COMMERCIALLY AVAILABLE IONTOPHORETIC DEVICES

III. COMMERCIALLY AVAILABLE IONTOPHORETIC DEVICES

A variety of iontophoretic devices are available with different types of power sources that vary in complexity from the simple battery-rheostat type to modern electronic circuitry (8,9). Table 3 provides a list of companies that produce iontophoresis equipment, their addresses and phone numbers, as well as a brief description of one specific model manufactured by each company. The commercial devices are safe, portable, and work well for the intended purpose.

IV. CONCLUSIONS The last 10–20 years have seen the development and optimization of the

technology of iontophoresis as a noninvasive method of drug delivery. Peptide and protein drugs (e.g., insulin and vasopressin) have been delivered iontophoretically without the pain and side effects associated with tradi- tional subcutaneous injection (10,165,166). Iontophoresis also has the potential to revolutionize clinical diagnosis and monitoring procedures in that it offers an avenue for extracting information from the body without the need for invasive procedures (3,167,168). Iontophoresis is already used clinically in physical therapy clinics, and an allergy patch test is close to commercial reality (33,169).

Ocular iontophoresis is fast, painless, safe, and, in most cases, results in the delivery of a high concentration of the drug to a specific ocular site. Experimentally, iontophoresis has proven extremely useful as a reliable sys- tem for inducing reactivation of herpes simplex virus in various animal models of this ocular disease. Clinically, ocular iontophoresis is potentially

a valuable adjunctive treatment for cytomegalovirus retinitis. In glaucoma studies, iontophoresis of fluorescein, adrenergic agents, and 5-fluorouracil has facilitated the study of aqueous humor dynamics, treatment of glau- coma, and the control of cellular proliferation of glaucoma surgery. Anesthetics and antibiotic/antifungal agents can be delivered transcorneally or transsclerally according to the site of infection. Ocular iontophoresis has

394 Myles et al. Table 3 Iontophoresis Equipment and Suppliers Company

Model number/description IOMED, Inc.

Phoresor II Auto model number PM900. This 2441 South 3850 West, Suite A

model provides an effective, safe, and easy to Salt Lake city, UT 84120

use system with a preset dose (40 mAmp-Mins) (801) 975-1191

for iontophoretic drug application to the skin. (800) 621-3347

This model is compact, easy to operate, fast to Fax (801) 975-7366

set-up, and portable. E-mail: es@iomed,com Website: www.iomed.com

Life-Tech, Inc. Iontophor-II model number 6111 PM/DX. This 4235 Greenbrier Drive

model provides a painless, safe, and effective Stafford, TX 77477

method of delivering high concentrations of (713) 495-9411

drug into a localized skin area. This unit is (800) 231-9841

battery operated, compact, and portable. It is Fax (281) 492-6646

an excellent unit for maintaining constant current. This model has dual site treatment function that enables you to treat two sites simultaneously. E-mail: admin@life-tech.com Website: www.life-tech.com

General Medical Company The Drionic unit. This compact iontophoresis 1935 Armacost Avenue

unit has FDA approval for home treatment of Los Angeles, CA 90025

hyperhidrosis. Battery-generated direct current. (310) 820-5881

E-mail: drionic@generalmedical.com (800) 432-5362

Website: www.drionic.com Fax (310) 826-5778

Wescor, Inc. Macroduct model 3700. This model is used for 459 South Main Street

sweat stimulation (pilocarpine iontophoresis), Logan, UT 84321

collection and analysis (via a sweat analyzer). It (435) 752-6011

is easy to operate and provides accurate and (800) 453-2725

reliable sweat testing.

Fax (435) 752-4127 E-mail: billie@wescor.com Website: www.dataloggersinc.com

Fischer Co., Inc Fischer Galvanic Unit, Model MD-1a is a 517 Commercial Street

high-output iontophoretic device ideally suited Glendale, CA 91203

for treatment of large areas (hyperhidrosis (818) 241-1178

patients). It produces DC current in two ranges (800) 525-3467

(0–10mAmp and 0–50mAmp). Available to Fax (323) 245-2748

physicians or by prescription only. E-mail: info@rafischer. com Website: www.rafischer. com

Ocular Iontophoresis 395 Table 3 Continued

Company Model number/description Dagan Corporation

Dagan 6400 Advanced model. Micro- 2855 Park Avenue

Iontophoresis current generator. Delivers Minneapolis, MN 55407

precise drug delivery without batteries. Power (612) 827-5959

is 100 to 115 volts AC. Current range is 0–1000 Fax (612) 827-6535

n/Amp. E-mail: sales@dagan. com Website: www.dagan.com

MedTherm Corporation Electro-Medicator Model A1 (Distributed by 2604 Newby Road

Pamir Electronics corp.: 603 N. Gordon Drive, Huntsville, AL 35805

Exton PA 19341; (610) 594-8537). This model (205) 837-2000

is used for dental research and clinical practice. It is easy to operate and has AC charging or direct use of AC. E-mail: pamir@pamir.com Website: www.pamir.com

Parkell Desensitron II model number ID643DGC. This 155 Schmitt Boulevard

model is used for treating hypersensitive teeth Farmingdale, NY 11735

by iontophoresis of fluoride ions. Current range (631) 249-1134

is 0–0.5mAmp.

(800) 243-7446 E-mail: info@parkell.com Fax (631) 249-1242

Website: www.parkell.com MedTronic, Inc.

Model 9820. This iontophoretic device is part 7000 Central Ave., NE

of complete system (Model 9800) for sweat Minneapolis, MN 55432

analysis after pilocarpine iontophoresis. (612) 574-4000

E-mail

(800) 525-5552 Website: www.medtronic.com Fax (612) 785-6541

also been used to introduce genes into the anterior and posterior segments of the rabbit eye (170).

