Pulmonary deposition of radionucleotide-labeled palivizumab : proof-of-concept study
- Rajapaksa, Anushi, Do, Lien, Suryawijaya Ong, Darren, Sourial, Magdy, Bischof, Robert
- Authors: Rajapaksa, Anushi , Do, Lien , Suryawijaya Ong, Darren , Sourial, Magdy , Bischof, Robert
- Date: 2020
- Type: Text , Journal article
- Relation: Frontiers in Pharmacology Vol. 11, no. (2020), p.
- Full Text:
- Reviewed:
- Description: Objective: Current prevention and/or treatment options for respiratory syncytial virus (RSV) infections are limited as no vaccine is available. Prophylaxis with palivizumab is very expensive and requires multiple intramuscular injections over the RSV season. Here we present proof-of-concept data using nebulized palivizumab delivery as a promising new approach for the prevention or treatment of severe RSV infections, documenting both aerosol characteristics and pulmonary deposition patterns in the lungs of lambs. Design: Prospective animal study. Setting: Biosecurity Control Level 2-designated large animal research facility at the Murdoch Children’s Research Institute, Melbourne, Australia. Subjects: Four weaned Border-Leicester/Suffolk lambs at 5 months of age. Interventions: Four lambs were administered aerosolized palivizumab conjugated to Tc-99m, under gaseous anesthesia, using either the commercially available AeroNeb Go® or the investigational HYDRA device, placed in-line with the inspiratory limb of a breathing circuit. Lambs were scanned in a single-photon emission computed tomography (SPECT/CT) scanner in the supine position during the administration procedure. Measurements and Main Results: Both the HYDRA and AeroNeb Go® produced palivizumab aerosols in the 1–5 µm range with similar median (geometric standard deviation and range) aerosol droplet diameters for the HYDRA device (1.84 ± 1.40 μm, range = 0.54–5.41μm) and the AeroNeb Go® (3.07 ± 1.56 μm, range = 0.86–10 μm). Aerosolized palivizumab was delivered to the lungs at 88.79–94.13% of the total aerosolized amount for all lambs, with a small proportion localized to either the trachea or stomach. No difference between devices were found. Pulmonary deposition ranged from 6.57 to 9.25% of the total dose of palivizumab loaded in the devices, mostly in the central right lung. Conclusions: Aerosolized palivizumab deposition patterns were similar in all lambs, suggesting a promising approach in the control of severe RSV lung infections. © Copyright © 2020 Rajapaksa, Do, Suryawijaya Ong, Sourial, Veysey, Beare, Hughes, Yang, Bischof, McDonnell, Eu, Yeo, Licciardi and Mulholland. ***Please note that there are multiple authors for this article therefore only the name of the first 5 including Federation University Australia affiliate “Robert Bishof” is provided in this record***
- Description: The authors thank Rebecca Sutton for her technical assistance on lamb management, and Kera Pethybridge and Ellie Wright for her technical assistance on nuclear imaging. This study is?supported by a Jack Brockhoff Foundation Early Career Research Grant and a National Health and Medical Research Council (NHMRC) Early Career Fellowship (GNT1123030) awarded to AR, and the Victorian Government?s Operational Infrastructure Support Program. PL is supported by an NHMRC Career Development Fellowship (GNT1165084).
- Authors: Rajapaksa, Anushi , Do, Lien , Suryawijaya Ong, Darren , Sourial, Magdy , Bischof, Robert
- Date: 2020
- Type: Text , Journal article
- Relation: Frontiers in Pharmacology Vol. 11, no. (2020), p.
