In vitro and in vivo assessment of the abuse potential of PF614, a novel BIO-MD™ prodrug of oxycodone

2017 ◽  
Vol 13 (1) ◽  
pp. 39 ◽  
Author(s):  
D. Lynn Kirkpatrick, PhD ◽  
William K. Schmidt, PhD ◽  
Ricardo Morales, BSc ◽  
John Cremin, PhD ◽  
Julie Seroogy, BSc ◽  
...  
Keyword(s):  
Room Temperature ◽  
Extended Release ◽  
Ex Vivo ◽  
Liver Microsomes ◽  
Release Profile ◽  
Opioid Agonist ◽  
Pharmacologically Active ◽  
Household Chemicals

Objective: The need for pain medication which will not lead to abuse is well recognized. Ensysce has designed prodrug analogs of the commonly used pain medications including hydromorphone, oxycodone (OC), hydrocodone, and morphine that limit their use to oral delivery, two of which are in clinical development. This study was undertaken to demonstrate that PF614, an extended-release prodrug of OC, allows the release of OC as designed when delivered orally, yet it resists ex vivo extraction with household chemicals and is pharmacologically inactive when administered by nonoral routes (nasal and parenteral), thereby substantially reducing its intravenous (IV) and intranasal abuse potential.Methods: In vitro and in vivo methods were used to determine release of OC from PF614 and to show potential μ-opioid receptor activity. Plasma and cerebral spinal fluid levels of OC were evaluated following in vivo IV administration of PF614 in rats. In vitro extraction of OC from PF614 was explored using enzymes, common solvents, and household chemicals at room temperature and elevated temperature over time to determine release of OC from the prodrug.Results: PF614 was stable with in vitro exposure to human plasma, saliva, and liver microsomes or culinary enzyme preparations. PF614 was stable (≥90 percent remaining as intact prodrug) under all room temperature conditions evaluated for 24 hours. At 80 °C for 1 hour, no OC was released. Incubation at 80 °C for 24 hours in vinegar or vodka produced a conversion to OC of 6 percent. Incubation with trypsin at 37 °C converted PF614 approximately stoichiometric to OC with half-life of 4 hours. PF614's penetration of the central nervous system was 83-fold lower than OC and it had a 6.5-fold reduced potency as a μ-opioid agonist. Finally, oral PF614 delivers OC into plasma with an extended-release profile in dogs (reduced Cmax; delayed Tmax).Conclusions: The Bio-Activated Molecular Delivery prodrug design limits the use of PF614 to the intended oral route of delivery with reduced potential for IV or nasal abuse, as it cannot be activated intravenously or nasally to provide an active opioid. Unlike existing opioid formulations, the extended-release profile of PF614 cannot be accelerated by chewing or ex vivo extraction to pharmacologically active substances.

scholarly journals Development of Chitosan–Tripolyphosphate Nanoparticles as Glycopeptide Antibiotic Reservoirs and Ex vivo Evaluation for Their Potential to Enhance the Corneal Permeation in Ocular Drug Delivery

2021 ◽  
Author(s):  
Farhad Safari ◽  
Shahla Mirzaeei ◽  
Ghobad Mohammadi
Keyword(s):  
Ftir Spectroscopy ◽  
High Performance ◽  
Ex Vivo ◽  
Antimicrobial Efficacy ◽  
Ocular Delivery ◽  
In Vivo Evaluation ◽  
Pharmacologically Active ◽  
Corneal Permeation

