Establishing “abuse-deterrence equivalence” for generic abuse-deterrent opioid formulations: A proposed development framework

Abuse-deterrent formulations are one strategy for mitigating the epidemic of prescription opioid abuse. Regulatory guidance documents describe the requirements for developing abuse-deterrent formulations of novel drugs and formulations; however, they do not address “abuse-deterrence equivalence” for generic formulations. As generics may be produced with different excipients and formulations compared to reference drugs, differences in their properties may impact their abuse-deterrent features. Currently, it is unclear what specific studies are needed to support generic abuse-deterrence claims. This commentary outlines several recommendations on the in vitro and in vivo testing required, including the conditions for conducting a human abuse potential study.

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Linking Epigenomics With Prescription Opioid Abuse and High Impact Musculoskeletal Pain

Case Medical Research ◽

10.31525/ct1-nct03947749 ◽

2019 ◽

Author(s):

Keyword(s):

Musculoskeletal Pain ◽

High Impact ◽

Opioid Abuse ◽

Prescription Opioid ◽

Prescription Opioid Abuse

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Current Challenges in the Development of Vaccines and Drugs Against Emerging Vector-borne Diseases

Current Medicinal Chemistry ◽

10.2174/0929867325666181105121146 ◽

2019 ◽

Vol 26 (16) ◽

pp. 2974-2986 ◽

Cited By ~ 4

Author(s):

Kwang-sun Kim

Keyword(s):

New Host ◽

In Vivo Models ◽

Vector Borne Diseases ◽

Novel Drugs ◽

Huge Impact ◽

Tick Borne Disease ◽

Vector Borne ◽

Living Organisms

Vectors are living organisms that transmit infectious diseases from an infected animal to humans or another animal. Biological vectors such as mosquitoes, ticks, and sand flies carry pathogens that multiply within their bodies prior to delivery to a new host. The increased prevalence of Vector-Borne Diseases (VBDs) such as Aedes-borne dengue, Chikungunya (CHIKV), Zika (ZIKV), malaria, Tick-Borne Disease (TBD), and scrub typhus has a huge impact on the health of both humans and livestock worldwide. In particular, zoonotic diseases transmitted by mosquitoes and ticks place a considerable burden on public health. Vaccines, drugs, and vector control methods have been developed to prevent and treat VBDs and have prevented millions of deaths. However, development of such strategies is falling behind the rapid emergence of VBDs. Therefore, a comprehensive approach to fighting VBDs must be considered immediately. In this review, I focus on the challenges posed by emerging outbreaks of VBDs and discuss available drugs and vaccines designed to overcome this burden. Research into promising drugs needs to be upgraded and fast-tracked, and novel drugs or vaccines being tested in in vitro and in vivo models need to be moved into human clinical trials. Active preventive tactics, as well as new and upgraded diagnostics, surveillance, treatments, and vaccination strategies, need to be monitored constantly if we are to manage VBDs of medical importance.

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Aspiration Revisited: Prospective Evaluation of a Physiologically Pressurized Model With Animal Correlation and Broader Applicability to Filler Complications

Aesthetic Surgery Journal ◽

10.1093/asj/sjab194 ◽

2021 ◽

Author(s):

Hyoung-Jin Moon ◽

Won Lee ◽

Ji-Soo Kim ◽

Eun-Jung Yang ◽

Hema Sundaram

Keyword(s):

