Novel Liposomal Rolipram Formulation for Clinical Application to Reduce Emesis
Leila Gobejishvili,1 Walter E Rodriguez,1 Philip Bauer,2 Yali Wang,1 Chirag Soni,2 Todd Lydic,3 Shirish Barve,1 Craig McClain,1 Claudio Maldonado4 1Department of Medicine, School of Medicine, University of Louisville, Louisville, KY, USA; 2Endoprotech, Inc., Louisville, KY, USA; 3Lipidomics Center,...
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| Format: | Article |
| Language: | English |
| Published: |
Dove Medical Press
2022-05-01
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| Series: | Drug Design, Development and Therapy |
| Subjects: | |
| Online Access: | https://www.dovepress.com/novel-liposomal-rolipram-formulation-for-clinical-application-to-reduc-peer-reviewed-fulltext-article-DDDT |
| _version_ | 1817981761629454336 |
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| author | Gobejishvili L Rodriguez WE Bauer P Wang Y Soni C Lydic T Barve S McClain C Maldonado C |
| author_facet | Gobejishvili L Rodriguez WE Bauer P Wang Y Soni C Lydic T Barve S McClain C Maldonado C |
| author_sort | Gobejishvili L |
| collection | DOAJ |
| description | Leila Gobejishvili,1 Walter E Rodriguez,1 Philip Bauer,2 Yali Wang,1 Chirag Soni,2 Todd Lydic,3 Shirish Barve,1 Craig McClain,1 Claudio Maldonado4 1Department of Medicine, School of Medicine, University of Louisville, Louisville, KY, USA; 2Endoprotech, Inc., Louisville, KY, USA; 3Lipidomics Center, Michigan State University, East Lansing, MI, USA; 4Department of Physiology, School of Medicine, University of Louisville, Louisville, KY, USACorrespondence: Claudio Maldonado, Department of Physiology, School of Medicine, University of Louisville, 500 S. Preston Street, HSC A-1115, Louisville, KY, 40292, USA, Tel +1 (502) 852-1078, Email claudio.maldonado@louisville.edu Leila Gobejishvili, Department of Medicine, School of Medicine, University of Louisville, 505 S. Hancock Street, CTR 516, Louisville, KY, 40202, USA, Tel +1 (502) 852-0361, Fax +1 (502) 852-8927, Email l0gobe01@louisville.eduIntroduction: The phosphodiesterase 4 (PDE4) inhibitor, rolipram, has beneficial effects on tissue inflammation, injury and fibrosis, including in the liver. Since rolipram elicits significant CNS side-effects in humans (ie, nausea and emesis), our group developed a fusogenic lipid vesicle (FLV) drug delivery system that targets the liver to avoid adverse events. We evaluated whether this novel liposomal rolipram formulation reduces emesis.Methods: C57Bl/6J male mice were used to compare the effect of three doses of free and FLV-delivered (FLVs-Rol) rolipram in a behavioral correlate model of rolipram-induced emesis. Tissue rolipram and rolipram metabolite levels were measured using LC-MS/MS. The effect of FLVs-Rol on brain and liver PDE4 activities was evaluated.Results: Low and moderate doses of free rolipram significantly reduced anesthesia duration, while the same doses of FLVs-Rol had no effect. However, the onset and duration of adverse effects (shortening of anesthesia period) elicited by a high dose of rolipram was not ameliorated by FLVs-Rol. Post-mortem analysis of brain and liver tissues demonstrated that FLVs affected the rate of rolipram uptake by liver and brain. Lastly, administration of a moderate dose of FLVs-Rol attenuated endotoxin induced PDE4 activity in the liver with negligible effect on the brain.Discussion: The findings that the low and moderate doses of FLVs-Rol did not shorten the anesthesia duration time suggest that FLV delivery prevented critical levels of drug from crossing the blood-brain barrier (BBB) to elicit CNS side-effects. However, the inability of high dose FLVs-Rol to prevent CNS side-effects indicates that there was sufficient unencapsulated rolipram to cross the BBB and shorten anesthesia duration. Notably, a moderate dose of FLVs-Rol was able to decrease PDE4 activity in the liver without affecting the brain. Taken together, FLVs-Rol has a strong potential for clinical application for the treatment of liver disease without side effects.Keywords: liposomes, rolipram, side-effects, PDE4, liver |
| first_indexed | 2024-04-13T23:10:24Z |
| format | Article |
| id | doaj.art-1790d2812a114611bece55fa695dcc55 |
| institution | Directory Open Access Journal |
| issn | 1177-8881 |
| language | English |
| last_indexed | 2024-04-13T23:10:24Z |
| publishDate | 2022-05-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | Drug Design, Development and Therapy |
