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Introduction Intraoperative floppy iris syndrome (IFIS) describes an entity encountered during surgical removal of a cataract that is characterized by a flaccid iris and inhibition of dilation of the pupil required for successful cataract surgery.

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Introduction

Intraoperative floppy iris syndrome (IFIS) describes an entity encountered during surgical removal of a cataract that is characterized by a flaccid iris and inhibition of dilation of the pupil required for successful cataract surgery.

The occurrence of IFIS during cataract surgery is particularly troubling as it dramatically increases the likelihood of surgical complications during the cataract procedure and is often recalcitrant to any form of treatment.

Patients may experience more pain, a longer recovery period and less improvement in visual acuity than a patient with an uncomplicated cataract removal in which IFIS is absent.

In many cases IFIS is related to use of various systemic drugs, notably, those medications used to treat benign prostatic hypertrophy such as Flomax (tamsulosin) in men.

Interestingly, IFIS has been noted to occur up to a year after discontinuation of Flomax

Data Analysis

There was no statistically significant difference in the amount of tamsulosin or chloroquine bound to RPE tissue. In contrast, doxazosin was found to demonstrate statistically significantly reduced RPE binding compared to tamsulosin and chloroquine alike.

In the iris, chloroquine was again found to demonstrate the highest binding level, followed by tamsulosin and doxazosin. Although tamsulosin was found to bind to iris tissue in amounts exceeding doxazosin, the absolute levels was lower than compared with RPE. Doxazosin demonstrated the lowest level of binding for both RPE and iris respectively.

For all statistically analyses, α = 0.05 (one way ANOVA with Bonferroni sub testing).

Melanin Binding Characteristics of α-1 Adrenergic Receptor Antagonists Jeffrey S. Gaynes1, Cedomir Micic1,Jeffrey A. Borgia1 Bruce I. Gaynes2, 1Department of Biochemistry, Rush University Medical Center, Chicago, IL 2Department of Ophthalmology, Loyola University Medical Center, Chicago, IL

Conclusion

Results of this study suggest that tamsulosin demonstrates significant binding potential to both RPE and iris tissue alike.

The amphilic nature of chloroquine is mimicked by tamsulosin which is widely used for treatment of benign prostatic hypertrophy.

It is posited that due to melanin binding, tamsulosin is adsorbed into iris tissue and tightly bound to iridial melanin resulting in prolongation of its normal pharmacologic activity as an α1 receptor antagonists.

Although IFIS is seen with other α-1 antagonists such as doxazosin, the incidence of IFIS with α -1 antagonists aside from tamsulosin is reduced.

In summary, despite limitation, the results of this study support the hypothesis that tamsulosin demonstrated binding affinity to ocular melanin. Further study is required to elucidate the relationship between tamsulosin melanin binding and the occurrence of IFIS.

Purpose

The purpose of this investigation is to elucidate the melanin binding affinity of Flomax/tamsulosin and other similar α-1 receptor antagonists. If such affinity exists, this such affinity may imply a cause for IFIS occurrence well after discontinuation of Flomax.

It is thought that due to the presence of a highly characteristic secondary amine group in both the anti-malarial drug chloroquine (a compound with a high melanin binding affinity) and Flomax/tamsulosin that is not found in any other α-1 receptor antagonist, Flomax will demonstrate a substantial melanin binding affinity.

Figure 1 – Structure of Flomax Figure 2 – Structure of Chloroquine

Methods

Synthetic Experiment:

Synthetic melanin was synthesized by combining L-DOPA with polyphenol oxidase (tyrosinase) followed by incubation and centrifugation for a total yield of 10.0mg of substance. 1.0mg/mL solutions of drug (Flomax/tamsulosin and prazosin) were incubated with 3.0mg of synthetic melanin overnight with constant agitation. After 24 hours of incubation the melanin samples are washed by resuspending in phosphate buffer three times. After the samples are washed 100µl of acetonitrile (Sigma-Aldrich, St. Louis, MO) are added and the samples are centrifuged. The eluent is then collected from each sample and analyzed via liquid chromatography – tandem mass spectrometry (LC-MS/MS).

Tissue Experiment:

Retinal Pigmented Epithelium – Choroid (RPE) and iridial tissue is excised from four bovine eyes obtained from a local abattoir. In duplicate, 1.0mg/mL solutions of drug (Flomax/tamsulosin, chloroquine, and doxazosin) is are incubated for 24 hours with each type of tissue with constant agitation. Following incubation samples are washed by resuspending in phosphate buffer three times. After the samples are washed 100µl of acetonitrile (Sigma-Aldrich, St. Louis, MO) is added to each and the samples are centrifuged. The eluent is then collected from each sample and analyzed via liquid chromatography – tandem mass spectrometry (LC-MS/MS).

Liquid Chromatography – Tandem Mass Spectrometry (LC-MS/MS):

Concentration of drug that bound to melanin (synthetic and tissue) is determined by means of LC-MS/MS.

The instrument used is a Waters Voyageur HPLC linked to a Thermo TSQuantum Triple Quad Mass Spectrometer. A two solvent, fifteen minute method with a 7 minute linear gradient (5-95% MeOH +0.1% formic acid) was used along with a Waters XBridge C18, 2x100 mm, 3.5µm particle size column with internal standards 1000µg/mL 100ng/mL.

Drug Binding Data

Figure 3 – Drug Bound to Synthetic Melanin Figure 4 – Drug Bound to RPE Tissue Figure 5 – Drug Bound to Iris Tissue

*Denotes statistically significant difference from chlroquine (p<0.05)

References

Chang, D., & Campbell, J. (2005, April). Intraoperative Floppy Iris Syndrome Associated with Tamsulosin. Journal of Cataract and Refractive Surgery 31(4), 664-673.

Gaynes, BI. (2007, March 26). Tamsulosin (Flomax) and Cataract Surgery [Letter to the editor]. Investigative Ophthalmology and Visual Science, 47(9).

Acknowledgments

This work was supported in part by the Department of Veterans Affairs, Richard A. Perritt Charitable Foundation, The Illinois Society for the Prevention of Blindness and Niles North High School.


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