- Full Text:
- Reviewed:
- Description: Objective: Current prevention and/or treatment options for respiratory syncytial virus (RSV) infections are limited as no vaccine is available. Prophylaxis with palivizumab is very expensive and requires multiple intramuscular injections over the RSV season. Here we present proof-of-concept data using nebulized palivizumab delivery as a promising new approach for the prevention or treatment of severe RSV infections, documenting both aerosol characteristics and pulmonary deposition patterns in the lungs of lambs. Design: Prospective animal study. Setting: Biosecurity Control Level 2-designated large animal research facility at the Murdoch Children’s Research Institute, Melbourne, Australia. Subjects: Four weaned Border-Leicester/Suffolk lambs at 5 months of age. Interventions: Four lambs were administered aerosolized palivizumab conjugated to Tc-99m, under gaseous anesthesia, using either the commercially available AeroNeb Go® or the investigational HYDRA device, placed in-line with the inspiratory limb of a breathing circuit. Lambs were scanned in a single-photon emission computed tomography (SPECT/CT) scanner in the supine position during the administration procedure. Measurements and Main Results: Both the HYDRA and AeroNeb Go® produced palivizumab aerosols in the 1–5 µm range with similar median (geometric standard deviation and range) aerosol droplet diameters for the HYDRA device (1.84 ± 1.40 μm, range = 0.54–5.41μm) and the AeroNeb Go® (3.07 ± 1.56 μm, range = 0.86–10 μm). Aerosolized palivizumab was delivered to the lungs at 88.79–94.13% of the total aerosolized amount for all lambs, with a small proportion localized to either the trachea or stomach. No difference between devices were found. Pulmonary deposition ranged from 6.57 to 9.25% of the total dose of palivizumab loaded in the devices, mostly in the central right lung. Conclusions: Aerosolized palivizumab deposition patterns were similar in all lambs, suggesting a promising approach in the control of severe RSV lung infections. © Copyright © 2020 Rajapaksa, Do, Suryawijaya Ong, Sourial, Veysey, Beare, Hughes, Yang, Bischof, McDonnell, Eu, Yeo, Licciardi and Mulholland. ***Please note that there are multiple authors for this article therefore only the name of the first 5 including Federation University Australia affiliate “Robert Bishof” is provided in this record***
- Description: The authors thank Rebecca Sutton for her technical assistance on lamb management, and Kera Pethybridge and Ellie Wright for her technical assistance on nuclear imaging. This study is?supported by a Jack Brockhoff Foundation Early Career Research Grant and a National Health and Medical Research Council (NHMRC) Early Career Fellowship (GNT1123030) awarded to AR, and the Victorian Government?s Operational Infrastructure Support Program. PL is supported by an NHMRC Career Development Fellowship (GNT1165084).
Dynamics of IL-4 and IL-13 expression in the airways of sheep following allergen challenge
- Liravi, Bahar, Piedrafita, David, Nguyen, Gary, Bischof, Robert
- Authors: Liravi, Bahar , Piedrafita, David , Nguyen, Gary , Bischof, Robert
- Date: 2015
- Type: Text , Journal article
- Relation: BMC Pulmonary Medicine Vol. 15, no. 1 (2015), p. 1-11
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- Reviewed:
- Description:
Background: IL-4 and IL-13 play a critical yet poorly understood role in orchestrating the recruitment and activation of effector cells of the asthmatic response and driving the pathophysiology of allergic asthma. The house dust mite (HDM) sheep asthma model displays many features of the human condition and is an ideal model to further elucidate the involvement of these critical Th
2 cytokines. We hypothesized that airway exposure to HDM allergen would induce or elevate the expression profile of IL-4 and IL-13 during the allergic airway response in this large animal model of asthma. Methods: Bronchoalveolar lavage (BAL) samples were collected from saline-and house dust mite (HDM)-challenged lung lobes of sensitized sheep from 0 to 48h post-challenge. BAL cytokines (IL-4, IL-13, IL-6, IL-10, TNF-aα) were each measured by ELISA. IL-4 and IL-13 expression was assessed in BAL leukocytes by flow cytometry and in airway tissue sections by immunohistology. Results: IL-4 and IL-13 were increased in BAL samples following airway allergen challenge. HDM challenge resulted in a significant increase in BAL IL-4 levels at 4h compared to saline-challenged airways, while BAL IL-13 levels were elevated at all time-points after allergen challenge. IL-6 levels were maintained following HDM challenge but declined after saline challenge, while HDM administration resulted in an acute elevation in IL-10 at 4h but no change in TNF-aα levels over time. Lymphocytes were the main early source of IL-4, with IL-4 release by alveolar macrophages (AMs) prominent from 24h post-allergen challenge. IL-13 producing AMs were increased at 4 and 24h following HDM compared to saline challenge, and tissue staining provided evidence of IL-13 expression in airway epithelium as well as immune cells in airway tissue. Conclusion: In a sheep model of allergic asthma, airway inflammation is accompanied by the temporal release of key cytokines following allergen exposure that primarily reflects the Th2 -driven nature of the immune response in asthma. The present study demonstrates for the first time the involvement of IL-4 and IL-13 in a relevant large animal model of allergic airways disease. © 2015 Liravi et al.
