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Pharmacokinetics for topically applied caffeine in the rat
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ophthalmology. (Gullstrand lab)
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ophthalmology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Ophthalmology.
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2014 (English)In: Experimental Eye Research, ISSN 0014-4835, E-ISSN 1096-0007, Vol. 122, 94-101 p.Article in journal (Refereed) Published
Abstract [en]

Topically applied caffeine was recently identified as a promising candidate molecule for cataract prevention. Little is known about the pharmacokinetics for topically applied caffeine. Potential toxicity of 72 mM caffeine on the ocular surface and the lens was qualitatively monitored and no toxic effects were observed. The concentration of caffeine was measured in the lens and the blood after topical application of 72 mM caffeine to groups of 10 animals sacrificed at 30, 60, 90 and 120 min after topical application. The lens concentration decreased throughout the observation period while the blood concentration increased up to 120 min. Further, the concentration of caffeine in the lens and blood was measured 30 min after topical application of caffeine, the concentration of caffeine being 0.72, 3.34, 15.51 and 72 mM depending on group belonging, in groups of 10 animals. The caffeine concentration in lens and blood, respectively, increased proportionally to the caffeine concentration topically applied. The rat blood concentrations achieved were far below the equivalent threshold dose of FDA recommended daily dose for humans. This information is important for further development of caffeine eye drops for cataract prevention.

Place, publisher, year, edition, pages
2014. Vol. 122, 94-101 p.
National Category
URN: urn:nbn:se:uu:diva-224891DOI: 10.1016/j.exer.2014.03.009ISI: 000336009500012OAI: oai:DiVA.org:uu-224891DiVA: diva2:719099
Available from: 2014-05-22 Created: 2014-05-22 Last updated: 2015-01-23Bibliographically approved
In thesis
1. Prevention of Experimental Cataract Induced by UVR
Open this publication in new window or tab >>Prevention of Experimental Cataract Induced by UVR
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cataract is the leading cause of blindness in the world and is defined by opacification of the normally transparent lens of the eye. The major avoidable cause of cataract is ultraviolet radiation (UVR), but no current strategies have been developed to prevent the onset of cataract. Apoptosis and internal and external antioxidant systems that inhibit apoptosis have been shown to play a significant role in cataractogenesis.

The main purposes of this thesis were to study the time evolution of apoptosis, to develop the concept of a protection factor (PF), and to investigate the effect of thioltransferase (Grx1) and topical caffeine in UVR cataract development. Further, to elucidate pharmacokinetics and influence on iris diameter of topical caffeine.

Sprague Dawley rats were exposed to UVR and TUNEL staining of the lens sections was analysed. Grx1+/+ and Grx1-/- mice were exposed to 5 sub-doses of UVR. Based on the difference of light scattering between Grx1+/+ and Grx1-/- mice, the concept of the PF was developed. Topical caffeine and a placebo were applied to the eyes of separate groups of Sprague Dawley rats that were exposed to sub-doses of UVR and protective effect was evaluated. Penetration of topical caffeine in Sprague Dawley rats to lens and blood was analysed by high performance liquid chromatography. Pupil diameter was measured in groups of unilaterally and bilaterally caffeine-treated ketamine/xylazine anesthetized Sprague Dawley rats.

TUNEL-labeling peaked between 5 and 120 hours after UVR exposure. The PF of Grx1 was 1.3. Moreover, topically administered caffeine protected against UVR-induced cataract development with a PF of 1.23. Topical caffeine peaked at 30 min in the lens, increased up to 120 min in the blood and antagonized ketamine/xylazine-induced mydriasis.

In conclusion, UVR induces apoptosis, which is evidenced by the peak of TUNEL-labeling at 24 hours after UVR exposure. The PF is an objective relative measure of protective properties that allows the comparison of different antioxidant systems and administered antioxidant substances. Grx1 and caffeine are protective against UVR-induced cataract. Topically administered caffeine penetrates to the lens and inhibits UVR-induced apoptosis. Additionally, a miotic effect of caffeine is described for the first time.

Place, publisher, year, edition, pages
Uppsala: Uppsala universitet, 2014. 44 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1036
cataract, ultraviolet radiation, apoptosis, thioltransferase, caffeine
National Category
urn:nbn:se:uu:diva-232955 (URN)978-91-554-9055-3 (ISBN)
Public defence
2014-11-28, Enghoffsalen, Ing. 50, plan 1., Akademiska Sjukhuset, Uppsala, 13:00 (English)
Available from: 2014-11-06 Created: 2014-09-28 Last updated: 2015-01-23

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