Summary
Dorzolamide, on the basis of its pharmacological profile and lack of undesirable side effects in safety assessment studies together with the fact that it could be formulated in solution at 2%, underwent extensive clinical studies.
Early clinical studies in the development of dorzolamide have been described elsewhere (Maren, 1995; Serle and Podos, 1995). In a 1-year study in which a comparison was undertaken in patients for intraocular pressure lowering effects between 2% dorzolamide administered three times daily, 0.5% betaxolol twice daily, and 0.5% timolol twice daily, the peak reductions in intraocular pressure were 23, 21, and 25%, respectively. Tachyphylaxis did not develop to dorzolamide nor were electrolyte and/or systemic side effects encountered (Strahlman et al., 1995). The latter is consistent with results of a pharmacokinetic study in humans in which plasma levels of dorzolamide were lower than the limit of detection (5 ng/ml) at a time when the red blood cell content of dorzolamide had reached steady state which was appreciably less than the red blood cell content of the enzyme (Biollaz et al., 1995). Patients taking 0.5% timolol twice daily received either 2% dorzolamide twice daily or 2% pilocarpine four times daily for 6 months and the additional reductions in intraocular pressure elicited by dorzolamide and pilocarpine were very similar. However, pilocarpine usage resulted in a higher discontinuation rate (Strahlman et al., 1996). In a separate study in which dorzolamide and pilocarpine were compared at these dosage schedules, patients preferred dorzolamide to pilocarpine by a ratio of over 7 to 1 in terms of quality of life (Laibovitz et al., 1995).
In summary, the quest for a topical, ocular hypotensive, CA inhibitor, though time-consuming, was a successful one with the introduction of dorzolamide into general clinical practice.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Baldwin, J. J., Ponticello, G. S., Anderson, P. S., Christy, M. E., Murcko, M. A., Randall, W. C., Schwam, H., Sugrue, M. F., Springer, J. P., Gautheron, P., Grove, J., Mallorga, P., Viader, M.-P., McKeever, B. M., and Navia, M. A., 1989, Thienothiopyran-2 sulfonamides: Novel topically active carbonic anhydrase inhibitors for the treatment of glaucoma, J. Med. Chem. 32:2510–2513.
Becker, B., 1954, Decrease in intraocular pressure in man by a carbonic anhydrase inhibitor, Diamox, Am. J. Ophthalmol. 37:13–14.
Biollaz, J., Munafo, A., Buclin, T., Gervasoni, J.-P., Magnin, J. L., Jaquet, F., and Brunner-Ferber, F., 1995, Whole-blood pharmacokinetics and metabolic effects of the topical carbonic anhydrase inhibitor dorzolamide, Eur. J. Clin. Pharmacol. 47:453–460.
Blacklock, T. J., Sohar, P., Butcher, J. W., Lamanec, T., and Grabowski, E. J. J., 1993, An enantioselective synthesis of the topically-active carbonic anhydrase inhibitor MK-507: 5,6-Dihydro-(S)-4-(ethylamino)-(S)-6-methyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide-hydrochloride, J. Org. Chem. 58:1672–1679.
Bucher, J. R., Huff, J., Haseman, J. K., Eustis, S. L., Elwell, M. R., Davis, W. E., and Meierhenry, E. E., 1990, Toxicology and carcinogenicity studies of diuretics in F344 rats and B6C3F1 mice. 1. Hydrochlorothiazide, J. Appl. Toxicol. 10:359–367.
Durand-Cavagna, G., Delort, P., Gordon, L. R., Peter, C. P., and Boussiquet-Leroux, C., 1992, Urothelial hyperplasia induced by carbonic anhydrase inhibitors (CAIs) in animals and its relationship to urinary Na and pH, Fundam. Appl. Toxicol. 18:137–143.
Durand-Cavagna G., Gerin, G., and Gordon, L. R., 1996, Evaluating delayed contact hypersensitivity reactions from ocular medications, J. Toxicol. Cut. Ocular Toxicol. 15:235–248.
Fukushima, S., and Cohen, S. M., 1980, Saccharin-induced hyperplasia of the rat urinary bladder, Cancer Res. 40:734–736.
Graham, S. L., Shepard, K. L., Anderson, P. S., Baldwin, J. J., Best, D. B., Christy, M. E., Freedman, M. B., Gautheron, P., Habecker, C. N., Hoffman, J. M., Lyle, P. A., Michelson, S. R., Ponticello, G. S., Robb, C. M., Schwam, H., Smith, A. M., Smith, R. L., Sondey, J. M., Strohmaier, K. M., Sugrue, M. F., and Varga, S. L., 1989, Topically active carbonic anhydrase inhibitors. 2. Benzo(b) thiophenesulfonamide derivatives with ocular hypotensive activity, J. Med. Chem. 32:2548–2554.