- Authors: Liravi, Bahar , Piedrafita, David , Nguyen, Gary , Bischof, Robert
- Date: 2015
- Type: Text , Journal article
- Relation: BMC Pulmonary Medicine Vol. 15, no. 1 (2015), p. 1-11
- Full Text:
- Reviewed:
- Description:
Background: IL-4 and IL-13 play a critical yet poorly understood role in orchestrating the recruitment and activation of effector cells of the asthmatic response and driving the pathophysiology of allergic asthma. The house dust mite (HDM) sheep asthma model displays many features of the human condition and is an ideal model to further elucidate the involvement of these critical Th
2 cytokines. We hypothesized that airway exposure to HDM allergen would induce or elevate the expression profile of IL-4 and IL-13 during the allergic airway response in this large animal model of asthma. Methods: Bronchoalveolar lavage (BAL) samples were collected from saline-and house dust mite (HDM)-challenged lung lobes of sensitized sheep from 0 to 48h post-challenge. BAL cytokines (IL-4, IL-13, IL-6, IL-10, TNF-aα) were each measured by ELISA. IL-4 and IL-13 expression was assessed in BAL leukocytes by flow cytometry and in airway tissue sections by immunohistology. Results: IL-4 and IL-13 were increased in BAL samples following airway allergen challenge. HDM challenge resulted in a significant increase in BAL IL-4 levels at 4h compared to saline-challenged airways, while BAL IL-13 levels were elevated at all time-points after allergen challenge. IL-6 levels were maintained following HDM challenge but declined after saline challenge, while HDM administration resulted in an acute elevation in IL-10 at 4h but no change in TNF-aα levels over time. Lymphocytes were the main early source of IL-4, with IL-4 release by alveolar macrophages (AMs) prominent from 24h post-allergen challenge. IL-13 producing AMs were increased at 4 and 24h following HDM compared to saline challenge, and tissue staining provided evidence of IL-13 expression in airway epithelium as well as immune cells in airway tissue. Conclusion: In a sheep model of allergic asthma, airway inflammation is accompanied by the temporal release of key cytokines following allergen exposure that primarily reflects the Th2 -driven nature of the immune response in asthma. The present study demonstrates for the first time the involvement of IL-4 and IL-13 in a relevant large animal model of allergic airways disease. © 2015 Liravi et al.