There are several ongoing ocular iontophoresis studies that are parti- cularly pertinent to this discussion and should be noted. Chapon et al. (171), using rabbits, have shown that transscleral iontophoresis delivered 15 times more of the anti-CMV agent ganciclovir to the retina and 6.5 times more to the choroid (6 h posttreatment 370 and 828 ng/mg, respectively) than topical administration. At 3 days posttreatment, retinal levels of ganciclovir remained significantly higher than those achieved by oral administration, intravenous injection, topical application, or intravitreal injection. Chauvaud et al. (172) presented initial findings of a Phase II clinical trial

396 Myles et al. for transscleral iontophoresis of the anti-inflammatory corticosteroid

SoluMedrol (hemisuccinate methylprednisolone). Transscleral iontophor- esis of SoluMedrol was safe, well tolerated, and easily applicable to the treatment of severe ocular inflammation thereby reducing the systemic side effects of corticotherapy. Hayden et al. (173) studied transscleral ion- tophoresis of the anticancer drug carboplatin in transgenic mice with her- editary retinoblastoma. A dose-dependent inhibition of intraocular tumor formation was observed following repetitive iontophoretic treatment. These results suggest that transscleral iontophoresis of carboplatin may be useful, as well as advantageous, in the treatment of intraocular pediatric retino- blastoma. Ocular iontophoresis is not a panacea for all eye disorders, but it is a viable alternative delivery system for those substances that are not amenable to topical application and/or require repeated administration over an extended period of time.

ACKNOWLEDGMENTS Louis P. Gangarosa, D.D.S., Ph.D., is acknowledged as the person who

introduced iontophoresis to one of the authors (JMH). The authors wish to acknowledge the editorial assistance and research collaboration of A. K. Mitra, Ph.D. Specific research from the laboratory of JMH was supported in part by U.S. Public Health Service grant EY06311 and EY08871; EY02377 (Eye Center Core Grant); an unrestricted grant from Research to Prevent Blindness (RPB); Dr. Hill is an RPB Scientific Investigator Award recipient. The authors wish to acknowledge the secretarial assistance of Mrs. Carole Hoth. The authors also wish to acknowledge the student workers with special thanks to Ms. Kristina Braud and Ms. Kathy Vu. None of the authors have any financial or proprietary interest in any agents or devices mentioned in this review.

REFERENCES 1. Sing, P., and Maibach, H. I. (1994). Iontophoresis in drug delivery: Basic

principles and applications. Crit. Rev. Therp. Drug Carrier Systems, 11:161– 213. 2. Guy, R. H., Kalia, Y. N., Delgado-Charro, M. B., Merino, V., Lopez, A., and Marro, D. (2000). Iontophoresis: electrorepulsion and electroosmosis. J. Control Release , 64:129–132. 3. Merino, V., Kalia, Y. N., and Guy, R. H. (1997). Transdermal therapy and diagnosis by iontophoresis. Trends Biotechnol, 15:288–290.

Ocular Iontophoresis 397 4. Duke-Elder, S. (1962). Iontophoresis. In The Foundations of Ophthalmology,

Vol. VII. C. V. Mosby, St. Louis, pp. 507–514. 5. Harris, R. (1967). Iontophoresis, in Therapeutic Electricity and Ultraviolet Radiation (S. Licht, ed.), Waverly Press, Baltimore, pp. 156–178. 6. Banga, A. K., and Chien, Y. W. (1988). Iontophoretic delivery of drugs: fundamentals, development and biomedical applications. J. Control Release,

7 :1–24. 7. Nair, V, Pillai, O, Poduri, R., and Panchagnula, R. (1999). Transdermal iontophoresis. Part I: Basic principles and considerations. Meth. Find. Exp. Clin. Pharmacol ., 21:139–151. 8. Tyle, P. (1986). Iontophoretic devices for drug delivery. Review. Pharm. Res.,

3 :318–326. 9. Garrison, J. (1998). Iontophoresis: an alternative drug-delivery system. Med. Device Technol ., 9:32–36. 10. Hirvonen, J., Kalia, Y. N., and Guy, R. H. (1996). Transdermal delivery of peptides by iontophoresis. Nature Biotechnol., 14:1710–1713. 11. Shofner, R. S., Kaufman, H. E., and Hill, J. M. (1989). New horizons in ocular drug delivery. Ophthalmol. Clin. North Am., 2:15–24. 12. Sarraf, D., and Lee, D. A. (1994). The role of iontophoresis in ocular drug delivery. J. Ocular Pharm., 10:69–81. 13. Sasaki, H., Yamamura, K., Mukai, T., Nishida, K., Nakamura, J., Nakashima, M., and Ichikawa, M. (1999). Enhancement of ocular drug pene- tration. Crit. Rev. Ther. Drug Carrier Syst., 16:85–146. 14. Shriber, W. J. (1975). The direct current and ion transfer. In: A Manual of Electrotherapy (W. J. Shriber, ed.). Lea & Febiger, Philadelphia, p. 124. 15. Turrell, W. J. (1921). Therapeutic action of the constant current. Proc. R. Soc. Med ., 14:41–52. 16. Morton, W. J. (1898). Cataphoresis of Electric Medicament Surgery. American Technical Book, New York. 17. Leduc, S. (1900). Introduction of medicinal substances into the depth of tis- sues by electric current. Ann. Electrobiol., 3:545–550. 18. Leduc, S. (1908). Electric Ions and Their Use in Medicine. Rebman Ltd., London. 19. Wirtz, R. (1908). Die Ionentherapie in der Augenheilkunde. Klin. Monatsbl. Augenheilkd ., 46:543–579. 20. Morisot, L. (1927). L’iontherapie ou ionisation appliquee au traitement des affections ocu-laires. Clin. Ophthalmol., 31:5–16. 21. Erlanger, G. (1936). On the scientific and practical value of ionization in ophthalmology. Recent advances and researchers. Br. J. Ophthalmol.,

20 :213–229. 22. Erlanger, G. (1939). Iontophoretic medication in ophthalmology. Theoretic and practical aspects. Arch. Phys. Ther., 20:16–24. 23. Erlanger, G. (1954). Iontophoresis: a scientific and practical tool in ophthal- mology. Ophthalmologica, 128:232–246.

