Pharmaceutical Characterization of MyoNovin, a Novel Skeletal Muscle Regenerator: in silico, in vitro and in vivo Studies
PURPOSE: MyoNovin is a novel skeletal muscle-regenerating compound developed through synthesis of two nitro groups onto a guaifenesin backbone to deliver nitric oxide to skeletal muscle with a potential to treat muscle atrophy. The purpose of this study was to utilize in silico, in vitro, and in viv...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-03-01
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| Series: | Journal of Pharmacy & Pharmaceutical Sciences |
| Online Access: | https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/29683 |
| _version_ | 1797718852724850688 |
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| author | Samaa Alrushaid Neal M. Davies Judy E. Anderson Tyson Le Jaime A. Yáñez Zaid H. Maayah Ayman O.S. El-Kadi Ousama Rachid Casey L. Sayre Raimar Löbenberg Frank J. Burczynski |
| author_facet | Samaa Alrushaid Neal M. Davies Judy E. Anderson Tyson Le Jaime A. Yáñez Zaid H. Maayah Ayman O.S. El-Kadi Ousama Rachid Casey L. Sayre Raimar Löbenberg Frank J. Burczynski |
| author_sort | Samaa Alrushaid |
| collection | DOAJ |
| description | PURPOSE: MyoNovin is a novel skeletal muscle-regenerating compound developed through synthesis of two nitro groups onto a guaifenesin backbone to deliver nitric oxide to skeletal muscle with a potential to treat muscle atrophy. The purpose of this study was to utilize in silico, in vitro, and in vivo approaches to characterize MyoNovin and examine its safety, biodistribution, and feasibility for drug delivery. METHODS: In silico software packages were used to predict the physicochemical and biopharmaceutical properties of MyoNovin. In vitro cardiotoxicity was assessed using human cardiomyocytes (RL-14) while effects on CYP3A4 metabolic enzyme and antioxidant activity were examined using commercial kits. A novel HPLC assay was developed to measure MyoNovin concentration in serum, and delineate initial pharmacokinetic and acute toxicity after intravenous administration (20 mg/kg) to male Sprague-Dawley rats. RESULTS: MyoNovin showed relatively high lipophilicity with a LogP value of 3.49, a 20-fold higher skin permeability (19.89 cm/s*107) compared to guaifenesin (0.66 cm/s*107), and ~10-fold higher effective jejunal permeability (2.24 cm/s*104) compared to guaifenesin (0.26 cm/s*104). In vitro, MyoNovinwas not cytotoxic to cardiomyocytes at concentrations below 8 μM and did not inhibit CYP3A4 or show antioxidant activity. In vivo, MyoNovin had a short half-life (t1/2) of 0.16 h, and a volume of distribution Vss of 0.62 L/kg. Biomarkers of MyoNovincardiac and renal toxicity did not differ significantly from baseline control levels.CONCLUSIONS: The predicted high lipophilicity and skin permeability of MyoNovin render it a potential candidate for transdermal administration while its favourable intestinal permeation suggests it may be suitable for oral administration. Pharmacokinetics following IV administration of MyoNovin were delineated for the first time in a rat model. Preliminary single 20 mg/kg dose assessment of MyoNovin suggest no influenceon cardiac troponin or β-N-Acetylglucosaminidase.