Normal Saline ◽

False Negative ◽

Vascular Complications ◽

Filler Injection ◽

Negative Results ◽

Needle Position ◽

False Negative Results ◽

In Vivo Testing

Abstract Background Aspiration testing before filler injection is controversial. Some believe that aspiration can help prevent inadvertent intravascular injection, while others cite false-negative results and question its value given that the needle position always changes somewhat during injection procedures. Objectives To test the relation of false-negative results to the viscosity of the material within the needle lumen and determine whether a less viscous material within the needle lumen could decrease the incidence of false-negative results. Methods In vitro aspiration tests were performed using 30-G and 27-G needle gauges, two cross-linked hyaluronic acid fillers, normal saline bags pressurized at 140 and 10 mmHg to mimic human arterial and venous pressures, and three needle lumen conditions (normal saline, air, and filler). Testing was repeated three times under each study condition (72 tests in total). For in vivo correlation, aspiration tests were performed on femoral arteries and central auricular veins in three rabbits (4–5 aspirations per site, 48 tests in total). Results In vitro and in vivo testing using 30-G needles containing filler both showed false-negative results on aspiration testing. In vitro and in vivo testing using needles containing saline or air showed positive findings. Conclusions False-negative results from aspiration testing may be reduced by pre-filling the needle lumen with saline rather than a filler. The pressurized system may help overcome challenges of animal models with intravascular pressures significantly different from those of humans. The adaptability of this system to mimic various vessel pressures may facilitate physiologically relevant studies of vascular complications.

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Effective decellularisation of human saphenous veins for biocompatible arterial tissue engineering applications: Bench optimisation and feasibility in vivo testing

Journal of Tissue Engineering ◽

10.1177/2041731420987529 ◽

2021 ◽

Vol 12 ◽

pp. 204173142098752

Author(s):

Nadiah S Sulaiman ◽

Andrew R Bond ◽

Vito D Bruno ◽

John Joseph ◽

Jason L Johnson ◽

...

Keyword(s):

Tissue Engineering ◽

Mechanical Strength ◽

Vascular Tissue ◽

Sodium Dodecyl ◽

Host Cells ◽

Replacement Model ◽

In Vivo Testing ◽

Vascular Scaffolds

Human saphenous vein (hSV) and synthetic grafts are commonly used conduits in vascular grafting, despite high failure rates. Decellularising hSVs (D-hSVs) to produce vascular scaffolds might be an effective alternative. We assessed the effectiveness of a detergent-based method using 0% to 1% sodium dodecyl sulphate (SDS) to decellularise hSV. Decellularisation effectiveness was measured in vitro by nuclear counting, DNA content, residual cell viability, extracellular matrix integrity and mechanical strength. Cytotoxicity was assessed on human and porcine cells. The most effective SDS concentration was used to prepare D-hSV grafts that underwent preliminary in vivo testing using a porcine carotid artery replacement model. Effective decellularisation was achieved with 0.01% SDS, and D-hSVs were biocompatible after seeding. In vivo xeno-transplantation confirmed excellent mechanical strength and biocompatibility with recruitment of host cells without mechanical failure, and a 50% patency rate at 4-weeks. We have developed a simple biocompatible methodology to effectively decellularise hSVs. This could enhance vascular tissue engineering toward future clinical applications.

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DDEL-12. NANOPARTICLE DELIVERY OF DOXORUBICIN FOR THE TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

Neuro-Oncology ◽

10.1093/neuonc/noaa222.047 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii286-iii286

Author(s):

Caitlin Ung ◽

Maria Tsoli ◽

Jie Liu ◽

Domenico Cassano ◽

Dannielle Upton ◽

...

Keyword(s):

Treatment Strategies ◽

Pediatric Brain Tumors ◽

Diffuse Intrinsic Pontine Glioma ◽

Confocal Imaging ◽

Cell Content ◽

Potent Effect ◽

Orthotopic Mouse Model ◽

In Vivo Testing

Abstract DIPGs are the most aggressive pediatric brain tumors. Currently, the only treatment is irradiation but due to its palliative nature patients die within 12 months. Effective delivery of chemotherapy across the blood-brain barrier (BBB) has been a key challenge for the eradication of this disease. We have developed a novel gold nanoparticle functionalised with human serum albumin (Au-NP, 98.8 ±19 nm) for the delivery of doxorubicin. In this study, we evaluated the cytotoxic efficacy of doxorubicin delivered through gold nanoparticles (Au-NP-Dox). We found that DIPG neurospheres were equally sensitive to doxorubicin and Au-NP-Dox (at equimolar concentration) by alamar blue assay. Colony formation assays demonstrated a significantly more potent effect of Au-NP-Dox compared to doxorubicin alone, while the Au-NP had no effect. Furthermore, western blot analysis indicated increased apoptotic markers cleaved Parp, caspase 3/7 and phosphorylated H2AX in Au-NP-Dox treated DIPG neurospheres. Live cell content and confocal imaging demonstrated significantly higher uptake of Au-NP-Dox compared to doxorubicin alone. Treatment of a DIPG orthotopic mouse model with Au-NP-Dox showed no signs of toxicity with stable weights being maintained during treatment. However, in contrast to the above in vitro findings the in vivo study showed no anti-tumor effect possibly due to poor penetration of Au-NP-Dox into the brain. We are currently evaluating whether efficacy can be improved using measures to open the BBB transiently. This study highlights the need for rigorous in vivo testing of new treatment strategies before clinical translation to reduce the risk of administration of ineffective treatments.