Grove, J., Quint, M. P., and Plazonnet, B., 1995, Influence of pH on the ocular penetration of the topical carbonic anhydrase inhibitor, MK-507, in the albino rabbit, Invest. Ophthalmol. Vis. Sci. 36:S159.
Hageman, G. S., Zhu, X. L., Waheed, A., and Sly, W. S., 1991, Localization of carbonic anhydrase IV in a specific capillary bed of the human eye, Proc. Natl. Acad. Sci. USA 88:2716–2720.
Hansen, G. P., Tisher, C. C., and Robinson, R. R., 1980, Response of the collecting duct to disturbances of acid-base and potassium balance, Kidney Int. 17:326–337.
Hasegawa, R., and Cohen, S. M., 1986, The effect of different salts of saccharin on the rat urinary bladder, Cancer Lett. 30:261–268.
Laibovitz, R., Strahlman, E. R., Barber, B. L., and Strohmaier, K. M., 1995, Comparison of quality of life and patient preference of dorzolamide and pilocarpine as adjunctive therapy to timolol in the treatment of glaucoma, J. Glaucoma 4:306–313.
Layton, W. M., and Hallesy, D. W., 1965, Deformity of forelimbs in rats: Association with high doses of acetazolamide, Science 149:306–308.
Liesegang, T. J., 1996, Glaucoma: Changing concepts and future directions, Mayo Clin. Proc. 71:689–694.
Lippa, E. A., 1991, The eye: Topical carbonic anhydrase inhibitors, in: The Carbonic Anhydrases (R. E. Tashian, G. Gros, and N. D. Carter, eds.), pp. 171–181, Plenum Press, New York.
Lippa, E. A., von Denffer, H. A., Hofmann, H. M., and Brunner-Ferber, F. L., 1988, Local tolerance and activity of MK-927, a novel topical carbonic anhydrase inhibitor, Arch. Ophthalmol. 106:1694–1696.
Lippa, E. A., Schuman, J. S., Higginbotham, E. S., Kass, M. A., Weinreb, R. N., Skuta, G. L., Epstein, D. L., Shaw, B., Holder, D. J., Deasy, D. A., and Wilensky, J. T, 1991, MK-507 versus Sezolamide, Ophthalmology 98:308–313.
Lütjen-Drecoll, E., Lönnerholm, G., and Eichhorn, M., 1983, Carbonic anhydrase distribution in the human and monkey eye by light and electron microscopy, Graefe’s Arch. Clin. Exp. Ophthalmol. 220:285–291.
Magnusson, B., and Kligman, A. M., 1969, The identification of contact allergens by animal assay: The guinea pig maximization test, J. Invest. Dermatol. 52:268–276.
Maren, T. H., 1967, Carbonic anhydrase: Chemistry, physiology, and inhibition, Physiol. Rev. 47:595–781.
Maren, T. H., 1995, The development of topical carbonic anhydrase inhibitors, J. Glaucoma 4:49–62.
Maren, T. H., Mayer, E., and Wadsworth, B. C., 1954, Carbonic anhydrase inhibition. I. The pharmacology of Diamox® 2-acetylamino-l,3,4-thiadiazole-5-suIfonamide, Bull. Johns Hopkins Hosp. 95:199–243.
Moses, A. R. (ed.), 1981, Adler’s Physiology of the Eye, 7th ed., p. 20, Mosby, St. Louis.
Owen, R. A., Durand-Cavagna, G., Molon-Noblot, S., Boussiquet-Leroux, C., Berry, P., Tonkonoh, N., Peter, C. P., and Gordon, L. R., 1993, Renal papillary cytoplasmic granularity and potassium depletion induced by carbonic anhydrase inhibitors in rats, Toxicol. Pathol. 21:449–55.
Ponticello, G. S., Freedman, M. B., Habecker, C. N., Lyle, P. A., Schwam, H., Varga, S. L., Christy, M. E., Randall, W. C., and Baldwin, J. J., 1987, Thienothiopyran-2-sulfonamides: A novel class of water-soluble carbonic anhydrase inhibitors, J. Med. Chem. 30:591–597.
Ponticello, G. S., Freedman, M. B., Habecker, C. N., Holloway, M. K., Amato, J. S., Conn, R. S., and Baldwin, J. J., 1988, Utilization of α,β-unsaturated acids as Michael acceptors for the synthesis of thieno[2,3-b] thiopyrans, J. Org. Chem. 53:9–13.
Robbins, S. L., Cotran, R. S., and Kumar, V., 1984, Pathologic Basis of Disease, p. 1319, Saunders, Philadelphia.
Schwam, H., Michelson, S. R., Sondey, J. M., and Smith, R. L., 1984, L-645,151, a topically effective ocular hypotensive carbonic anhydrase inhibitor: Part I. Biochemistry and metabolism. Invest. Ophthalmol. Vis. Sci. 25(SuppI.):180.