This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page. |
| first_indexed | 2024-03-12T08:56:14Z |
| format | Article |
| id | doaj.art-e895d65cc6e748e6b35ead553dc5471e |
| institution | Directory Open Access Journal |
| issn | 1482-1826 |
| language | English |
| last_indexed | 2024-03-12T08:56:14Z |
| publishDate | 2018-03-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Journal of Pharmacy & Pharmaceutical Sciences |
| spelling | doaj.art-e895d65cc6e748e6b35ead553dc5471e2023-09-02T16:01:59ZengFrontiers Media S.A.Journal of Pharmacy & Pharmaceutical Sciences1482-18262018-03-01211s10.18433/J3MS8HPharmaceutical Characterization of MyoNovin, a Novel Skeletal Muscle Regenerator: in silico, in vitro and in vivo StudiesSamaa Alrushaid0Neal M. Davies1Judy E. Anderson2Tyson Le3Jaime A. Yáñez4Zaid H. Maayah5Ayman O.S. El-Kadi6Ousama Rachid7Casey L. Sayre8Raimar Löbenberg9Frank J. Burczynski10College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB. CANADA.Department of Biological Sciences, Faculty of Science, and Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.YARI International Group, New Brunswick, NJ 08901 and INDETEC Corp., Lima Perú.Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB. CANADA.Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB. CANADA.Pharmaceutical Sciences Section, College of Pharmacy, Qatar University, Doha, Qatar.College of Pharmacy, Roseman University of Health Sciences, South Jordan.Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, AB. CANADA.College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. Department of Pharmacology & Therapeutics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.PURPOSE: MyoNovin is a novel skeletal muscle-regenerating compound developed through synthesis of two nitro groups onto a guaifenesin backbone to deliver nitric oxide to skeletal muscle with a potential to treat muscle atrophy. The purpose of this study was to utilize in silico, in vitro, and in vivo approaches to characterize MyoNovin and examine its safety, biodistribution, and feasibility for drug delivery. METHODS: In silico software packages were used to predict the physicochemical and biopharmaceutical properties of MyoNovin. In vitro cardiotoxicity was assessed using human cardiomyocytes (RL-14) while effects on CYP3A4 metabolic enzyme and antioxidant activity were examined using commercial kits. A novel HPLC assay was developed to measure MyoNovin concentration in serum, and delineate initial pharmacokinetic and acute toxicity after intravenous administration (20 mg/kg) to male Sprague-Dawley rats. RESULTS: MyoNovin showed relatively high lipophilicity with a LogP value of 3.49, a 20-fold higher skin permeability (19.89 cm/s*107) compared to guaifenesin (0.66 cm/s*107), and ~10-fold higher effective jejunal permeability (2.24 cm/s*104) compared to guaifenesin (0.26 cm/s*104). In vitro, MyoNovinwas not cytotoxic to cardiomyocytes at concentrations below 8 μM and did not inhibit CYP3A4 or show antioxidant activity. In vivo, MyoNovin had a short half-life (t1/2) of 0.16 h, and a volume of distribution Vss of 0.62 L/kg. Biomarkers of MyoNovincardiac and renal toxicity did not differ significantly from baseline control levels.CONCLUSIONS: The predicted high lipophilicity and skin permeability of MyoNovin render it a potential candidate for transdermal administration while its favourable intestinal permeation suggests it may be suitable for oral administration. Pharmacokinetics following IV administration of MyoNovin were delineated for the first time in a rat model. Preliminary single 20 mg/kg dose assessment of MyoNovin suggest no influenceon cardiac troponin or β-N-Acetylglucosaminidase. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/29683 |
| spellingShingle | Samaa Alrushaid Neal M. Davies Judy E. Anderson Tyson Le Jaime A. Yáñez Zaid H. Maayah Ayman O.S. El-Kadi Ousama Rachid Casey L. Sayre Raimar Löbenberg Frank J. Burczynski Pharmaceutical Characterization of MyoNovin, a Novel Skeletal Muscle Regenerator: in silico, in vitro and in vivo Studies Journal of Pharmacy & Pharmaceutical Sciences |
| title | Pharmaceutical Characterization of MyoNovin, a Novel Skeletal Muscle Regenerator: in silico, in vitro and in vivo Studies |
| title_full | Pharmaceutical Characterization of MyoNovin, a Novel Skeletal Muscle Regenerator: in silico, in vitro and in vivo Studies |
| title_fullStr | Pharmaceutical Characterization of MyoNovin, a Novel Skeletal Muscle Regenerator: in silico, in vitro and in vivo Studies |
| title_full_unstemmed | Pharmaceutical Characterization of MyoNovin, a Novel Skeletal Muscle Regenerator: in silico, in vitro and in vivo Studies |
| title_short | Pharmaceutical Characterization of MyoNovin, a Novel Skeletal Muscle Regenerator: in silico, in vitro and in vivo Studies |
| title_sort | pharmaceutical characterization of myonovin a novel skeletal muscle regenerator in silico in vitro and in vivo studies |
| url | https://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/29683 |
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