Ability of Poly-L-arginine to Enhance Drug Absorption into Aqueous Humor and Vitreous Body after Instillation in Rabbits
The effect of poly-L-arginine with a molecular weight of 35.5 kDa (PLA) on the ocular absorption of hydrophilic molecules after instillation was examined in rabbits in vivo. FITC-labeled dextran (3.8 kDa, FD-4) and pyridoxamine were used as model hyprophilic molecules for absorption. The potential t...
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| Published in | Biological & pharmaceutical bulletin Vol. 30; no. 9; pp. 1768 - 1772 |
|---|---|
| Main Authors | , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Japan
The Pharmaceutical Society of Japan
01.09.2007
Japan Science and Technology Agency |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0918-6158 1347-5215 1347-5215 |
| DOI | 10.1248/bpb.30.1768 |
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| Abstract | The effect of poly-L-arginine with a molecular weight of 35.5 kDa (PLA) on the ocular absorption of hydrophilic molecules after instillation was examined in rabbits in vivo. FITC-labeled dextran (3.8 kDa, FD-4) and pyridoxamine were used as model hyprophilic molecules for absorption. The potential toxicity of PLA was evaluated by microscopic observation of the cornea, production of TNF-α, and the thickness of the corneal epithelia and stroma. The concentration of pyridoxamine and FD-4 in aqueous humor 30 min after a single instillation of a solution of PLA was 29- and 16-fold higher than that without PLA, respectively, but the drug concentrations were not determined in the vitreous body. Repetitive instillation of PLA every 30 min for 150 min achieved 31.1- and 13.3-fold increases in pyridoxamine and FD-4 in aqueous humor, respectively. Furthermore, significant amounts of pyridoxamine and FD-4 were detected in the vitreous body after the repetitive instillation of PLA, even although very little of these drugs was detected in the vitreous body in the control eye without PLA. On the other hand, repetitive instillation of PLA did not induce any alteration of corneal epithelial and stromal thickness, production of TNF-α, and disruption of the epithelial and stromal morphologies and neutrophil infiltration. Our findings suggest that PLA may be useful in promoting drug delivery of hydrophilic drugs to the ocular tissues without producing any significant corneal damage and inflammation. |
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| AbstractList | The effect of poly-L-arginine with a molecular weight of 35.5 kDa (PLA) on the ocular absorption of hydrophilic molecules after instillation was examined in rabbits in vivo. FITC-labeled dextran (3.8 kDa, FD-4) and pyridoxamine were used as model hyprophilic molecules for absorption. The potential toxicity of PLA was evaluated by microscopic observation of the cornea, production of TNF-alpha, and the thickness of the corneal epithelia and stroma. The concentration of pyridoxamine and FD-4 in aqueous humor 30 min after a single instillation of a solution of PLA was 29- and 16-fold higher than that without PLA, respectively, but the drug concentrations were not determined in the vitreous body. Repetitive instillation of PLA every 30 min for 150 min achieved 31.1- and 13.3-fold increases in pyridoxamine and FD-4 in aqueous humor, respectively. Furthermore, significant amounts of pyridoxamine and FD-4 were detected in the vitreous body after the repetitive instillation of PLA, even although very little of these drugs was detected in the vitreous body in the control eye without PLA. On the other hand, repetitive instillation