398 Myles et al. 24. Von Sallmann, L., and Meyer, K. (1944). Penetration of penicillin into the eye.

Arch. Ophthalmol ., 31:1–7. 25. Von Sallmann, L. (1944). Penicillin and sulfadiazine in the treatment of experimental intraocular infections with Staphylococcus aureus and Clostridium welchii . Arch. Ophthalmol., 31:54–61. 26. Von Sallmann, L. (1945). Penetration of penicillin into the eye. Arch. Ophthalmol ., 34:195–201. 27. Witzel, S. H., Fielding, I. Z., and Ormsby, H. L. (1956). Ocular penetration of antibiotics by iontophoresis. Am. J. Ophthalmol., 42:89–95. 28. Ichihashi, T. (1936). Effect of drugs on the sweat glands by cataphoresis and an effective method for suppression of local sweating: Observation on the effect of diaphoretics and adiaphoretics. J. Oriental Med., 25:101–102. 29. Gibson, L. E., and Cooke, R. E. (1959). A test for concentration of electro- lytes in sweat in cystic fibrosis of the pancreas utilizing pilocarpine by ionto- phoresis. Pediatrics., 23:545–549. 30. Carter, E. P., Barrett, A. D., Heeley, A. F., and Kuzemko, J. A. (1984). Improved sweat test method for the diagnosis of cystic fibrosis. Arch. Dis. Child ., 59:919–922. 31. Hall, S. K., Stableforth, D. E., and Green, A. (1990). Sweat sodium and chloride concentrations—essential criteria for the diagnosis of cystic fibrosis in adults. Ann. Clin. Biochem., 27:318–320. 32. Sloan, J. B., and Soltani, K. (1986). Iontophoresis in dermatology: A review. J. Am. Acad. Dermatol ., 15:671–684. 33. Kassan, D. G., Lynch, A. M., and Stiller, M. J. (1996). Physical enhancement of dermatologic drug delivery: Iontophoresis and phonophoresis. J. Am. Acad. Dermatol ., 34:657–666. 34. Stolman, L. P. (1998). Treatment of hyperhidrosis. Dermatol. Clin., 16:863– 869.

35. Murphy, R., and Harrington, C.I. (2000). Treating hyperhidrosis: Iontophoresis should be tried before other treatments (letter). BMJ, 321 :702–703. 36. Gangarosa, L. P., and Park, N. H. (1978). Practical considerations in ionto- phoresis of fluoride for desensitizing dentin. J. Prosthet. Dent., 39:173–178. 37. Krauser, J. T. (1986). Hypersensitive teeth. Part II: Treatment. J. Prosthet. Dent ., 56(3):307–311. 38. Greenbaum, S. S., and Bernstein, E. F. (1994). Comparison of iontophoresis of lidocaine with a eutetic mixture of lidocaine and prilocaine (EMLA) for topically administered local anesthesia. J. Dermatol. Surg. Oncol., 20:579–583. 39. Zempsky, W. T., Anand, K. J. S., Sullivan, K. M., Fraser, D., and Cucina, K. (1998). Lidocaine iontophoresis for topical anesthesia before intravenous line placement in children. J. Pediatr., 132:1061–1063. 40. DeCou, J. M., Abrams, R. S., Hammond, J. H., Lowder, L. R., and Gauderer, W. L. (1999). Iontophoresis: a needle-free, electrical system of local anesthesia delivery for pediatric surgical office procedures. J. Pediatr. Surg. , 34:946–949.

Ocular Iontophoresis 399 41. Squire, S. J., Kirchhoff, K. T., and Hissong, K. (2000). Comparing two meth-

ods of topical anesthesia used before intravenous cannulation in pediatric patients. J. Pediatr. Health Care., 14:68–72. 42. Hill, J. M., O’Callaghan, R. J., and Hobden, J. A. (1993). Ocular iontophor- esis. In: Ophthalmic Drug Delivery Systems (A. K. Mitra, ed.). Marcel Dekker, New York, pp. 331–354. 43. Callegan, M. C., O’Callaghan, R. J., and Hill, J. M. (1994). Pharmacokinetic considerations in the treatment of bacterial keratitis. Clin. Pharmacokinet.,

27 :129–149. 44. Pillai, O., Nair, V., Poduri, R., and Panchagnula, R. (1999). Transdermal iontophoresis. Part II: Peptide and protein delivery. Methods Find. Exp. Clin. Pharmacol ., 21:229–240. 45. Jones, R. F., and Maurice, D. M. (1966). New methods of measuring the rate of aqueous flow in man with fluorescein. Exp. Eye Res., 5:208–220. 46. Starr, P. A. J. (1966). Changes in aqueous flow determined by fluorophoto- metry. Trans. Ophthalmol. Soc. U.K., 86:639–646. 47. Holm, O. (1968). A photogrammetric method for estimation of the pupillary aqueous flow in the living human eye. I. Acta Ophthalmol., 46:254–277. 48. Brubaker, R. F. (1982). The flow of aqueous humor in the human eye. Trans. Am. Ophthalmol. Soc ., 80:391–474. 49. Latina, M. A., Dobrogowski, M., March, W. F., and Birngruber, R. (1990). Laser sclerostomy by pulsed-dye laser and goniolens. Arch. Ophthalmol., 108 :1745–1750. 50. Latina, M. A., Melamed, S., March, W. F., Kass, M. A., and Kolker, A. E. (1992). Gonioscopic Ab Interno Laser Sclerostomy. A pilot study in glaucoma patients. Ophthalmology, 99:1736–1744. 51. Melamed, S., Solomon, A., Neumann, D., Hirsch, A., Blumenthal, M., and Belkin, M. (1993). Internal sclerostomy using laser ablation of dyed sclera in glaucoma patients: a pilot study. Br. J. Ophthalmol., 77;139–144. 52. Grossman, R. E., Sarraf, D., and Lee, D. A. (1993). Iontophoresis of methy- lene blue for gonioscopic pulsed dye laser sclerostomy. J. Ocul. Pharmacol.,

9 :277–285. 53. Sarraf, D., and Lee, D. A. (1993). Iontophoresis of reactive black 5 for pulsed dye laser sclerostomy. J. Ocul Pharmacol. Ther., 9:25–33. 54. Kitazawa, Y., Nose, H., and Horie, T. (1973). The effects of chemical sym- pathectomy on intraocular pressure of the normal human subjects. Acta Soc. Ophthalmol. Jpn ., 77:1901–1903. 55. Kitazawa, Y., and Horie, T. (1974). Denervation supersensitivity induced by chemical sympathectomy with 6-hydroxydopamine. Jpn. J. Ophthalmol.,

18 :109–118. 56. Kitazawa, Y., Nose, H., and Horie, T. (1975). Chemical sympathectomy with 6-hydroxydopamine in the treatment of primary open-angle glaucoma. Am. J. Ophthalmol ., 79:98–103.

