Quantification of unbound concentration of ticagrelor in plasma as a proof of mechanism biomarker of the reversal agent, MEDI2452

There is an increased use of oral anticoagulants for the prevention of venous and arterial thrombosis. Vitamin-K antagonists have been used for decades as the main oral anticoagulants but they have the draback a complex therapeutic management, slow onset of action and by a different oral intake caused by dietary vitamin K intake. New non-vitamin K antagonist oral anticoagulants (NOACs) have been developed to overcome the limitations of warfarin. Their management is easier as it requires a fixed daily dose without coagulation monitoring. Although their therapeutic profile is safe, proper attention should be paid in case of unexpected need for the reversal of their coagulation effect and in case a patient needs to have a scheduled surgery. For non-acute cardiac surgery, discontinuation of NOACs should start at least 48 hours prior surgery. Intracranial bleedings associated with NOACs are less dangerous comparing to those warfarin-induced. NOACs need to be stopped ≥24 hours in case of elective surgery for low bleeding-risk procedures and ≥48 hours for high bleeding-risk surgery in patients with normal renal function and 72 hours in case of reduced CrCl < 80. The therapy with NOACs should be resumed from 48 to 72 hours after the procedure depending on the perceived bleeding, type of surgery and thrombotic risks. There are some available NOAC reversal agents acting within 5 to 20 minutes. In case of lack of reversal agent, adequate diuresis, renal replacement therapy and activated charcoal in case of recent ingestion should be considered.

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Analgesic drug development: proof-of-mechanism and proof-of-concept in early phase clinical studies

Medicine in Drug Discovery ◽

10.1016/j.medidd.2021.100083 ◽

2021 ◽

Vol 10 ◽

pp. 100083

Author(s):

Hemme J. Hijma ◽

Geert Jan Groeneveld

Keyword(s):

Drug Development ◽

Clinical Studies ◽

Early Phase ◽

Proof Of Concept ◽

Analgesic Drug ◽

Proof Of Mechanism

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Preparation and application of a fluoropolymer emulsion as novel wettability reversal agent

Colloids and Surfaces A Physicochemical and Engineering Aspects ◽

10.1016/j.colsurfa.2020.125985 ◽

2021 ◽

Vol 612 ◽

pp. 125985

Author(s):

Yanling Wang ◽

Lei Liang ◽

Yongfei Li ◽

Bin Liu ◽

Longhao Tang

Keyword(s):

Reversal Agent

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Applied Nanotechnologies in Anticoagulant Therapy: From Anticoagulants to Coagulation Test Performance of Drug Delivery Systems

Applied Nano ◽

10.3390/applnano2020009 ◽

2021 ◽

Vol 2 (2) ◽

pp. 98-117

Author(s):

Yuri B. G. Patriota ◽

Luíse L. Chaves ◽

Evren H. Gocke ◽

Patricia Severino ◽

Mônica F. R. Soares ◽

...

Keyword(s):

Drug Delivery ◽

Anticoagulant Therapy ◽

Test Performance ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Delivery Systems ◽

Reversal Agent ◽

Laboratory Assessment ◽

Administration Routes

Heparin-based delivery systems have been explored to improve their therapeutic efficacy and to reduce toxicity for different administration routes. Regardless of the applied drug delivery system (DDS), the evaluation of anticoagulant performance is instrumental for the development of a suitable DDS. The understanding of the range of anticoagulant assays, together with their key applications and limitations, is essential both within the context of scientific research and for clinical usage. This review provides an overview of the current anticoagulant therapy and discusses the advantages and limitations of currently available anticoagulant assays. We also discuss studies involving low-molecular-weight heparin (LMWH)-based nanocarriers with emphasis on their anticoagulation performance. Conventional anticoagulants have been used for decades for the treatment of many diseases. Direct oral anticoagulants have overcome some limitations of heparins and vitamin K antagonists. However, the lack of an accurate laboratory assessment, as well as the lack of a factor “xaban” (Xa) inhibitor reversal agent, remains a major problem associated with these anticoagulants. LMWHs represent anticoagulant agents with noteworthy efficacy and safety, and they have been explored to improve their outcomes with various nanocarriers through several administration routes. The main problems related to LMWHs have been surmounted, and improved efficiency may be achieved through the use of DDSs.

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Oral SMN2 splicing modifiers in spinal muscular atrophy: Proof-of-mechanism and ongoing clinical studies

European Journal of Paediatric Neurology ◽

10.1016/j.ejpn.2017.04.1234 ◽

2017 ◽

Vol 21 ◽

pp. e226

Author(s):

Anne Marquet ◽

Stefan Sturm ◽

Heidemarie Kletzl ◽

Andreas Günther ◽

Christian Czech ◽

...

Keyword(s):

Spinal Muscular Atrophy ◽

Clinical Studies ◽

Muscular Atrophy ◽

Proof Of Mechanism

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Willingness to use a wearable device capable of detecting and reversing overdose among people who use opioids in Philadelphia

Harm Reduction Journal ◽

10.1186/s12954-021-00522-3 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Katie Kanter ◽

Ryan Gallagher ◽

Feyisope Eweje ◽

Alexander Lee ◽

David Gordon ◽

...

