additionally, AUC:MIC ratios were calculated using OMC MIC90 for two main pathogens of interest in ABSSSI and CABP, respectively, Staphylococcus aureus (0.25 mg/L) and Streptococcus pneumoniae (0.12 mg/L). In vivo AUC:MIC targets for stasis and 1-log kill used were 21.9 and 57.7 (S. aureus) and 31.2 and 65.8 (S. pneumoniae). Results Day 2 and 5 AUCs are shown in the Figure. AUCs on Day 2 were lower for the two regimens without loading doses and were 72% (IV) and 73% (oral) of those with a loading dose. However, at steady state on Day 5, no-load regimen AUCs were essentially the same at 98% for both the IV and oral regimens. Despite lower AUCs on Day 2 for the no-load regimens, the AUC:MIC ratio would still be expected to exceed the stasis threshold for both pathogens and the 1-log kill threshold for S. pneumoniae (figure). This same pattern was also noted on Day 5. Conclusion Exposure as assessed using AUC was lower early on in therapy on Day 2 for both IV and oral regimens. However, exposures were not different on Day 5 at steady state. Despite lower exposure on Day 2, OMC would still be expected to meet or exceed PK/PD thresholds associated with stasis for S. aureus and S. pneumoniae. The 1-log kill threshold was exceeded for S. pneumoniae. Further studies are needed to confirm any clinical impact of the omission of OMC loading doses. Disclosures All authors: No reported disclosures.

BOS172738, a highly potent and selective RET inhibitor, for the treatment of RET-altered tumors including RET-fusion+ NSCLC and RET-mutant MTC: Phase 1 study results.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3008-3008
Author(s):  
Patrick Schoffski ◽  
Byoung Chul Cho ◽  
Antoine Italiano ◽  
Herbert H. F. Loong ◽  
Christophe Massard ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Dose Escalation ◽  
Safety Profile ◽  
Phase 1 ◽  
Brain Lesion ◽  
Therapeutic Window ◽  
Clinical Activity ◽  
Phase 1 Study ◽  
Multiple Tumor ◽  
Study Results

3008 Background: RET (REarranged during Transfection) gene alterations (mutations and fusions) leading to constitutive kinase activity are identified as drivers of disease progression in multiple tumor types, including non-small cell lung cancer (NSCLC) and medullary thyroid cancer (MTC). BOS172738 is an investigational, potent, selective oral RET kinase inhibitor. This next-generation inhibitor was designed with nanomolar potency against RET and >300-fold selectivity against vascular endothelial growth factor receptor 2, to maximize the potential therapeutic window. Methods: NCT03780517 is a phase 1 study consisting of a dose-escalation and dose-expansion phase. During the escalation, 67 patients with RET-altered advanced solid tumors received once-daily oral doses of BOS172738 (10-150 mg). Intra-patient dose escalation was allowed as was over-accrual to dose levels deemed to be safe. Study endpoints were safety (CTCAE v. 4.03), tolerability and confirmed overall response rate (ORR; RECIST 1.1). The data cutoff was Dec. 11, 2020. Results: BOS172738 exhibited a favorable safety profile (n=67) for long-term administration with most treatment-emergent adverse events (TEAEs) classified as grade ≤2 and deemed unrelated to drug. The most common TEAEs were creatinine phosphokinase (CPK) increase (54%), dyspnea (34%), facial edema, aspartate aminotransferase elevation, anemia (25% each), neutropenia, diarrhea (22% each), fatigue (21%), and constipation (20%). BOS172738 was not associated with hypertension or significant hepatoxicity. BOS172738 demonstrated broad anti-tumor activity with an investigator-assessed ORR of 33% (n=18/54), a NSCLC ORR of 33% (n=10/30), MTC ORR of 44% (n=7/16, including 1 complete response) and one patient with RET fusion+ pancreatic cancer reported a partial response. Responders included patients with brain metastases with one patient whose brain lesion decreased by 43%. The median duration of response has not been reached. Many patients remain on study, including the longest of 659 days, at data cutoff. BOS172738 exhibited dose-dependent exposure (AUC, Cmax), rapid absorption (median Tmax 1 to 4.5 h), and an extended half-life (approximately 65 hours) maximizing target coverage. Conclusions: BOS172738 is a highly potent and selective RET inhibitor with a differentiated safety profile and clinical activity against RET-altered tumors, including patients with brain metastases. BOS172738 continues to be evaluated in patients with NSCLC, MTC, and in patients previously treated with other selective RET inhibitors. Clinical trial information: NCT03780517.