400 Myles et al. 57. Watanabe, H., Levene, R. Z., and Bernstein, M. R. (1977). 6-

Hydroxydopamine therapy in glaucoma. Trans. Am. Acad. Ophthalmol. Otolaryngol ., 83:69–77. 58. Colasanti, B. K., and Trotter, R. R. (1977). Enhanced ocular penetration of the methyl ester of alpha-methyl-para-tyrosine after iontophoresis. Arch. Int. Pharmacodyn. Ther ., 228:171–176. 59. Blumenkranz, M. S., Clafin, A., and Hajek, A. S. (1984). Selection of ther- apeutic agents for intraocular proliferative disease. Arch. Ophthalmol., 102 :598–604. 60. Kondo, M., and Araie, M. (1989). Iontophoresis of 5-fluorouracil into the conjunctiva and sclera. Invest. Ophthalmol. Vis. Sci., 30:583–585. 61. Zempsky, W. T., and Ashburn, M. A. (1998). Iontophoresis: noninvasive drug delivery. Am. J. Anesthesiol., 25:158–162. 62. Sisler, H. A. (1978). Iontophoretic local anesthesia for conjunctival surgery. Ann. Ophthalmol ., 10:597–598. 63. Meyer, D. R., Lindberg, J. V., and Vasquez, R. J. (1990). Iontophoresis for eyelid anesthesia. Ophthalmic Surg., 21:845–848. 64. Havener, W. H. (1978). Corticosteroid therapy. In: Ocular Pharmacology, 4th

ed. CV Mosby, St. Louis, pp. 143–174. 65. Lachaud, J. P. (1965). Considerations on the use of corticosteroids by ioniza- tion in certain ocular diseases. Bull. Soc. Ophthalmol. France, 65:84–89. 66. Lam, T. T., Edward, D. P., Zhu, X., and Tso, M. O. M. (1989). Transscleral iontophoresis of dexamethasone. Arch. Ophthalmol., 107:1368–1371. 67. Behar-Cohen, F. F., Parel, J.-M., Pouliquen, Y., Thillaye-Goldenberg, B., Goureau, O., Heydolph, S., Courtois, Y., and DeKozak, Y. (1997). Iontophoresis of dexamethasone in the treatment of endotoxin-induced-uvei- tis in rats. Exp. Eye Res., 65:533–545. 68. Pagano, G., Bruno, A., Cavallo-Perin, P., Cesco, L., and Imbimbo, B. (1989). Glucose intolerance after short-term administration of corticosteroids in healthy subjects. Arch. Int. Med., 149:1098–1091. 69. Yoshida, M., Yoshimura, N., Hangai, M., Tanihara, H., and Honda, Y. (1994). Interleukin-1 a, interleukin-1 b, and tumor necrosis factor gene expres- sion in endotoxin-induced uveitis. Invest. Ophthalmol. Vis. Sci., 35:1107–1113. 70. Grossman, R. E., Chu, D. F., and Lee, D. A. (1990). Regional ocular genta- micin levels after transcorneal and transscleral iontophoresis. Invest. Ophthalmol. Vis. Sci ., 31:909–916. 71. Fishman, P. H., Jay, W. M., Hill, J. M., Rissing, J. P., and Shockley, R. K. (1984). Iontophoresis of gentamicin into aphakic rabbit eyes: sustained vitreal levels. Invest. Ophthalmol. Vis. Sci., 25:343–345. 72. Hughes, L., and Maurice, D. (1984). A fresh look at iontophoresis. Arch. Ophthalmol. , 102;1825–1829. 73. Frucht-Pery, J., Solomon, A., Doron, R., Ever-Hadani, P., Manor, O., and Shapiro, M. (1996). Efficacy of iontophoresis in the rat cornea. Graefes Arch. Clin. Exp. Ophthalmol ., 234:765–769.

Ocular Iontophoresis 401 74. Frucht-Pery, J., Goren, D., Solomon, A., Siganos, C. S., Mechoulam, H.,

Ever-Hadani, P., and Shapiro, M. (1999). The distribution of gentamicin in the rabbit cornea following iontophoresis to the central cornea. J. Ocular Pharm. Therapeut ., 15:251–256. 75. Barza, M., Peckman, C., and Baum, J. (1986). Transscleral iontophoresis of cefazolin, ticarcillin, and gentamicin in the rabbit. Ophthalmology, 93:133– 139. 76. Barza, M., Peckman, C., and Baum, J. (1987). Transscleral iontophoresis as an adjunctive treatment for experimental endophthalmitis. Arch. Ophthalmol., 105 :1418–1420. 77. Burstein, N. L., Leopold, I. H., and Bernaacchii, D. B. (1985). Transscleral iontophoresis of gentamicin. J. Ocul. Pharmacol., 1:363–368. 78. Barza, M. M., Peckman, C., and Baum, J. (1987). Transscleral iontophoresis of gentamicin in monkeys. Invest. Ophthalmol. Vis. Sci., 28:1033–1036. 79. Rootman, D. S., Hobden, J. A., Jantzen, J. A., Gonzales, V. R., O’Callaghan, R. J., and Hill, J. M. (1988). Iontophoresis of tobramycin for the treatment of experimental Pseudomonas keratitis in the rabbit. Arch. Ophthalmol., 106:262– 265. 80. Hobden, J. A., Rootman, D. S., O’Callaghan, R. J., and Hill, J. M. (1988). Iontophoretic application of tobramycin to uninfected and Pseudomonas aer- uginosa -infected rabbit corneas. Antimicrob. Agents Chemother., 32:978–981. 81. Rootman, D. S., Jantzen, J. A., Gonzalez, J. R. Fischer, M., Beuerman, R., and Hill, J. M. (1988). Pharmacokinetics and safety of transcorneal ionto- phoresis of tobramycin in the rabbit. Invest. Ophthalmol. Vis. Sci., 29:1397– 1401. 82. Hobden, J. A., O’Callaghan, R. J., Hill, J. M., Reidy, J. J., Rootman, D. S., and Thompson, H. W. (1989). Tobramycin iontophoresis into corneas infected with drug-resistant Pseudomonas aeruginosa. Curr. Eye Res.,