Purpose: The present investigation aimed to prepare Vancomycin-loaded nanoparticles (VAN-NPs) using chitosan (CS) and tripolyphosphate (TPP) besides exploring the effects of changing CS/TPP ratio on the physicochemical properties, corneal permeation, and ocular delivery of the prepared NPs. Methods: Different pre-formulations were prepared using the modified ionic gelation process, then were characterized in terms of size distribution. Optimized formulations were furtherly evaluated by some characteristic tools such as Fourier-transform infrared (FTIR) spectroscopy and thermogravimetric analysis (TGA). The in vitro antimicrobial efficacy and drug release amounts along with the Ex-vivo corneal permeation of NPs through the sheep cornea were investigated. Quantification was performed using High-Performance Liquid Chromatography. Results: Spherical and uniformly distributed NPs were developed with a mean particle size varied between 215–290 nm. FTIR spectroscopy confirmed that the CS/TPP cross-linking has taken place without affecting the pharmacologically active moiety of the drug. The obtained zeta potential values were in the range of +34 to +37 mV, which could ensure the stability of formulations. TGA analysis indicated enhanced thermal stability for the encapsulated drug compared to the plain drug. Formulations indicated suitable antimicrobial efficacy while releasing more than 90% of the drug during 24 h. NPs offered a 10-fold enhancement in corneal permeation compared to the drug solution. Conclusions: Although further in vivo evaluation is still required to completely confirm the efficacy of the formulations, the enhanced release and corneal permeation of the drug suggest that the prepared NPs are suitable for ocular delivery of VAN.

scholarly journals Topical Delivery of Apremilast Loaded Nanostructured Lipid Carrier Based Hydrogel for Psoriasis Therapy

2021 ◽  
pp. 7-20
Author(s):  
S. M. Sindhoor ◽  
Marina Koland
Keyword(s):  
Electron Microscopy ◽  
Transmission Electron Microscopy ◽  
Extended Release ◽  
Ex Vivo ◽  
Entrapment Efficiency ◽  
Transmission Electron ◽  
Psoriasis Therapy ◽  
Systemic Side Effects

Background: Apremilast (APR) is an orally administered selective phosphodiesterase 4 inhibitor approved to treat plaque psoriasis and psoriatic arthritis and is available as an oral tablet formulation. However, its systemic side effects limit its application. The low solubility and permeability of apremilast make it difficult to administer it through the skin. Hence an attempt is made to incorporate apremilast into a suitable nanocarrier to facilitate its topical delivery. Aims: To formulate and characterize Apremilast loaded nanostructured lipid carriers for the management of psoriasis to reduce the systemic side effects. Methodology: Apremilast loaded Nanostructured Lipid carriers (NLC) were prepared by melt emulsification accompanied by probe sonication. The formulation was prepared using GMS, Sefsol 218, Tween 80 and Transcutol P as Solid Lipid, Liquid lipid, Surfactant and Penetration Enhancer. The NLC was incorporated into carbapol 934 dispersion to convert it into a gel. The NLC formulation was evaluated for size, Polydispersity Index, Zeta Potential, Entrapment efficiency,  Transmission Electron Microscopy. After that, the NLC gel was examined for Spreadability, Extrudabilty, Viscosity, In vitro drug release, Ex vivo permeation, Skin deposition and In vivo studies. Results: The formulated Apremilast loaded showed particle size of less than 200 nm (i.e.170.32nm) with a narrow PDI of 0.267. Entrapment efficiency revealed that 89.26±01.22% of the drug was entrapped. Transmission electron microscopy images confirmed the spherical nature of the nanocarrier. The extended-release pattern of the formulated NLC for 24h was observed in the in vitro release studies and followed the Higuchi model(R2=0.9966). Ex vivo permeability showed a 6.14 fold increase in permeability and 74.05±0.25% deposition of apremilast loaded NLC gel compared to apremilast gel. The formulation was stable for three months without significant changes. In vivo skin studies showed that the prepared NLC did not have any skin irritation potential. The antipsoriatic activity demonstrated by the Apremilast loaded NLC gel in the imiquimod induced psoriasis model in mice was comparable to the standard treatment. Conclusion: Apremilast loaded NLC demonstrated enhanced permeation, improved skin retention and extended-release compared to conventional gel. The developed formulation can be an alternative for psoriasis therapy after clinical trials in the future.

scholarly journals In vitro and in vivo efficacy of the novel oral proteasome inhibitor NNU546 in multiple myeloma

2020 ◽  
Author(s):  
Hui Zhou ◽  
Meng Lei ◽  
Wang Wang ◽  
Mengjie Guo ◽  
Jia Wang ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitor ◽  
Ex Vivo ◽  
Active Form ◽  
Selective Inhibition ◽  
Endoplasmic Reticulum Stress Response ◽  
Pharmacologically Active ◽  
Intravenous And Oral Administration