scholarly journals Phase 1 healthy volunteer willingness to participate and enrollment preferences

2017 ◽  
Vol 14 (5) ◽  
pp. 537-546 ◽  
Author(s):  
Stephanie C Chen ◽  
Ninet Sinaii ◽  
Gabriella Bedarida ◽  
Mark A Gregorio ◽  
Ezekiel Emanuel ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Side Effects ◽  
Healthy Volunteers ◽  
Financial Incentives ◽  
Phase 1 ◽  
The United States ◽  
Willingness To Participate ◽  
Invasive Procedures ◽  
Wide Range ◽  
Human Vaccine

Background/aims: Healthy volunteers in phase 1 clinical trials contribute to the development of safe drugs and other biologics and accept risks and burdens without anticipated health benefits from participation. Although emerging data have shown that healthy volunteers are influenced by risk, some still worry that financial incentives lead them to take on unreasonable risk. Yet little is known about healthy volunteers’ preferences and how they make choices about enrolling in research studies. Methods: We surveyed 654 healthy volunteers at the end of their participation in a phase 1 Pfizer trial in the United States, Belgium, and Singapore to examine their reported willingness to enroll in studies of different types, with various procedures, and with possible side-effects. Results: The majority of respondents were willing to join many kinds of studies, but fewer were willing to participate in first-in-human vaccine studies or studies of psychiatric drugs than in other study types. With regard to procedures, a substantial proportion were unwilling to participate in studies that involved invasive procedures, such as a lumbar puncture (45.4%) and bone marrow biopsy (42.3%), but willing to participate in studies with less invasive procedures such as a computed tomography scan of the heart (86.8%), magnetic resonance imaging (87.4%), and skin allergy testing (86.8%). Although there was some variation by gender and region, the majority were willing to participate in studies with side-effects like pain (80%) or nausea and vomiting (64%), but only a minority were willing to join if the research drug would result in their having a one in a million chance of death (34.4%), a small chance of kidney damage (16.7%), or influence how their mind works (23.2%; Figure 4). Conclusion: Our results suggest that healthy volunteers are willing to participate in a wide range of types of phase 1 clinical trials, and express preferences for low risk and familiar studies and study procedures, preferences which are partially affected by offers of payment.

Residual homing of α4β7-expressing β1+PI16+ regulatory T cells with potent suppressive activity correlates with exposure-efficacy of vedolizumab

Gut ◽  
2021 ◽  
pp. gutjnl-2021-324868
Author(s):  
Emily Becker ◽  
Mark Dedden ◽  
Christine Gall ◽  
Maximilian Wiendl ◽  
Arif Bülent Ekici ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Subset ◽  
Therapeutic Window ◽  
Fixed Dose ◽  
Cell Trafficking ◽  
Wide Range ◽  
Functional Consequences ◽  
Exposure Levels

ObjectiveThe anti-α4β7 integrin antibody vedolizumab is administered at a fixed dose for the treatment of IBDs. This leads to a wide range of serum concentrations in patients and previous studies had suggested that highest exposure levels are associated with suboptimal clinical response. We aimed to determine the mechanisms underlying these non-linear exposure-efficacy characteristics of vedolizumab.DesignWe characterised over 500 samples from more than 300 subjects. We studied the binding of vedolizumab to T cells and investigated the functional consequences for dynamic adhesion, transmigration, gut homing and free binding sites in vivo. Employing single-cell RNA sequencing, we characterised α4β7 integrin-expressing T cell populations ‘resistant’ to vedolizumab and validated our findings in vitro and in samples from vedolizumab-treated patients with IBD. We also correlated our findings with a post-hoc analysis of the Gemini II and III studies.ResultsRegulatory T (TReg) cells exhibited a right-shifted vedolizumab binding profile compared with effector T (TEff) cells. Consistently, in a certain concentration range, the residual adhesion, transmigration, homing of and availability of functional α4β7 on TReg cells in vivo was higher than that of/on TEff cells. We identified a vedolizumab-‘resistant’ α4β7-expressing β1+PI16+ TReg cell subset with pronounced regulatory properties as the substrate for this effect. Our observations correlated with exposure-efficacy data from Gemini II and III trials.ConclusionCompletely blocking TEff cell trafficking with vedolizumab, while simultaneously permitting residual homing of powerful TReg cells in an optimal ‘therapeutic window’ based on target exposure levels might be a strategy to optimise treatment outcomes in patients with IBD.