Effective pulmonary delivery of an aerosolized plasmid DNA vaccine via surface acoustic wave nebulization
- Rajapaksa, Anushi, Ho, Jenny, Qi, Aaisha, Bischof, Robert, Nguyen, Tri-Hung, Tate, Michelle, Piedrafita, David, McIntosh, Michelle, Yeo, Leslie, Meeusen, Els, Coppel, Ross, Friend, James
- Authors: Rajapaksa, Anushi , Ho, Jenny , Qi, Aaisha , Bischof, Robert , Nguyen, Tri-Hung , Tate, Michelle , Piedrafita, David , McIntosh, Michelle , Yeo, Leslie , Meeusen, Els , Coppel, Ross , Friend, James
- Date: 2014
- Type: Text , Journal article
- Relation: Respiratory Research Vol. 15, no. 1 (2014), p. 1-12
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- Reviewed:
- Description: Background: Pulmonary-delivered gene therapy promises to mitigate vaccine safety issues and reduce the need for needles and skilled personnel to use them. While plasmid DNA (pDNA) offers a rapid route to vaccine production without side effects or reliance on cold chain storage, its delivery to the lung has proved challenging. Conventional methods, including jet and ultrasonic nebulizers, fail to deliver large biomolecules like pDNA intact due to the shear and cavitational stresses present during nebulization.Methods: In vitro structural analysis followed by in vivo protein expression studies served in assessing the integrity of the pDNA subjected to surface acoustic wave (SAW) nebulisation. In vivo immunization trials were then carried out in rats using SAW nebulized pDNA (influenza A, human hemagglutinin H1N1) condensate delivered via intratracheal instillation. Finally, in vivo pulmonary vaccinations using pDNA for influenza was nebulized and delivered via a respirator to sheep.Results: The SAW nebulizer was effective at generating pDNA aerosols with sizes optimal for deep lung delivery. Successful gene expression was observed in mouse lung epithelial cells, when SAW-nebulized pDNA was delivered to male Swiss mice via intratracheal instillation. Effective systemic and mucosal antibody responses were found in rats via post-nebulized, condensed fluid instillation. Significantly, we demonstrated the suitability of the SAW nebulizer to administer unprotected pDNA encoding an influenza A virus surface glycoprotein to respirated sheep via aerosolized inhalation.Conclusion: Given the difficulty of inducing functional antibody responses for DNA vaccination in large animals, we report here the first instance of successful aerosolized inhalation delivery of a pDNA vaccine in a large animal model relevant to human lung development, structure, physiology, and disease, using a novel, low-power (<1 W) surface acoustic wave (SAW) hand-held nebulizer to produce droplets of pDNA with a size range suitable for delivery to the lower respiratory airways. © 2014 Rajapaksa et al.; licensee BioMed Central Ltd.
- Authors: Rajapaksa, Anushi , Ho, Jenny , Qi, Aaisha , Bischof, Robert , Nguyen, Tri-Hung , Tate, Michelle , Piedrafita, David , McIntosh, Michelle , Yeo, Leslie , Meeusen, Els , Coppel, Ross , Friend, James
- Date: 2014
- Type: Text , Journal article
- Relation: Respiratory Research Vol. 15, no. 1 (2014), p. 1-12
- Full Text:
- Reviewed:
- Description: Background: Pulmonary-delivered gene therapy promises to mitigate vaccine safety issues and reduce the need for needles and skilled personnel to use them. While plasmid DNA (pDNA) offers a rapid route to vaccine production without side effects or reliance on cold chain storage, its delivery to the lung has proved challenging. Conventional methods, including jet and ultrasonic nebulizers, fail to deliver large biomolecules like pDNA intact due to the shear and cavitational stresses present during nebulization.Methods: In vitro structural analysis followed by in vivo protein expression studies served in assessing the integrity of the pDNA subjected to surface acoustic wave (SAW) nebulisation. In vivo immunization trials were then carried out in rats using SAW nebulized pDNA (influenza A, human hemagglutinin H1N1) condensate delivered via intratracheal instillation. Finally, in vivo pulmonary vaccinations using pDNA for influenza was nebulized and delivered via a respirator to sheep.Results: The SAW nebulizer was effective at generating pDNA aerosols with sizes optimal for deep lung delivery. Successful gene expression was observed in mouse lung epithelial cells, when SAW-nebulized pDNA was delivered to male Swiss mice via intratracheal instillation. Effective systemic and mucosal antibody responses were found in rats via post-nebulized, condensed fluid instillation. Significantly, we demonstrated the suitability of the SAW nebulizer to administer unprotected pDNA encoding an influenza A virus surface glycoprotein to respirated sheep via aerosolized inhalation.Conclusion: Given the difficulty of inducing functional antibody responses for DNA vaccination in large animals, we report here the first instance of successful aerosolized inhalation delivery of a pDNA vaccine in a large animal model relevant to human lung development, structure, physiology, and disease, using a novel, low-power (<1 W) surface acoustic wave (SAW) hand-held nebulizer to produce droplets of pDNA with a size range suitable for delivery to the lower respiratory airways. © 2014 Rajapaksa et al.; licensee BioMed Central Ltd.