8 :1163–1169. 83. Physician’s Desk Reference . (1977). Medical Economics Company, Montvale, N.J. 84. Hobden, J. A., Reidy, J. J., O’Callaghan, R. J., and Hill, J. M. (1990). Ciprofloxacin iontophoresis for aminoglycoside-resistant Pseudomonas kera- titis. Invest. Ophthalmol. Vis. Sci., 31:1940–1944. 85. Yoshizumi, M. O., Cohen, D., Verbukh, I., Leinwand, M., Kim, J., and Lee,

D. A. (1991). Experimental transscleral iontophoresis of ciprofloxacin. J. Ocular Pharm ., 7:163–167. 86. Choi, T. B., and Lee, D. A. (1988). Transscleral and transcorneal iontophor- esis of vancomycin in rabbit eyes. J. Ocular Pharmacol., 4:153–164. 87. Grossman, R., and Lee, D. A. (1989). Transscleral and transcorneal ionto- phoresis of ketoconazole in the rabbit eye. Ophthalmology, 96:724–729. 88. Boniuk, I. (1972). The cytomegaloviruses and the eye. Int. Ophthalmol. Clin.,

402 Myles et al. 89. Miller, R. F., Howard, M. R., Frith, P., Perrons, C. J., Pecorella, I., and

Lucas, S. B. (2000). Herpes-virus infection of eye and brain in HIV. Sex. Transm. Inf ., 76:282–286. 90. Friedman, A. H., Orellana, J., Freeman, W. R., Luntz, M. H., Starr, M. B., Tapper, M. L., et al. (1983). Cytomegalovirus retinitis: a manifestation of the acquired immune deficiency syndrome (AIDS). Br. J. Ophthalmol., 67:372– 380. 91. Oberg, B. (1983). Antiviral effects of phosphonoformate (PFA foscarnet sodium). Pharmacol. Ther., 19:387–415. 92. Fannibg, M. M., Read, S.. E., Benson, M., Vas, S., Rachlis, A., Kozousek, V., et al. (1990). Foscarnet therapy of cytomegalovirus retinitis in AIDS. J. Acquir. Immune Defic. Syndr ., 3:472–479. 93. Jacobson, M. A., and O’Donnell, J. J. (1991). Approaches to the treatment of cytomegalovirus retinitis: Ganciclovir and Foscarnet. J. Acquir. Immune Defic ., Syndr., 4 (Suppl. 1):S11–S15. 94. She, S.-C., Peyman, G. A., and Schulman, J. A. (1988). Toxicity of intravitreal injection of foscarnet in the rabbit eye. Int. Ophthalmol., 12:151–154. 95. Diaz-Llopis, M., Chipont, E., Sanchez, S., Espana, E., Navea, A., and Menezo, J. L. (1992). Intravitreal foscarnet for cytomegalovirus retinitis in

a patient with acquired immunodeficiency syndrome. Am. J. Ophthalmol., 114 :742–747. 96. Kreiger, A. E., Foos, R. Y., and Yoshizumi, M. O. (1992). Intravitreous granulation tissue and retinal detachment following pars plana injection for cytomegalovirus retinopathy. Graefe’s Arch. Clin. Exp. Ophthalmol., 230:197– 198. 97. Sarraf, D., Equi, R. A., Holland, G. N., Yoshizumi, M. O., and Lee, D. A. (1993). Transscleral iontophoresis of foscarnet. Am. J. Ophthalmol., 115:748– 754. 98. Yoshizumi, M. O., Lee, D. A., Sarraf, D. A., Equi, R. A., and Verdon, W. (1995). Ocular toxicity of iontophoretic foscarnet in rabbits. J. Ocul. Pharmacol. Ther ., 11:183–189. 99. Anand, R., Nightingale, S. D., Fish, R. H., Smith, T. J., and Ashton, P. (1993). Control of cytomegalovirus retinitis using sustained release of intra- ocular ganciclovir. Arch., Ophthalmol., 111:223–227.

100. Yoshizumi, M. O., Roca, J. A., Lee, D. A., Lee, G., and Gomez, I. (1996). Ocular iontophoretic supplementation of intravenous foscarnet therapy. Am. J. Ophthalmol ., 122:86–90.

101. Yoshizumi, M. O., Dessouki, A., Lee, D. A., and Lee, G. (1997). Determination of Ocular toxicity in multiple applications of foscarnet ionto- phoresis. J. ocular Pharmacol. Therapeut., 13:529–536.

102. Hill, J. M., Wen, R., and Halford, W. P. (1998). Pathogenesis and molecular biology of ocular HSV in the rabbit. In: Herpes Simplex Virus Protocols (MS Brown, AR Maclean, eds.). Humana Press, Inc., Totowa, NJ, pp. 291–315.

103. Kaufman, H. E., and Rayfield, M. A. (1988). In: The Cornea: Viral Conjunctivitis and Keratitis (H. E. Kaufman, B. A. Barron, M. B.

Ocular Iontophoresis 403 McDonald, and S. R. Waltman, eds.). Churchill Livingstone, New York, pp.

299–331. 104. Hill, J. M., Gangarosa, L. P., and Park, N. H. (1977). Iontophoretic applica- tion of antiviral chemotherapeutic agents. Ann. NY Acad. Sci., 284:604–612. 105. Hill, J. M., Park, N. H., Gangarosa, L. P., Hull, D. S., Tuggle, C. L., Bowman, K., and Green, K. (1978). Iontophoretic application of vidarabine monophosphate into rabbit eyes. Invest. Ophthalmol. Vis. Sci., 17:473–476.

