Selective serotonin inhibitors and their perspectives in ophthalmology

Serotonin plays an important role in maintaining homeostasis due to a broad spectrum of receptors localized in nearly every part of the body, i.e., central nervous system, vegetative ganglia, cardiac and lung reflexogenic zone, smooth muscles, internal organs and microcirculatory bloodstream, ocular tissues and optic tract. Serotonin levels can be altered by serotonin receptor blockade. Dusopharm (naftidrofuryl), a drug with complex mechanism of action, inhibits 5-HT2 receptors. Selective inhibiting of 5-HT2 receptors of vascular endothelial and smooth muscle cells decreases vasoconstrictor effects of serotonin that releases from atherosclerosisand hypoxia-damaged vascular endothelium and prevents thrombocyte aggregation. In addition, naftidrofuryl is the antagonist of vasoconstrictor action of endothelin-1 expressed by vascular endothelium. Experiments with isolated rabbit smooth myocytes demonstrate that naftidrofuryl prevents endothelin-1 binding with endothelial serotonin receptors and smooth myocyte contraction. Naftidrofuryl improves blood flow owing to its effect on blood rheological properties (increases erythrocyte deformability and decreases their aggregation). This paper reviews the studies of Dusopharm in patients with intermittent claudication, post-insult conditions, diabetic retinopathy, age-related macular degeneration (AMD), glaucoma, and central retinal vein and its branches occlusion. These data allow to include Dusopharm in the complex therapy of central retinal vein and its branches occlusion, diabetic retinopathy, age-related macular degeneration (AMD), glaucoma, peripheral retinal degeneration, and retinal detachment to improve and stabilize visual functions and microcirculation. 

1. Negri L. Vittorio Erspamer (1909-1999). Med. Secoli. 2006; 18 (1): 97-113.

2. Twarog B.M., Page I.H. Serotonin content of some mammalian tissues and urine and a method for its determination. Am. J. Physiol. 1953; 175 (1): 157-161.

3. Cohen Z., Bouchelet I., Olivier A., Villemure J.G., Ball R., Stanimirovic D.B., Hamel E. Multiple microvascular and astroglial 5-hydroxytryptamine receptors subtypes in human brain: molecular and pharmacologic characterization. J. Cereb. Blood Flow Metab. 1999; 9 (8): 908-917.

4. Kaplan K. L., Broekman M. J., Chernoff A. Platelet a-granule proteins: studies on release and subcellular localization. Blood. 1979; 53 (4): 604-618.

5. Elhadd T., Kirk G., McLaren M., Newton R., Greene S., Belch J. Endothelial integrity, soluble adhesion molecules and platelet markers in Type 1 diabetes mellitus. Diabet. Med. 1999; 16 (1): 86-87.

6. Rea M. A., Rickard G. E. 5-HT (IB) receptor agonist inhibits light-induced suppression of pineal melatonin production. Brain. Res. 2000; 2: 424-428.

7. Nash M., Flanigan Т., Leslie R., Osborne N. Serotonin 2A receptors mRNA expression in rat retinal pigment epithelial cells. Ophthalmic Res. 1999; 31 (1): 1-4.

8. Strader A.D., Woods S.C. Gastrointestinal hormones and food intake. Gastroenterology. 2005; 128; 175-191.

9. Zvenigorodskaya L.A., Kucherenko T.V. [Eating behavior and hormones of eating behavior in metabolic syndrome patients]. Tipy pishchevogo povedeniya i gormony pishchevogo povedeniya u bol’nykh s metabolicheskim sindromom. [Experimental & Clinical Gastroenterology]. Eksperimental’naya i klinicheskaya gastroenterologiya. 2007; 1: 24-27. (in Russ.).

10. Buczko W., Watys Т., Kacharewicz I. The role of endothelium in antithrombotic effect of the rennin-angiotensin system blockade. J. Physiol. Pharmacol. 1999; 50: 499-507.

11. Rabini R.A., Petruzzi E. Diabetes mellitus and subjects’ ageing: A study on the ATP content and ATPrelated enzyme activities in human erythrocytes. Eur.J. Clin. Invest. 1997; 4: 327-332.

12. Du Y., Cramer M., Lee C.A., Tang J., Muthusamy A., Antonetti D.A., Jin H., Palczewski K., Kern T.S. Adrenergic and serotonin receptors affect retinal superoxide generation in diabetic mice: relationship to capillary degeneration and permeability. FASEB J. 2015. [Epub ahead of print].