Single-dose pharmacokinetics and lung function of nebulized niclosamide ethanolamine in sheep
- Weiss, Anne, Bischof, Robert, Landersdorfer, Cornelia, Nguyen, Tri-Hung, Davies, Andrew, Ibrahim, Jibrill, Wynne, Paul, Wright, Phillip, Ditzinger, Gunter, Montgomery, Alan, Meeusen, Els, McIntosh, Michelle, Sommer, Morten
- Authors: Weiss, Anne , Bischof, Robert , Landersdorfer, Cornelia , Nguyen, Tri-Hung , Davies, Andrew , Ibrahim, Jibrill , Wynne, Paul , Wright, Phillip , Ditzinger, Gunter , Montgomery, Alan , Meeusen, Els , McIntosh, Michelle , Sommer, Morten
- Date: 2023
- Type: Text , Journal article
- Relation: Pharmaceutical Research Vol. 40, no. 8 (2023), p. 1915-1925
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- Description: Purpose: Niclosamide is approved as an oral anthelminthic, but its low oral bioavailability hinders its medical use requiring high drug exposure outside the gastrointestinal tract. An optimized solution of niclosamide for nebulization and intranasal administration using the ethanolamine salt has been developed and tested in a Phase 1 trial. In this study we investigate the pulmonary exposure of niclosamide following administration via intravenous injection, oral administration or nebulization. Methods: We characterized the plasma and pulmonary pharmacokinetics of three ascending doses of nebulized niclosamide in sheep, compare it to intravenous niclosamide for compartmental PK modelling, and to the human equivalent approved 2 g oral dose to investigate in the pulmonary exposure of different niclosamide delivery routes. Following a single-dose administration to five sheep, niclosamide concentrations were determined in plasma and epithelial lining fluid (ELF). Non-compartmental and compartmental modeling was used to characterize pharmacokinetic profiles. Lung function tests were performed in all dose groups. Results: Administration of all niclosamide doses were well tolerated with no adverse changes in lung function tests. Plasma pharmacokinetics of nebulized niclosamide behaved dose-linear and was described by a 3-compartmental model estimating an absolute bioavailability of 86%. ELF peak concentration and area under the curve was 578 times and 71 times higher with nebulization of niclosamide relative to administration of oral niclosamide. Conclusions: Single local pulmonary administration of niclosamide via nebulization was well tolerated in sheep and resulted in substantially higher peak ELF concentration compared to the human equivalent oral 2 g dose. © 2023, The Author(s).
- Authors: Weiss, Anne , Bischof, Robert , Landersdorfer, Cornelia , Nguyen, Tri-Hung , Davies, Andrew , Ibrahim, Jibrill , Wynne, Paul , Wright, Phillip , Ditzinger, Gunter , Montgomery, Alan , Meeusen, Els , McIntosh, Michelle , Sommer, Morten
- Date: 2023
- Type: Text , Journal article
- Relation: Pharmaceutical Research Vol. 40, no. 8 (2023), p. 1915-1925
- Full Text:
- Reviewed:
- Description: Purpose: Niclosamide is approved as an oral anthelminthic, but its low oral bioavailability hinders its medical use requiring high drug exposure outside the gastrointestinal tract. An optimized solution of niclosamide for nebulization and intranasal administration using the ethanolamine salt has been developed and tested in a Phase 1 trial. In this study we investigate the pulmonary exposure of niclosamide following administration via intravenous injection, oral administration or nebulization. Methods: We characterized the plasma and pulmonary pharmacokinetics of three ascending doses of nebulized niclosamide in sheep, compare it to intravenous niclosamide for compartmental PK modelling, and to the human equivalent approved 2 g oral dose to investigate in the pulmonary exposure of different niclosamide delivery routes. Following a single-dose administration to five sheep, niclosamide concentrations were determined in plasma and epithelial lining fluid (ELF). Non-compartmental and compartmental modeling was used to characterize pharmacokinetic profiles. Lung function tests were performed in all dose groups. Results: Administration of all niclosamide doses were well tolerated with no adverse changes in lung function tests. Plasma pharmacokinetics of nebulized niclosamide behaved dose-linear and was described by a 3-compartmental model estimating an absolute bioavailability of 86%. ELF peak concentration and area under the curve was 578 times and 71 times higher with nebulization of niclosamide relative to administration of oral niclosamide. Conclusions: Single local pulmonary administration of niclosamide via nebulization was well tolerated in sheep and resulted in substantially higher peak ELF concentration compared to the human equivalent oral 2 g dose. © 2023, The Author(s).