Abstract Background Proteasome inhibition demonstrates highly effective impact on multiple myeloma (MM) treatment. Here, we aimed to examine anti-tumor efficiency and underlying mechanisms of a novel well tolerated orally applicable proteasome inhibitor NNU546 and its hydrolyzed pharmacologically active form NNU219. Methods Enzyme activities and inhibition assays was performed to evaluate the effect of NNU219 on proteasome. To explore the anti-MM activity of NNU219 and its related mechanism, multiple in vitro assays such as cell viability, cell cycle and apoptosis assays, Co-immunoprecipitation (Co-IP) and ubiquitination, NF-κB inhibition assay were conducted. Furthermore, in vivo studies were performed to determine the effects of NNU219 on tumors. Results NNU219 showed more selective inhibition to proteasome catalytic subunits and less off-target effect than bortezomib ex vivo. Moreover, intravenous and oral administration of either NNU219 or NNU546 led to more sustained pharmacodynamic inhibitions of proteasome activities compared with bortezomib. Importantly, NNU219 exhibited potential anti-MM activity in both MM cell lines and primary samples in vitro. The anti-MM activity of NNU219 was associated with induction of G2/M-phase arrest, as well as induction of apoptosis via activation of the caspase cascade and endoplasmic reticulum stress response. At well-tolerated doses, significant growth-inhibitory effects of NNU219 and NNU546 were observed in 3 different human MM xenograft mouse models. Furthermore, such observation was even found in the presence of a bone marrow microenvironment. Conclusion Taken together, these findings provided the basis for clinical trial of NNU546 to determine its potential as a candidate for MM treatment.

scholarly journals Interaction Between Florfenicol and Doxycycline Involving Cytochrome P450 3A in Goats (Capra hricus)

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiaojing Wang ◽  
Yaqin Yang ◽  
María-Aránzazu Martínez ◽  
Marta Martínez ◽  
Bernardo Lopez-Torres ◽  
...  
Keyword(s):  
Health Hazard ◽  
Liver Microsomes ◽  
Quantitative Prediction ◽  
Withdrawal Period ◽  
Cytochrome P450 3A ◽  
Key Enzyme ◽  
Liver And Kidney ◽  
Pharmacologically Active

When two drugs are combined, drug-drug interactions (DDI) often occur. Metabolic DDI usually occur due to inhibition of the metabolism of one drug by the other. This leads to an increase in the plasma concentration of the drug whose metabolism is inhibited. The objective of this research study was to verify the DDI risk of two antibacterial, florfenicol (FF) and doxycycline (DOX) due to metabolism. Because food containing residues of any pharmacologically active substance could potentially constitute a public health hazard, we selected a food producing animal, goat, goat liver microsomes and recombinant metabolic enzymes, for in vivo and in vitro metabolism studies. In vitro experiments showed that CYP3A was the key enzyme subfamily in FF metabolism, DOX slowed down FF metabolism and R440 was possibly the key amino acid in the metabolic interaction between FF and DOX. In vivo studies in the goats showed that DOX inhibited up-regulation of CYP3A24 gene expression produced by FF; in liver and kidney, DOX slightly slowed down FF metabolism. Quantitative prediction of DDI risk suggest that when DOX is used in combination with FF in veterinary medicine, may result in a clinical significant increase of FF plasma and tissue concentrations, resulting a prevalence of harmful tissue residues of medicinal products in the food chain. Through our experimentation, when DOX is used in combination with FF, the withdrawal period of FF in the kidney was extended by 1 day. Otherwise, an appropriate withdrawal period (20 days) of FF was established for FF and DOX combined use to ensure that the animal can be safely slaughtered for food.

scholarly journals Formulation Strategies to Improve Nose-to-Brain Delivery of Donepezil