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In vitro and in vivo testing and correlation for oral controlled/ modified release dosage forms. report of the 2nd workshop held December 1988, Washington, DC. U.S.A.

Journal of Controlled Release ◽

10.1016/0168-3659(90)90064-z ◽

1990 ◽

Vol 14 (1) ◽

pp. 95-106 ◽

Cited By ~ 4

Author(s):

Jerome P. Skelly ◽

Gordon L. Amidon ◽

William H. Barr ◽

Leslie Z. Benet ◽

James E. Carter ◽

...

Keyword(s):

Dosage Forms ◽

Washington Dc ◽

Modified Release ◽

In Vivo Testing

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Causal inference for evaluating prescription opioid abuse using trend‐in‐trend design

Pharmacoepidemiology and Drug Safety ◽

10.1002/pds.4736 ◽

2019 ◽

Vol 28 (5) ◽

pp. 716-725

Author(s):

Nabarun Dasgupta ◽

John Schwarz ◽

Sean Hennessy ◽

Askhan Ertefaie ◽

Richard C. Dart

Keyword(s):

Causal Inference ◽

Opioid Abuse ◽

Prescription Opioid ◽

Prescription Opioid Abuse

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Coagulation under Mild Hypothermia Assessed by Thromboelastometry

Transfusion Medicine and Hemotherapy ◽

10.1159/000513922 ◽

2021 ◽

pp. 1-7

Author(s):

Tobias Nitschke ◽

Philipp Groene ◽

Alice-Christin Acevedo ◽

Tobias Kammerer ◽

Simon T. Schäfer

Keyword(s):

Mild Hypothermia ◽

Onset Time ◽

Rotational Thromboelastometry ◽

Lysis Time ◽

Sample Data ◽

In Vivo Testing ◽

Fibrinolytic Capacity ◽

Clot Formation Time

Introduction: While previous studies have shown a significant impact of extreme hypo- and hyperthermia on coagulation, effects of much more frequently occurring perioperative mild hypothermia are largely unknown. This study therefore aimed to analyze the effects of mild hypothermia using rotational thromboelastometry in vitro. Materials and Methods: Twelve healthy volunteers were included in this study. Standard thromboelastometric tests (EXTEM, INTEM, FIBTEM) were used to evaluate coagulation in vitro at 39, 37, 35.5, 35, and 33°C. Beyond standard thromboelastometric tests, we also evaluated the effects of mild hypothermia on the TPA-test (ClotPro, Enicor GmbH, Munich, Germany), a new test which aims to detect fibrinolytic capacity by adding tissue plasminogen activator to the sample. Data are presented as the median with 25/75th percentiles. Results: Extrinsically activated coagulation (measured by EXTEM) showed a significant increase in clot formation time (CFT; 37°C: 90 s [81/105] vs. 35°C: 109 s [99/126]; p = 0.0002), while maximum clot firmness (MCF) was not significantly reduced. Intrinsically activated coagulation (measured by INTEM) also showed a significant increase in CFT (37°C: 80 s [72/88] vs. 35°C: 94 s [86/109]; p = 0.0002) without significant effects on MCF. Mild hypothermia significantly increased both the lysis onset time (136 s [132/151; 37°C] vs. 162 s [141/228; 35°C], p = 0.0223) and lysis time (208 s [184/297; 37°C] vs. 249 s [215/358; 35°C]; p = 0.0259). Conclusion: This demonstrates that even under mild hypothermia coagulation is significantly altered in vitro. Perioperative temperature monitoring and management are greatly important and can help to prevent mild hypothermia and its adverse effects. Further investigation and in vivo testing of coagulation under mild hypothermia is needed.

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