Aerosol delivery of palivizumab in a neonatal lamb model of respiratory syncytial virus infection
- Edirisinghe, Hasindu, Rajapaksa, Anushi, Royce, Simon, Sourial, Magdy, Bischof, Robert, Anderson, Jeremy, Sarila, Gulcan, Nguyen, Cattram, Mulholland, Kim, Do, Lien, Licciardi, Paul
- Authors: Edirisinghe, Hasindu , Rajapaksa, Anushi , Royce, Simon , Sourial, Magdy , Bischof, Robert , Anderson, Jeremy , Sarila, Gulcan , Nguyen, Cattram , Mulholland, Kim , Do, Lien , Licciardi, Paul
- Date: 2023
- Type: Text , Journal article
- Relation: Viruses Vol. 15, no. 11 (2023), p.
- Full Text:
- Reviewed:
- Description: (1) Background: Palivizumab has been an approved preventative monoclonal antibody for respiratory syncytial virus (RSV) infection for over two decades. However, due to its high cost and requirement for multiple intramuscular injections, its use has been limited mostly to high-income countries. Following our previous study showing the successful lung deposition of aerosolised palivizumab in lambs, this current study evaluated the “proof-of-principle” effect of aerosolised palivizumab delivered as a therapeutic to neonatal lambs following RSV infection. (2) Methods: Neonatal lambs were intranasally inoculated with RSV-A2 on day 0 (day 3 post-birth) and treated with aerosolised palivizumab 3 days later (day 3 post-inoculation). Clinical symptoms, RSV viral load and inflammatory response were measured post-inoculation. (3) Results: Aerosolised therapeutic delivery of palivizumab did not reduce RSV viral loads in the nasopharynx nor the bronchoalveolar lavage fluid, but resulted in a modest reduction in inflammatory response at day 6 post-inoculation compared with untreated lambs. (4) Conclusions: This proof-of-principle study shows some evidence of aerosolised palivizumab reducing RSV inflammation, but further studies using optimized protocols are needed in order to validate these findings. © 2023 by the authors.
- Authors: Edirisinghe, Hasindu , Rajapaksa, Anushi , Royce, Simon , Sourial, Magdy , Bischof, Robert , Anderson, Jeremy , Sarila, Gulcan , Nguyen, Cattram , Mulholland, Kim , Do, Lien , Licciardi, Paul
- Date: 2023
- Type: Text , Journal article
- Relation: Viruses Vol. 15, no. 11 (2023), p.
- Full Text:
- Reviewed:
- Description: (1) Background: Palivizumab has been an approved preventative monoclonal antibody for respiratory syncytial virus (RSV) infection for over two decades. However, due to its high cost and requirement for multiple intramuscular injections, its use has been limited mostly to high-income countries. Following our previous study showing the successful lung deposition of aerosolised palivizumab in lambs, this current study evaluated the “proof-of-principle” effect of aerosolised palivizumab delivered as a therapeutic to neonatal lambs following RSV infection. (2) Methods: Neonatal lambs were intranasally inoculated with RSV-A2 on day 0 (day 3 post-birth) and treated with aerosolised palivizumab 3 days later (day 3 post-inoculation). Clinical symptoms, RSV viral load and inflammatory response were measured post-inoculation. (3) Results: Aerosolised therapeutic delivery of palivizumab did not reduce RSV viral loads in the nasopharynx nor the bronchoalveolar lavage fluid, but resulted in a modest reduction in inflammatory response at day 6 post-inoculation compared with untreated lambs. (4) Conclusions: This proof-of-principle study shows some evidence of aerosolised palivizumab reducing RSV inflammation, but further studies using optimized protocols are needed in order to validate these findings. © 2023 by the authors.
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