106. Kwon, B. S., Gangarosa, L. P., Park, N. H., Hull, D. S., Fineberg, E., Wiggins, C., and Hill, J. M. (1979). Effects of iontophoretic and topical appli- cation of antiviral agents in treatment of experimental HSV-1 keratitis in rabbits. Invest. Ophthalmol. Vis. Sci., 18:984–988.

107. Hill, J. M., Kwon, B. S., Burch, K. D., deBack, J., Whang, I., Jones, G. T., Luke, B., Andrews, P., Harp, R., Shimomura, Y., Hull, D. S., and Gangarosa, L. P. (1982). Acyclovir and vidarabine monophosphate: a comparison of iontophoretic and intravenous administration for the treatment of HSV-1 stromal keratitis. Am. J. Med., 73:300–304.

108. Stevens, J. G., Newburn, A. B., and Cook, M. L. (1972). Latent herpes sim- plex virus from trigeminal ganglia of rabbits with recurrent eye infection. Nature (New Biology ), 235:216–217.

109. Stevens, J. G. (1994). Overview of herpesvirus latency. Semi. Virol., 5:191–196. 110. Rivera, L., Beuerman, R. W., and Hill, J. M. (1988). Corneal nerves contain

intra-axonal HSV-1 after virus reactivation by epinephrine iontophoresis. Curr. Eye Res ., 7:1001–1008.

111. Schmidt, D. D., Zyzanski, S., Ellner, J., Kumar, M. L., and Arno, J. (1985). Stress as a precipitating factor in subjects with recurrent herpes labialis. J. Family Pract ., 20:359–366.

112. Varnell, E. D., Kaufman, H. E., Hill, J. M., and Thompson, H. W. (1995). Cold stress-induced recurrences of herpetic keratitis in the squirrel monkey. Invest. Ophthalmol. Vis. Sci ., 36:1181–1183.

113. Hill, J. M., Garza, H. H., Helmy, M. F., Cook, S. D., Osborne, P. A., Johnson, E. M., Thompson, H. W., Green, L. C., O’Callaghan, R. J., and Gebhardt, B. M. (1997). Nerve growth factor antibody stimulates reactivation of ocular herpes simplex virus type 1 in latently infected rabbits. J. Neurovirol.,

3 :206–211. 114. Stanberry, L. R. (1994). Animal models and HSV latency. Sem. Virol., 5:213– 219. 115. Hill, J. M., Haruta, Y., and Rootman, D. S. (1987). Adrenergically induced

recurrent HSV-1 corneal epithelial lesions. Curr. Eye Res., 6:1065–1071. 116. Hill, J. M., Rayfield, M. A., and Haruta, Y. (1987). Strain specificity of spontaneous and adrenergically induced HSV-1 ocular reactivation in latently infected rabbits. Curr. Eye Res., 6:91–97.

117. Hill, J. M., Shimomura, Y., Kwon, B. S., and Gangarosa, L. P. (1986). Iontophoresis of epinephrine isomers to rabbit eyes induced HSV-1 ocular shedding. Invest. Ophthalmol. Vis. Sci., 26:1299–1303.

404 Myles et al. 118. Kwon, B. S., Gangarosa, L. P., Burch, K. D., deBack, J., and Hill, J. M.

(1981). Induction of ocular herpes simplex virus shedding by iontophoresis of epinephrine into rabbit cornea. Invest. Ophthalmol. Vis. Sci., 21:442–449.

119. Kwon, B. S., Gangarosa, L. P., Green, K., and Hill, J. M. (1982). Kinetics of ocular herpes simplex virus shedding induced by epinephrine iontophoresis. Invest. Ophthalmol. Vis. Sci ., 22:818–821.

120. Willey, D. E., Trousdale, M. D., and Nesburn, A. B. (1984). Reactivation of murine latent HSV infection by epinephrine iontophoresis. Invest. Ophthalmol. Vis. Sci ., 25: 945–950.

121. Gordon, Y. J., Araullo-Cruz, T. P., Romanowski, E., Ruziczka, L., Balouris, C., Oren, J., Cheng, K. P., and Kim, S. (1986). The development of an improved murine iontophoresis reactivation model for the study of HSV-1 latency. Invest. Ophthalmol. Vis. Sci., 27:1230–1234.

122. Varnell E. D., Kaufman, H. E., Hill, J. M., and Wolf, R. H. (1987). A primate model for acute and recurrent herpetic keratitis. Curr. Eye Res., 6:277–279. 123. Rootman, D. S., Haruta, Y., and Hill, J. M. (1990). Reactivation of HSV-1 in primates by transcorneal iontophoresis of adrenergic agents. Invest. Ophthalmol. Vis. Sci ., 31:597–600.

124. Hill, J. M., Kwon, B. S., Shimomura, Y., Colborn, G. L., Yaghmai, F., and Gangarosa, L. P. (1983). Herpes simplex virus recovery in neural tissues after ocular HSV shedding induced by epinephrine iontophoresis to the rabbit cornea. Invest. Ophthalmol. Vis. Sci., 24:243–247.

125. Shimomura, Y., Gangarosa, L. P., Sr., Kataoka, M., and Hill, J. M. (1983). HSV-1 shedding by iontophoresis of 6-hydroxydopamine followed by topical epinephrine. Invest Ophthalmol Vis. Sci., 24:1588–1594.

126. Hill, J. M., Dudley, J. B., Shimomura, Y., and Kaufman, H. E. (1986). Quantitation and kinetics of induced HSV-1 ocular shedding. Curr. Eye. Res ., 5:241–246.

127. Haruta, Y., Rootman, D. S., and Hill, J. M. (1988). Recurrent HSV-1 corneal epithelial lesions by timolol iontophoresis in latently infected rabbits. Invest. Ophthalmol. Vis. Sci ., 29:387–392.

128. Hill, J. M., Shimomura, Y., Dudley, J. B., Berman, E., Haruta, Y., Kwon, B. S., and Maguire, L. J. (1987). Timolol induces HSV-1 ocular shedding in the latently infected rabbit. Invest. Ophthalmol. Vis. Sci., 28:585–590.