| spelling | doaj.art-1790d2812a114611bece55fa695dcc552022-12-22T02:25:33ZengDove Medical PressDrug Design, Development and Therapy1177-88812022-05-01Volume 161301130975012Novel Liposomal Rolipram Formulation for Clinical Application to Reduce EmesisGobejishvili LRodriguez WEBauer PWang YSoni CLydic TBarve SMcClain CMaldonado CLeila Gobejishvili,1 Walter E Rodriguez,1 Philip Bauer,2 Yali Wang,1 Chirag Soni,2 Todd Lydic,3 Shirish Barve,1 Craig McClain,1 Claudio Maldonado4 1Department of Medicine, School of Medicine, University of Louisville, Louisville, KY, USA; 2Endoprotech, Inc., Louisville, KY, USA; 3Lipidomics Center, Michigan State University, East Lansing, MI, USA; 4Department of Physiology, School of Medicine, University of Louisville, Louisville, KY, USACorrespondence: Claudio Maldonado, Department of Physiology, School of Medicine, University of Louisville, 500 S. Preston Street, HSC A-1115, Louisville, KY, 40292, USA, Tel +1 (502) 852-1078, Email claudio.maldonado@louisville.edu Leila Gobejishvili, Department of Medicine, School of Medicine, University of Louisville, 505 S. Hancock Street, CTR 516, Louisville, KY, 40202, USA, Tel +1 (502) 852-0361, Fax +1 (502) 852-8927, Email l0gobe01@louisville.eduIntroduction: The phosphodiesterase 4 (PDE4) inhibitor, rolipram, has beneficial effects on tissue inflammation, injury and fibrosis, including in the liver. Since rolipram elicits significant CNS side-effects in humans (ie, nausea and emesis), our group developed a fusogenic lipid vesicle (FLV) drug delivery system that targets the liver to avoid adverse events. We evaluated whether this novel liposomal rolipram formulation reduces emesis.Methods: C57Bl/6J male mice were used to compare the effect of three doses of free and FLV-delivered (FLVs-Rol) rolipram in a behavioral correlate model of rolipram-induced emesis. Tissue rolipram and rolipram metabolite levels were measured using LC-MS/MS. The effect of FLVs-Rol on brain and liver PDE4 activities was evaluated.Results: Low and moderate doses of free rolipram significantly reduced anesthesia duration, while the same doses of FLVs-Rol had no effect. However, the onset and duration of adverse effects (shortening of anesthesia period) elicited by a high dose of rolipram was not ameliorated by FLVs-Rol. Post-mortem analysis of brain and liver tissues demonstrated that FLVs affected the rate of rolipram uptake by liver and brain. Lastly, administration of a moderate dose of FLVs-Rol attenuated endotoxin induced PDE4 activity in the liver with negligible effect on the brain.Discussion: The findings that the low and moderate doses of FLVs-Rol did not shorten the anesthesia duration time suggest that FLV delivery prevented critical levels of drug from crossing the blood-brain barrier (BBB) to elicit CNS side-effects. However, the inability of high dose FLVs-Rol to prevent CNS side-effects indicates that there was sufficient unencapsulated rolipram to cross the BBB and shorten anesthesia duration. Notably, a moderate dose of FLVs-Rol was able to decrease PDE4 activity in the liver without affecting the brain. Taken together, FLVs-Rol has a strong potential for clinical application for the treatment of liver disease without side effects.Keywords: liposomes, rolipram, side-effects, PDE4, liverhttps://www.dovepress.com/novel-liposomal-rolipram-formulation-for-clinical-application-to-reduc-peer-reviewed-fulltext-article-DDDTliposomesrolipramside-effectspde4liver |
| spellingShingle | Gobejishvili L Rodriguez WE Bauer P Wang Y Soni C Lydic T Barve S McClain C Maldonado C Novel Liposomal Rolipram Formulation for Clinical Application to Reduce Emesis Drug Design, Development and Therapy liposomes rolipram side-effects pde4 liver |
| title | Novel Liposomal Rolipram Formulation for Clinical Application to Reduce Emesis |
| title_full | Novel Liposomal Rolipram Formulation for Clinical Application to Reduce Emesis |
| title_fullStr | Novel Liposomal Rolipram Formulation for Clinical Application to Reduce Emesis |
| title_full_unstemmed | Novel Liposomal Rolipram Formulation for Clinical Application to Reduce Emesis |
| title_short | Novel Liposomal Rolipram Formulation for Clinical Application to Reduce Emesis |
| title_sort | novel liposomal rolipram formulation for clinical application to reduce emesis |
| topic | liposomes rolipram side-effects pde4 liver |
| url | https://www.dovepress.com/novel-liposomal-rolipram-formulation-for-clinical-application-to-reduc-peer-reviewed-fulltext-article-DDDT |
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