Keyword(s):

Structured Interview ◽

Wearable Device ◽

Urban Setting ◽

Opioid Overdose ◽

Opioid Use ◽

Cross Sectional Survey ◽

Reversal Agent ◽

Response Options ◽

History Of ◽

Willingness To Use

Abstract Background The incidence of opioid-related overdose deaths has been rising for 30 years and has been further exacerbated amidst the COVID-19 pandemic. Naloxone can reverse opioid overdose, lower death rates, and enable a transition to medication for opioid use disorder. Though current formulations for community use of naloxone have been shown to be safe and effective public health interventions, they rely on bystander presence. We sought to understand the preferences and minimum necessary conditions for wearing a device capable of sensing and reversing opioid overdose among people who regularly use opioids. Methods We conducted a combined cross-sectional survey and semi-structured interview at a respite center, shelter, and syringe exchange drop-in program in Philadelphia, Pennsylvania, USA, during the COVID-19 pandemic in August and September 2020. The primary aim was to explore the proportion of participants who would use a wearable device to detect and reverse overdose. Preferences regarding designs and functionalities were collected via a questionnaire with items having Likert-based response options and a semi-structured interview intended to elicit feedback on prototype designs. Independent variables included demographics, opioid use habits, and previous experience with overdose. Results A total of 97 adults with an opioid use history of at least 3 months were interviewed. A majority of survey participants (76%) reported a willingness to use a device capable of detecting an overdose and automatically administering a reversal agent upon initial survey. When reflecting on the prototype, most respondents (75.5%) reported that they would wear the device always or most of the time. Respondents indicated discreetness and comfort as important factors that increased their chance of uptake. Respondents suggested that people experiencing homelessness and those with low tolerance for opioids would be in greatest need of the device. Conclusions The majority of people sampled with a history of opioid use in an urban setting were interested in having access to a device capable of detecting and reversing an opioid overdose. Participants emphasized privacy and comfort as the most important factors influencing their willingness to use such a device. Trial registration NCT04530591.

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CTNI-22. A PHASE 0/1 ‘TRIGGER’ TRIAL OF RIBOCICLIB PLUS EVEROLIMUS IN RECURRENT HIGH-GRADE GLIOMA

Neuro-Oncology ◽

10.1093/neuonc/noab196.247 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi64-vi64

Author(s):

Nader Sanai ◽

An-Chi Tien ◽

Jun Jiang ◽

Yu-Wei Chang ◽

Chelsea Pennington-Krygier ◽

...

Keyword(s):

High Grade Glioma ◽

High Grade ◽

Mtor Inhibition ◽

Who Grade ◽

Expansion Phase ◽

Pik3ca Mutations ◽

Pten Loss ◽

Drug Concentrations ◽

Phase 0 ◽

Unbound Concentration

Abstract BACKGROUND mTOR activation is a mechanism of resistance in CDK4/6 targeting. We evaluated tumor pharmacokinetics (PK) and tumor pharmacodynamics (PD) of combined CDK4/6 and mTOR inhibition in recurrent high-grade glioma (HGG) patients. METHODS Recurrent HGG patients with (1) intact RB, (2) CDKN2A/B deletion or CDK4/6 amplification, and (3) PTEN loss or PIK3CA mutations receive five days of presurgical ribociclib plus everolimus prior to resection at 2, 8 or 24 hours after the final dose. Beginning at 400mg QD ribociclib plus 2.5mg QD everolimus, six dose-escalations summit at 600mg QD plus 60mg QW. Gadolinium [Gd]-enhancing and nonenhancing tumor regions, CSF, and plasma are collected. Total and unbound drug concentrations are determined using validated LC-MS/MS methods. RB and S6 phosphorylation are compared to matched archival tissue. To select patients for a therapeutic expansion phase of combined drug therapy, the protocol includes a PK ‘trigger’ (i.e., for each drug, unbound concentration in Gd-nonenhancing tumor > 5-fold biochemical IC50) and a PD ‘trigger’ (i.e., for each tumor, > 30% decrease in pRB and pS6). RESULTS 21 patients with WHO Grade III (n=2) and IV (n=19) gliomas were enrolled into the Phase 0 component of the study. No dose-limiting toxicities were observed. In Gd-nonenhancing tumor regions, the median unbound concentration of ribociclib was 719 nM, whereas unbound everolimus tumor concentrations were undetectable. Across all dose-levels, 62% (13/21) and 22% (5/21) of tumors demonstrated decreased tumor RB and S6 phosphorylation, respectively. Tumor proliferation (MIB-1) was decreased in 67% (14/21) of all patients. No patients qualified for the therapeutic expansion phase. CONCLUSION In adult HGG, ribociclib achieves pharmacologically-relevant concentrations in Gd-nonenhancing tumor whereas everolimus exhibits no meaningful tumor penetration. These findings support further clinical development of ribociclib, but not everolimus, for the treatment of high-grade glioma patients.

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