Pharmaceutics ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 64 ◽  
Author(s):  
Lupe Carolina Espinoza ◽  
Marcelle Silva-Abreu ◽  
Beatriz Clares ◽  
María José Rodríguez-Lagunas ◽  
Lyda Halbaut ◽  
...  
Keyword(s):  
Ex Vivo ◽  
In Vitro Release ◽  
Spherical Shape ◽  
Release Profile ◽  
In Vivo Models ◽  
Tablet Form ◽  
Ex Vivo Permeation ◽  
Vitro Release

Donepezil (DPZ) is widely used in the treatment of Alzheimer’s disease in tablet form for oral administration. The pharmacological efficacy of this drug can be enhanced by the use of intranasal administration because this route makes bypassing the blood–brain barrier (BBB) possible. The aim of this study was to develop a nanoemulsion (NE) as well as a nanoemulsion with a combination of bioadhesion and penetration enhancing properties (PNE) in order to facilitate the transport of DPZ from nose-to-brain. Composition of NE was established using three pseudo-ternary diagrams and PNE was developed by incorporating Pluronic F-127 to the aqueous phase. Parameters such as physical properties, stability, in vitro release profile, and ex vivo permeation were determined for both formulations. The tolerability was evaluated by in vitro and in vivo models. DPZ-NE and DPZ-PNE were transparent, monophasic, homogeneous, and physically stable with droplets of nanometric size and spherical shape. DPZ-NE showed Newtonian behavior whereas a shear thinning (pseudoplastic) behavior was observed for DPZ-PNE. The release profile of both formulations followed a hyperbolic kinetic. The permeation and prediction parameters were significantly higher for DPZ-PNE, suggesting the use of polymers to be an effective strategy to improve the bioadhesion and penetration of the drug through nasal mucosa, which consequently increase its bioavailability.

The Role of Polyphenols in the Modulation of Plasma Non-Enzymatic Antioxidant Capacity (NEAC)

2012 ◽  
Vol 82 (3) ◽  
pp. 228-232 ◽  
Author(s):  
Mauro Serafini ◽  
Giuseppa Morabito
Keyword(s):  
Antioxidant Capacity ◽  
Dietary Intervention ◽  
Ex Vivo ◽  
The Body ◽  
Dietary Polyphenols ◽  
Enzymatic Antioxidant ◽  
Endogenous Antioxidant

Dietary polyphenols have been shown to scavenge free radicals, modulating cellular redox transcription factors in different in vitro and ex vivo models. Dietary intervention studies have shown that consumption of plant foods modulates plasma Non-Enzymatic Antioxidant Capacity (NEAC), a biomarker of the endogenous antioxidant network, in human subjects. However, the identification of the molecules responsible for this effect are yet to be obtained and evidences of an antioxidant in vivo action of polyphenols are conflicting. There is a clear discrepancy between polyphenols (PP) concentration in body fluids and the extent of increase of plasma NEAC. The low degree of absorption and the extensive metabolism of PP within the body have raised questions about their contribution to the endogenous antioxidant network. This work will discuss the role of polyphenols from galenic preparation, food extracts, and selected dietary sources as modulators of plasma NEAC in humans.

Evaluation of 99mTc-Label led Vitamin K4 as an Agent for Testicular Imaging

1991 ◽  
Vol 30 (01) ◽  
pp. 35-39 ◽  
Author(s):  
H. S. Durak ◽  
M. Kitapgi ◽  
B. E. Caner ◽  
R. Senekowitsch ◽  
M. T. Ercan
Keyword(s):  
Soft Tissue ◽  
Room Temperature ◽  
Normal Subjects ◽  
Left Testis ◽  
Wide Range ◽  
Activity Ratios ◽  
The Right ◽  
Radioactivity Levels