of PLA did not induce any alteration of corneal epithelial and stromal thickness, production of TNF-alpha, and disruption of the epithelial and stromal morphologies and neutrophil infiltration. Our findings suggest that PLA may be useful in promoting drug delivery of hydrophilic drugs to the ocular tissues without producing any significant corneal damage and inflammation.The effect of poly-L-arginine with a molecular weight of 35.5 kDa (PLA) on the ocular absorption of hydrophilic molecules after instillation was examined in rabbits in vivo. FITC-labeled dextran (3.8 kDa, FD-4) and pyridoxamine were used as model hyprophilic molecules for absorption. The potential toxicity of PLA was evaluated by microscopic observation of the cornea, production of TNF-alpha, and the thickness of the corneal epithelia and stroma. The concentration of pyridoxamine and FD-4 in aqueous humor 30 min after a single instillation of a solution of PLA was 29- and 16-fold higher than that without PLA, respectively, but the drug concentrations were not determined in the vitreous body. Repetitive instillation of PLA every 30 min for 150 min achieved 31.1- and 13.3-fold increases in pyridoxamine and FD-4 in aqueous humor, respectively. Furthermore, significant amounts of pyridoxamine and FD-4 were detected in the vitreous body after the repetitive instillation of PLA, even although very little of these drugs was detected in the vitreous body in the control eye without PLA. On the other hand, repetitive instillation of PLA did not induce any alteration of corneal epithelial and stromal thickness, production of TNF-alpha, and disruption of the epithelial and stromal morphologies and neutrophil infiltration. Our findings suggest that PLA may be useful in promoting drug delivery of hydrophilic drugs to the ocular tissues without producing any significant corneal damage and inflammation. The effect of poly-L-arginine with a molecular weight of 35.5 kDa (PLA) on the ocular absorption of hydrophilic molecules after instillation was examined in rabbits in vivo. FITC-labeled dextran (3.8 kDa, FD-4) and pyridoxamine were used as model hyprophilic molecules for absorption. The potential toxicity of PLA was evaluated by microscopic observation of the cornea, production of TNF-α, and the thickness of the corneal epithelia and stroma. The concentration of pyridoxamine and FD-4 in aqueous humor 30 min after a single instillation of a solution of PLA was 29- and 16-fold higher than that without PLA, respectively, but the drug concentrations were not determined in the vitreous body. Repetitive instillation of PLA every 30 min for 150 min achieved 31.1- and 13.3-fold increases in pyridoxamine and FD-4 in aqueous humor, respectively. Furthermore, significant amounts of pyridoxamine and FD-4 were detected in the vitreous body after the repetitive instillation of PLA, even although very little of these drugs was detected in the vitreous body in the control eye without PLA. On the other hand, repetitive instillation of PLA did not induce any alteration of corneal epithelial and stromal thickness, production of TNF-α, and disruption of the epithelial and stromal morphologies and neutrophil infiltration. Our findings suggest that PLA may be useful in promoting drug delivery of hydrophilic drugs to the ocular tissues without producing any significant corneal damage and inflammation. The effect of poly-L-arginine with a molecular weight of 35.5 kDa (PLA) on the ocular absorption of hydrophilic molecules after instillation was examined in rabbits in vivo. FITC-labeled dextran (3.8 kDa, FD-4) and pyridoxamine were