Sen Gupta, K. P., 1962, Hyperplasia of urinary tract epithelium induced by continuous administration of sulphonamide derivatives, Br. J. Cancer 16:110–119.
Serle, J. B., and Podos, S. M., 1995, Topical carbonic anhydrase inhibitors in the treatment of glaucoma, Ophthalmol. Clin. North Am. 8:315–325.
Shepard, K. L., Graham, S. L., Hudcosky, R. J., Michelson, S. R., Scholz, T. H., Schwam, H., Smith, A. M., Sondey, J. M., Strohmaier, K. M., Smith, R. L., and Sugrue, M. P., 1991, Topically active carbonic anhydrase inhibitors. 4. (Hydroxyalkyl)sulfonylbenzene and (hydroxyalkyl)sulfonylthiophenesulfonamides, J. Med. Chem. 34:3098–3105.
Shibata, M. A., Tamano, S., Kurata, Y., Hagiwara, A., and Fukushima, S., 1989, Participation of urinary sodium, potassium, pH and l-ascorbic acid in the proliferative response of the bladder epithelium after the oral administration of various salts and/or ascorbic acid to rats, Food Chem. Toxic. 27:403–413.
Smith, G. M., Alexander, R. S., Christianson, D. W., McKeever, B. M., Ponticello, G. S., Springer, J. P., Randall, W. C., Baldwin, J. J., and Habecker, C. N., 1994, Positions of His-64 and a bound water in human carbonic anhydrase II upon binding three structurally related inhibitors, Protein Sci. 3:118–125.
Strahlman, E., Tipping, R., Vogel, R., and the International Dorzolamide Study Group, 1995, A double-masked, randomized 1-year study comparing dorzolamide (Trusopt), timolol and betaxolol, Arch. Ophthalmol. 113:1009–1016.
Strahlman, E. R., Vogel, R., Tipping, R., Clineschmidt, C. M., and the Dorzolamide Additivity Study Group, 1996, The use of dorzolamide and pilocarpine as adjunctive therapy to timolol in patients with elevated intraocular pressure. Ophthalmology 103:1283–1293.
Sugrue, M. F., 1996, Review: The preclinical pharmacology of dorzolamide hydrochloride, a topical carbonic anhydrase inhibitor, J. Ocular Pharmacol. Ther. 12:363–376.
Sugrue, M. F., and O’Neill-Davisso, 1991, The effect of cyclooxygenase inhibition on the ocular hypotensive action of topical carbonic anhydrase inhibitors in rabbits, J. Ocular Pharmacol. 7:201–211.
Sugrue, M. F., Gautheron, P., Schmitt, C., Viader, M. P., Conquet, P., Smith, R. L., Share, N. N., and Stone, C. A., 1985, On the pharmacology of L-645,151: A topically effective ocular hypotensive carbonic anhydrase inhibitor, J. Pharmacol. Exp. Ther. 232:534–540.
Sugrue, M. F., Mallorga, P., Schwam, H., Baldwin, J. J., and Ponticello, G. S., 1990, A comparison of L-671,152 and MK-927, two topically effective ocular hypotensive carbonic anhydrase inhibitors, in experimental animals, Curr. Eye Res. 9:607–615.
Toback, F. G., Ordonez, N. G., Bortz, S. L., and Spargo, B. H., 1976, Zonal changes in renal structure and phospholipid metabolism in potassium-deficient rats, Lab. Invest. 34:115–124.
Wang, R.-F., Serle, J. B., Podos, S. M., and Sugrue, M. F., 1991, MK-507 (L-671,152), a topically active carbonic anhydrase inhibitor, reduces aqueous humor production in monkeys, Arch. Ophthalmol. 109:1297–1299.
Wistrand, P. J., 1951, Carbonic anhydrase in the anterior uvea of the rabbit, Acta Physiol. Scand. 24:144–148.
Yamazaki, Y., Miyamoto, S., and Sawa, M., 1994, Effect of MK-507 on aqueous humor dynamics in normal human eyes, Jpn. J. Ophthalmol. 38:92–96.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2002 Kluwer Academic Publishers
About this chapter
Cite this chapter
Ponticello, G.S., Sugrue, M.F., Plazonnet, B., Durand-Cavagna, G. (2002). Dorzolamide, a 40-Year Wait. In: Borchardt, R.T., Freidinger, R.M., Sawyer, T.K., Smith, P.L. (eds) Integration of Pharmaceutical Discovery and Development. Pharmaceutical Biotechnology, vol 11. Springer, Boston, MA. https://doi.org/10.1007/0-306-47384-4_24
Download citation
DOI: https://doi.org/10.1007/0-306-47384-4_24
Publisher Name: Springer, Boston, MA
Print ISBN: 978-0-306-45743-2
Online ISBN: 978-0-306-47384-5
eBook Packages: Springer Book Archive