Vitamin K4 was labelled with 99mTc with an efficiency higher than 97%. The compound was stable up to 24 h at room temperature, and its biodistribution in NMRI mice indicated its in vivo stability. Blood radioactivity levels were high over a wide range. 10% of the injected activity remained in blood after 24 h. Excretion was mostly via kidneys. Only the liver and kidneys concentrated appreciable amounts of radioactivity. Testis/soft tissue ratios were 1.4 and 1.57 at 6 and 24 h, respectively. Testis/blood ratios were lower than 1. In vitro studies with mouse blood indicated that 33.9 ±9.6% of the radioactivity was associated with RBCs; it was washed out almost completely with saline. Protein binding was 28.7 ±6.3% as determined by TCA precipitation. Blood clearance of 99mTc-l<4 in normal subjects showed a slow decrease of radioactivity, reaching a plateau after 16 h at 20% of the injected activity. In scintigraphic images in men the testes could be well visualized. The right/left testis ratio was 1.08 ±0.13. Testis/soft tissue and testis/blood activity ratios were highest at 3 h. These ratios were higher than those obtained with pertechnetate at 20 min post injection.99mTc-l<4 appears to be a promising radiopharmaceutical for the scintigraphic visualization of testes.

Significance of Platelet β-Adrenoceptors for Platelet Responses In Vivo and In Vitro

1992 ◽  
Vol 68 (06) ◽  
pp. 687-693 ◽  
Author(s):  
P T Larsson ◽  
N H Wallén ◽  
A Martinsson ◽  
N Egberg ◽  
P Hjemdahl
Keyword(s):  
Ex Vivo ◽  
High Dose ◽  
Platelet Aggregability ◽  
Adrenoceptor Agonist ◽  
Dose Infusion ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Factor Antigen

SummaryThe significance of platelet β-adrenoceptors for platelet responses to adrenergic stimuli in vivo and in vitro was studied in healthy volunteers. Low dose infusion of the β-adrenoceptor agonist isoprenaline decreased platelet aggregability in vivo as measured by ex vivo filtragometry. Infusion of adrenaline, a mixed α- and β-adrenoceptor agonist, increased platelet aggregability in vivo markedly, as measured by ex vivo filtragometry and plasma β-thromboglobulin levels. Adrenaline levels were 3–4 nM in venous plasma during infusion. Both adrenaline and high dose isoprenaline elevated plasma von Willebrand factor antigen levels β-Blockade by propranolol did not alter our measures of platelet aggregability at rest or during adrenaline infusions, but inhibited adrenaline-induced increases in vWf:ag. In a model using filtragometry to assess platelet aggregability in whole blood in vitro, propranolol enhanced the proaggregatory actions of 5 nM, but not of 10 nM adrenaline. The present data suggest that β-adrenoceptor stimulation can inhibit platelet function in vivo but that effects of adrenaline at high physiological concentrations are dominated by an α-adrenoceptor mediated proaggregatory action.

In Vivo Effect of Suloctidil as an Antiplatelet Agent

1979 ◽  
Vol 41 (03) ◽  
pp. 465-474 ◽  
Author(s):  
Marcia R Stelzer ◽  
Thomas S Burns ◽  
Robert N Saunders
Keyword(s):  
Ex Vivo ◽  
Antiplatelet Agent ◽  
Ratio Method ◽  
Platelet Aggregate ◽  
Permanent Effect ◽  
Platelet Aggregates ◽  
5 Ht Uptake ◽  
High Doses

SummaryThe relationship between the effects of suloctidil in vivo as an antiplatelet agent and in vitro as a modifier of platelet serotonin (5-HT) parameters was investigated. Suloctidil was found to be effective in reducing platelet aggregates formation in the retired breeder rat as determined using the platelet aggregate ratio method (PAR) with an ED50 of 16.1 mg/kg 24 hours post administration. In contrast to the hypothesis that 5-HT depletion is involved in the anti-aggregatory mechanism of suloctidil, no correlation was found between platelet 5- HT content and this antiplatelet activity. Reduction of platelet 5-HT content required multiple injections of high doses (100 mg/kg/day) of suloctidil. Suloctidil administration for 8 days at 100 mg/kg/day, which lowered platelet 5-HT content by 50%, resulted in no permanent effect on ex vivo platelet 5-HT uptake or thrombin-induced release, nor alteration in the plasma 5-HT level. However, these platelets exhibited a short-lived, significant increase in percent leakage of 5-HT after 30 minutes of incubation. Therefore, suloctidil treatment at high doses may with time result in platelet 5-HT depletion, however this effect is probably not related to the primary anti-aggregatory activity of the drug.

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