used as model hyprophilic molecules for absorption. The potential toxicity of PLA was evaluated by microscopic observation of the cornea, production of TNF-alpha, and the thickness of the corneal epithelia and stroma. The concentration of pyridoxamine and FD-4 in aqueous humor 30 min after a single instillation of a solution of PLA was 29- and 16-fold higher than that without PLA, respectively, but the drug concentrations were not determined in the vitreous body. Repetitive instillation of PLA every 30 min for 150 min achieved 31.1- and 13.3-fold increases in pyridoxamine and FD-4 in aqueous humor, respectively. Furthermore, significant amounts of pyridoxamine and FD-4 were detected in the vitreous body after the repetitive instillation of PLA, even although very little of these drugs was detected in the vitreous body in the control eye without PLA. On the other hand, repetitive instillation of PLA did not induce any alteration of corneal epithelial and stromal thickness, production of TNF-alpha, and disruption of the epithelial and stromal morphologies and neutrophil infiltration. Our findings suggest that PLA may be useful in promoting drug delivery of hydrophilic drugs to the ocular tissues without producing any significant corneal damage and inflammation. |
| Author | Nemoto, Eiichi Natsume, Hideshi Morimoto, Yasunori Akimoto, Masayuki Ueda, Hideo |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/17827737$$D View this record in MEDLINE/PubMed |
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| Cites_doi | 10.1016/S0886-3350(02)01691-7 10.1023/A:1018964823193 10.1016/S0039-6257(01)00211-9 10.1016/j.ijpharm.2003.12.018 10.1211/0022357021778367 10.1038/sj.eye.6701669 10.1016/S0378-5173(99)00100-3 10.1124/dmd.30.4.421 10.1023/A:1022485816755 10.1023/B:PHAM.0000026426.20012.36 10.1016/j.ophtha.2005.06.007 10.1016/S0939-6411(01)00149-7 10.1016/S0168-3659(02)00128-1 10.1016/0014-4835(92)90030-V 10.1016/S0928-0987(01)00172-5 10.1016/S0169-409X(01)00180-6 10.1038/227680a0 10.1056/NEJMp068185 10.1248/bpb.29.155 10.1023/B:PHAM.0000003383.86238.d1 10.1023/A:1015820009255 10.1177/026119290203002S10 10.1006/abio.2002.5638 10.1023/A:1016203725128 10.1056/NEJMoa042760 10.1089/108076803321637708 10.1201/9780203912072 10.1097/00006982-200410000-00002 |
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| References_xml | – reference: 8) Ohtake K., Maeno T., Ueda H., Natsume H., Morimoto Y., Pharm. Res., 20, 153—160 (2003). – reference: 20) Podder S. K., Moy K. C., Lee V. H., Exp. Eye Res., 54, 747—757 (1992). – reference: 30) Steinbrook R., N. Engl. J. Med., 533, 1409—1412 (2006). – reference: 25) Gragoudas E. S., Adamis A. P., Cunningham E. T., Jr., Feinsod M., Guyer D. R., N. Engl. J. Med., 351, 2805—2816 (2004). – reference: 27) Jager R. D., Aiello L. P., Patel S. C., Cunningham E. T., Jr., Retina, 24, 676—698 (2004). – reference: 29) Sasaki H., Igarashi Y., Nagano T., Nishida K., Nakamura J., Pharm. Res., 12, 1146—1150 (1995). – reference: 13) Khatri S., Lass J. H., Heinzel F. P., Petroll W. M., Gomez J., Diaconu E., Kalsow C. M., Pearlman E., Invest. Ophthalmol. Vis. Sci., 43, 2278—2284 (2002). – reference: 4) Wang J., Sakai S., Deguchi Y., Bi D., Tabata Y., Morimoto K., J. Pharm. Pharmacol., 54, 181—188 (2002). – reference: 22) Di Colo G., Zambito Y., Burgalassi S., Nardini I., Saettone M. F., Int. J. Pharm., 273, 37—44 (2004). – reference: 15) Laemini U. K., Nature (London), 227, 680—685 (1970). – reference: 6) Ohtake K., Natsume H., Ueda H., Morimoto Y., J. Control. Release, 82, 263—275 (2002). – reference: 11) Wilhelmus K. R., Surv. Ophthalmol., 45, 493—515 (2001). – reference: 1) Mitra A. K., “Ophthalmic Drug Delivery System,” Marcel Dekker, New York, 2003. – reference: 9) Ohtake K., Maeno T., Ueda H., Ogihara M., Natsume H., Morimoto Y., Pharm. Res., 20, 1838—1845 (2003). – reference: 24) Miyamoto M., Natsume H., Iwata S., Ohtake K., Yamaguchi M., Kobayashi D., Sugibayashi K., Yamashina M., Morimoto Y., Eur. J. Pharm. Biopharm., 52, 21—30 (2001). – reference: 21) Ismail I. M., Chen C. C., Richman J. B., Andersen J. S., Tang-Liu D. D., Pharm. Res., 9, 817—821 (1992). – reference: 7) Nemoto E., Takahashi H., Kobayashi D., Ueda H., Morimoto Y., Biol. Pham. Bull., 29, 155—160 (2006). – reference: 12) Bisp M., Bor M. V., Heinsvig E. M., Kall M. A., Nexo E., Anal. Biochem., 305, 82—89 (2002). – reference: 5) Natsume H., Iwata S., Ohtake K., Miyamoto M., Yamaguchi M., Hosoya K., Kobayashi D., Sugibayashi K., Morimoto Y., Int. J. Pharm., 185, 1—12 (1999). – reference: 14) Holzer M. P., Solomon K. D., Vroman D. T., Vargas L. G., Sandoval H. P., Kasper T. J., Apple D. J., J. Cataract Refract. Surg., 29, 542—549 (2003). – reference: 26) Cunningham E. T., Jr., Adamis A. P., Altaweel M., Aiello L. P., Bressler N. M., D'Amico D. J., Goldbaum M., Guyer D. R., Katz B., Patel M., Schwartz S. D., Ophthalmology, 112, 1747—1757 (2005). – reference: 28) Williams K. A., Brereton H. M., Farrall A., Standfield S. D., Taylor S. D., Kirk L. A., Coster D. J., Eye, 19, 910—913 (2005). – reference: 16) Sakanaka K., Kawazu K., Tomonari M., Kitahara T., Nakashima M., Kawakami S., Nishida K., Nakamura J., Sasaki H., Pharm. Res., 21, 770—776 (2004). – reference: 3) van der Lubben I. M., Verhoef J. C., Borchard G., Junginger H. E., Eur. J. Pharm. Sci., 14, 201—207 (2001). – reference: 19) Yamamura K., Sasaki H., Nakashima M., Ichikawa M., Mukai T., Nishida K., Nakamura J., Pharm. Res., 16, 1596—1601 (1999). – reference: 18) Acheampong A. A., Shackleton M., John B., Burke J., Wheeler L., Tang-Liu D., Drug Metab. Dispos., 30, 421—429 (2002). – reference: 2) Thanou M., Verhoef J. C., Junginger H. E., Adv. Drug Deliv. Rev., 50 (Suppl. 1), S91—S101 (2001). – reference: 10) Curren R. D., Harbell J. W., Altern. Lab. Anim., 30 (Suppl.), 69—74 (2002). – reference: 17) Maltese A., Bucolo C., J. Ocul. Pharmacol. Ther., 19, 171—179 (2003). – reference: 23) Wang J., Sakai S., Deguchi Y., Bi D., Tabata Y., Morimoto K., J. Pharm. 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| SubjectTerms | Absorption absorption enhancer Animals Aqueous Humor - drug effects Aqueous Humor - metabolism Blotting, Western Chromatography, High Pressure Liquid Corneal Stroma - drug effects Corneal Stroma - metabolism Epithelium, Corneal - drug effects Epithelium, Corneal - metabolism inflammation Inflammation - pathology instillation Lipopolysaccharides - pharmacology Male Peptides - pharmacology Pharmaceutical Preparations - metabolism poly-L-arginine Rabbits Stimulation, Chemical Tumor Necrosis Factor-alpha - pharmacology Vitreous Body - drug effects Vitreous Body - metabolism |
| Title | Ability of Poly-L-arginine to Enhance Drug Absorption into Aqueous Humor and Vitreous Body after Instillation in Rabbits |
| URI | https://www.jstage.jst.go.jp/article/bpb/30/9/30_9_1768/_article/-char/en https://www.ncbi.nlm.nih.gov/pubmed/17827737 https://www.proquest.com/docview/1449362831 https://www.proquest.com/docview/68248261 https://www.jstage.jst.go.jp/article/bpb/30/9/30_9_1768/_pdf |
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| ispartofPNX | Biological and Pharmaceutical Bulletin, 2007/09/01, Vol.30(9), pp.1768-1772 |
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