129. Rootman, D. S., Haruta, Y., Hill, J. M., and Kaufman, H. E. (1989). Trifluridine decreases ocular HSV-1 recovery, not recurrent HSV-1 lesions following timolol iontophoresis in the rabbit. Invest. Ophthalmol. Vis. Sci.,

30 :678–683. 130. Kaufman, H. E., Varnell, E. D., Gebhardt, B. M., Thompson, H. W., and Hill, J. M. (1996). Propranolol suppression of ocular HSV-1 recurrence and associated corneal lesions following spontaneous reactivation in the rabbit. Curr. Eye Res ., 9:1015–1021.

131. Gebhardt, B. M., and Kaufman, H. E. (1995). Propranolol suppresses reacti- vation of herpesvirus. Antiviral Res., 27:255–261.

Ocular Iontophoresis 405 132. Garza, H. H., Jr., and Hill, J. M. (1997). Effect of a beta-adrenergic antago-

nist, propranolol, on induced HSV-1 ocular recurrence in latently infected rabbits. Curr. Eye Res., 16:453–458.

133. Haruta, Y., Rootman, D. S., Xie, L., Kiritoshi, A., and Hill, J. M. (1989). Recurrent HSV-1 corneal lesions in rabbits induced by cyclophosphamide and dexamethasone. Invest. Ophthalmol. Vis. Sci., 30:371–376.

134. Wagner, E. K., and Bloom, D. C. (1997). Experimental investigation of herpes simplex virus latency. Clin. Microbiol. Rev., 10:419–443. 135. Miller, C. S., Danaher, R. J., and Jacob, R. J. (1998). Molecular aspects of herpes simplex virus I latency, reactivation, and recurrence. Crit. Rev. Oral Biol. Med ., 9:541–562.

136. Millhouse, S., and Wigdhal, B. (2000). Molecular circuitry regulating herpes simplex virus type 1 latency in neurons. J. Neurovirol., 6:6–24. 137. Stevens, J. G., Wagner, E. K., Devi-Rao, G. B., Cook, M. L., and Feldman, L. T. (1987). RNA complementary to a herpesvirus a gene mRNA is promi- nent in latently infected neurons. Science, 235:1056–1059.

138. Spivak, J. G., and Fraser, N. W. (1987). Detection of herpes simplex virus type 1 transcripts during latent infection in mice. J. Virol., 61:3841–3847. 139. Javier, R. T., Stevens, J. G., Dissette, V. B., and Wagner, E. K. (1988). A herpes simplex virus transcript abundant in latently infected neurons is dis- pensable for establishment of the latent state. Virology, 166:254–257.

140. Stevens, J. G. (1989). Human herpesviruses: a consideration of the latent state. Microbiol. Rev ., 53:318–332. 141. Rock, D. L., Nesburn, A. B., Ghiasi, H., Ong, I., Lewis, T. L., Lokensgard, J. R., and Wechsler, S. L. (1987). Detection of latency-related viral RNAs in trigeminal ganglia of rabbits latently infected with herpes simplex virus type 1. J. Virol ., 61:3820–3826.

142. Cook, S. D., Hill, J. M., Lynas, C., and Maitland, N. J. (1991). Latency- associated transcripts in corneas and ganglia of HSV-1 infected rabbits. Br. J. Ophthalmol ., 75:644–648.

143. Croen, K. D., Ostrove, J. M., Dragovic, L. J., Smialek, J. E., and Straus, S. E. (1987). Latent herpes simplex virus in human trigeminal ganglia. Detection of an immediate early gene ‘‘anti-sense’’ transcript by in situ hybridization. N. Engl. J. Med ., 317:1427–1432.

144. Kaye, S. B., Lynas, C., Patterson, A., Risk, J. M., McCarthy, K., and Hart, C. A. (1991). Evidence of herpes simplex viral latency in the human cornea. Br. J. Ophthalmol ., 75:195–200. 145. Fraser, N. W., Block, T. M., and Spivak, J. G. (1992). The latency-associated transcripts of herpes simplex virus: RNA in search of a function. Virology 191 :1–8.

146. Wagner, E. K., Flanagan, W. M., Devi-Rao, G., Zhang, Y. F., Hill, J. M., Anderson, K. P., and Stevens, J. G. (1988). The herpes simplex virus latency- associated transcript is spliced during the latent phase of infection. J. Virol.,

406 Myles et al. 147. Block, T. M., and Hill, J. M. (1997). The latency associated transcripts (LAT)

of herpes simplex virus: still no end in sight. J. Neurovirol., 3:313–321. 148. Farrell, M. J., Dobson, A. T., and Feldman, L. T. (1991). Herpes simplex virus-latency-associated transcript is a stable intron. Proc. Natl. Acad. Sci. USA , 88:790–794.

149. Hill, J. M., Sedarati, F., Javier, R. T., Wagner, E. K., and Stevens, J. G. (1990). Herpes simplex virus latent phase transcription facilitates in vivo reac- tivation. Virology, 174:117–125.

150. Hill, J. M., Maggioncalda, J. B., Garza, H. H., Jr., Su, Y.-H., Fraser, N. W., and Block, T. M. (1996). In vivo epinephrine reactivation of ocular herpes simplex virus type 1 in the rabbit is correlated to a 370-base-pair region

located between the promoter and the 5 0 end of the 2.0-kilobase latency-asso- ciated transcript. J. Virol., 70:7270–7274. 151. Bloom, D. C., Devi-Rao, G. B., Hill, J. M., Stevens, J. G., and Wagner, E. K. (1994). Molecular analysis of herpes simplex virus type 1 during epinephrine- induced reactivation of latently infected rabbits in vivo. J. Virol., 68:1283– 1292.

152. Bloom, D. C., Stevens, J. G., Hill, J. M., and Tran, R. K. (1997). Mutagenesis of a cAMP response element within the latency-associated transcript promoter of HSV-1 reduces adrenergic reactivation. Virology, 236:202–207.