scholarly journals The Evolution in Anxiety and Depression with the Progression of the Pandemic in Adult Populations from Eight Countries and Four Continents

2021 ◽  
Vol 18 (9) ◽  
pp. 4845
Author(s):  
Mélissa Généreux ◽  
Philip J. Schluter ◽  
Elsa Landaverde ◽  
Kevin KC Hung ◽  
Chi Shing Wong ◽  
...  
Keyword(s):  
Mental Health ◽  
Sense Of Coherence ◽  
Online Survey ◽  
Phase 1 ◽  
Weak Sense ◽  
The United States ◽  
The Philippines ◽  
Country Level ◽  
Important Variation ◽  
Wide Range

Nearly a year after the classification of the COVID-19 outbreak as a global pandemic, it is clear that different factors have contributed to an increase in psychological disorders, including public health measures that infringe on personal freedoms, growing financial losses, and conflicting messages. This study examined the evolution of psychosocial impacts with the progression of the pandemic in adult populations from different countries and continents, and identified, among a wide range of individual and country-level factors, which ones are contributing to this evolving psychological response. An online survey was conducted in May/June 2020 and in November 2020, among a sample of 17,833 adults (Phase 1: 8806; Phase 2: 9027) from eight countries/regions (Canada, the United States, England, Switzerland, Belgium, Hong Kong, the Philippines, New Zealand). Probable generalized anxiety disorder (GAD) and major depressive episode (MDE) were assessed. The independent role of potential factors was examined using multilevel logistic regression. Probable GAD or MDE was indicated by 30.1% and 32.5% of the respondents during phases 1 and 2, respectively (a 7.9% increase over time), with an important variation according to countries/regions (range from 22.3% in Switzerland to 38.8% in the Philippines). This proportion exceeded 50% among young adults (18–24 years old) in all countries except for Switzerland. Beyond young age, several factors negatively influenced mental health in times of pandemic; important factors were found, including weak sense of coherence (adjusted odds ratio aOR = 3.89), false beliefs (aOR = 2.33), and self-isolation/quarantine (aOR = 2.01). The world has entered a new era dominated by psychological suffering and rising demand for mental health interventions, along a continuum from health promotion to specialized healthcare. More than ever, we need to innovate and build interventions aimed at strengthening key protective factors, such as sense of coherence, in the fight against the adversity caused by the concurrent pandemic and infodemic.

Music after the Fall

2017 ◽  
Author(s):  
Tim Rutherford-Johnson
Keyword(s):  
New Media ◽  
Contemporary Music ◽  
The United States ◽  
Art Music ◽  
Sound Art ◽  
Musical Composition ◽  
Western Art ◽  
Wide Range ◽  
Definition Of ◽  
The Cold War

By the start of the 21st century many of the foundations of postwar culture had disappeared: Europe had been rebuilt and, as the EU, had become one of the world’s largest economies; the United States’ claim to global dominance was threatened; and the postwar social democratic consensus was being replaced by market-led neoliberalism. Most importantly of all, the Cold War was over, and the World Wide Web had been born. Music After The Fall considers contemporary musical composition against this changed backdrop, placing it in the context of globalization, digitization, and new media. Drawing on theories from the other arts, in particular art and architecture, it expands the definition of Western art music to include forms of composition, experimental music, sound art, and crossover work from across the spectrum, inside and beyond the concert hall. Each chapter considers a wide range of composers, performers, works, and institutions are considered critically to build up a broad and rich picture of the new music ecosystem, from North American string quartets to Lebanese improvisers, from South American electroacoustic studios to pianos in the Australian outback. A new approach to the study of contemporary music is developed that relies less on taxonomies of style and technique, and more on the comparison of different responses to common themes, among them permission, fluidity, excess, and loss.

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