153. Colgin, M. A., Smith, R. L., and Wilcox, C. L. (2001). Inducible cyclic AMP early repressor produces reactivation of latent herpes simplex virus type 1 in neurons in vitro. J. Virol., 75:2912–2920.

154. Loutsch, J. M., Perng, G.-C., Hill, J. M., Zheng, X., Marquart, M. E., Block, T. M., Ghiasi, H., Nesburn, A. B., and Wechsler, S. L. (1999). Identical 371- base-pair deletion mutations in the LAT genes of herpes simplex virus type 1 McKrae and 17syn+ result in different in vivo reactivation phenotypes. J. Virol ., 73:767–771.

155. Zheng, X., Marquart, M. E., Loutsch, J. M., Shah, P., Sainz, B., Ray, A., O’Callaghan, R. J., Kaufman, H. E., and Hill, J. M. (1999). HSV-1 migration in latently infected and naive rabbits after penetrating keratoplasty. Invest. Ophthalmol. Vis. Sci ., 40:2490–2497.

156. McGill, J. (1991). Herpes simplex latency and the eye. Br. J. Ophthalmol., 75 :641–642. 157. Cook, S. D., Ophth, F. C., and Hill, J. M. (1991). Herpes simplex virus: molecular biology and the possibility of corneal latency. Surv. Ophthalmol., 36 :140–148. 158. Bloom, D. C., Hill, J. M., Devi-Rao, G., Wagner, E. K., Feldman, L. T., and Stevens, J. G. (1996). A 348-base pair region in the latency-associated tran- script facilitates herpes simplex virus type 1 reactivation. J. Virol., 70:2449– 2459.

159. Perng, G.-C., Slanina, S. M., Ghiasi, H., Nesburn, A. B., and Wechsler, S. L. (1996). A 371-nucleotide region between the herpes simplex virus type 1 (HSV- 1) LAT promoter and the 2-kilobase LAT is not essential for efficient sponta- neous reactivation of latent HSV-1. J. Virol., 70:2014–2018.

Ocular Iontophoresis 407 160. Hill, J. M., Garza, H. H., Su, Y. H., Meegalla, R., Hanna, L. A., Loutsch, J.

M., Thompson, H. W., Varnell, E. D., Bloom, D. C., and Block, T. M. (1997). A 437-base pair deletion at the beginning of the latency-associated transcript promoter significantly reduced adrenergically induced herpes simplex virus type 1 ocular reactivation in latently infected rabbits. J. Virol., 71:6555–6559.

161. Devi-Rao, G. B., Aquilar, J. S., Rice, M. K., Garza, H. H., Jr., Bloom, D. C., Hill, J. M., and Wagner, E. K. (1997). Herpes simplex virus genome replica- tion and transcription during induced reactivation in the rabbit eye. J. Virol.,

71 :7039–7047. 162. Behar-Cohen, F. F., Savoldelli, M., Parel, J. M., Goureau, O., Thillaye- Goldenberg, B., Courtois, Y., Pouliquen, Y., and de Kozak, Y. (1998). Reduction of corneal edema in endotoxin-induced uveitis after application of L-NAME as nitric oxide synthase inhibitor in rats by iontophoresis. Invest. Ophthalmol. Vis. Sci ., 39:897–904.

163. Martin, R. E., Loutsch, J. M., Garza, H. H., Jr., Boedeker, D. J., and Hill, J. M. (1999). Iontophoresis of lysophosphatidic acid into rabbit cornea induces HSV-1 reactivation: evidence that neuronal signaling changes after infection. Mol. Vis ., 5:36, www.molvis.org/molvis/v5/p36/.

164. Dowd, N. P., Day, F., Timon, D., Cunningham, A. J., and Brown, L. (1999). Iontophoretic vincristine in the treatment of postherpetic neuralgia: A double- blind, randomized, controlled trial. J. Pain Symptom Manage., 17:175–180.

165. Santi, P., Volpato, N. M., Bettini, R., Catellani, P. L., Massimo, G., and Colombo, P. (1997). Transdermal iontophoresis of salmon calcitonin can reproduce the hypocalcemic effect of intravenous administration. Farmaco,

52 :445–448. 166. Chang, S. L., Hofmann, G. A., Zhang, L., Deftos, L. J., and Banga, A. K. (2000). Transdermal iontophoretic delivery of salmon calcitonin. Int. J. Pharm. , 200:107–113.

167. Mize, N. K., Buttery, M., Daddona, P., Morales, C., and Cormier, M. (1997). Reverse iontophoresis: monitoring prostaglandin E2 associated with cuta- neous inflammation in vivo. Exp. Dermatol., 6:298–302.

168. Merino, V., Lopez, A., Hochstrasser, D., and Guy, R. H. (1999). Noninvasive sampling of phenylalanine by reverse iontophoresis. J. Control Release, 61:65– 69.

169. Brasch, J., Huttemann, M., and Proksch, E. (2000). Iontophoresis of nickel elicits a delayed cutaneous response in sensitized individuals that is similar to an allergic patch test reaction. Contact Dermatitis, 42:36–41.

170. Asahara, T., Shinomiya, K., Naito, T., and Shiota, H. (1999). Induction of genes into the rabbit eye by iontophoresis. Acta Soc. Ophthalmol. Jpn., 103 :178–186.

171. Chapon, P., Voigt, M., Gautier, S., Behar-Cohen, F., O’Grady, G., and Parel, J.-M. (1999). Intraocular tissues pharmacokinetics of ganciclovir transscleral Coulomb Controlled iontophoresis in rabbits (abstr). IOVS/ARVO ,

40 (4):S189.

408 Myles et al. 172. Chauvaud, D., Behar-Cohen, F., Parel, J. M., and Renard, G. (2000).

Transscleral iontophoresis of corticosteroids: Phase II clinical trial (abstr). IOVS/ARVO 41 (4):S79.

173. Hayden, B. C., Voigt, M., Murray, T. G., Hernandez, E., Parel, J.-M., Cicciarelli, N., Feuer, W., Fulton, L., and O’Brien, J. M. (2000). Iontophoretic delivery of carboplatin in the treatment of murine transgenic retinoblastoma (abstr). IOVS/ARVO 41(4):S788.