13. Grueb M., Rohrbach J.M., Schlote T., Mielke J. Serotonin (5-HT7) receptor-stimulated activation of cAMP-PKA pathway in bovine corneal epithelial and endothelial cells. Ophthalmic Res. 2012; 48 (1): 22-27.

14. Erie J. C., Brue S. M., Chamberlain A. M, Hodge D. O. Selective serotonin reuptake inhibitor use and increased risk of cataract surgery: a population-based, casecontrol study. Am. J. Ophthalmol. 2014; 158 (1): 192-197.

15. Etminan M., Mikelberg F. S., Brophy J. M. Selective serotonin reuptake inhibitors and the risk of cataracts: a nested case-control study. Ophthalmology. 2010; 117 (6): 1251-1255.

16. Gupta V.B., Rajagopala M., Ravishankar B. Etiopathogenesis of cataract: an appraisal. Indian J. Ophthalmol. 2014; 62 (2): 103-110.

17. Epperson C. N., Terman M., Terman J. S., Hanusa B. H., Oren D. A., Peindl K. S., Wisner K.L. Randomized clinical trial of bright light therapy for antepartum depression: preliminary findings. J. Clin. Psychiatry. 2004; 65: 421-425.

18. Abizaid A., Mezei G., Thanarajasingam G., Horvath T.L. Estrogen enhances lightinduced activation of dorsal raphe serotonergic neurons. Eur.J. Neurosci. 2005; 21: 1536-1546.

19. Fite K.V., Janusonis S., Foote W., Bengston L. Retinal afferents to the dorsal raphe nucleus in rats and Mongolian gerbils. J. Comp. Neurol. 1999; 414: 469-484.

20. Fite K.V., Wu P.S., Bellemer A. Photostimulation alters c-Fos expression in the dorsal raphe nucleus. Brain Res. 2005; 1031: 245-252.

21. Goldsmith D.R., Wellington K. Naftidrofuryl: a review of its use in the treatment of intermittent claudication. Drugs Aging. 2005; 22 (11): 967-977.

22. Marconi A., Darquenne S., Boulmerka A., Mosnier M., D’Alessio P. Naftidrofyrildriven regulation of endothelial ICAM-1 involves nitric oxide. Free Radic. Biol. Med. 2003; 34 (5): 616-625.

23. Goldsmith D., Wellington K. Naftidrofyril: a review of its use in the treatment of intermittent claudication. Drugs Aging 2005; 22 (11): 967-977.

24. Brevetti G., Annecchini R., Bucur R. Intermittent claudication: pharmacoeconomic and quality-of-life aspects of treatment. Pharmacoeconomics. 2002; 20 (3): 169-181.

25. Butler J.V., Mulkerrin E.C., O`Keeffe S.T. Nocturnal leg cramps in older people. Postgrad. Med. J. 2002; 78: 596-598.

26. De Backer T.L. M., Vander Stichele R., Lehert P., Van Bortel L. Naftidrofuryl for intermittent claudication. Cochrane Database of Systematic Reviews. 2012; 16 (2): CD001368.

27. Jacoby D., Mohler III E.R. Drug treatment of intermittent claudication. Drugs. 2004; 64 (15): 1657-1670.

28. De Backer T.L. M., Vander Stichele R, Lehert P, Van Bortel L. Naftidrofuryl for intermittent claudication: meta-analysis based on individual patient data. Br.Med. J. 200910; 338: 603.

29. Meng Y., Squires H., Stevens J.W., Simpson E., Harnan S., Thomas S., Michaels J., Stansby G., O’Donnell M.E. Cost-effectiveness of cilostazol, naftidrofuryl oxalate, and pentoxifylline for the treatment of intermittent claudication in people with peripheral arterial disease. Angiology. 2014; 65 (3): 190-197.

30. Squires H., Simpson E., Meng Y., Harnan S., Stevens J., Wong R., Thomas S., Michaels J., Stansby G. A systematic review and economic evaluation of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease. Health Technol. Assess. 2011;15 (40): 1-210.

31. Möller H.J., Hartmann A., Kessler C., Rainer M., Brown T., Gamand S., Lehert P. Naftidrofuryl in the treatment of vascular dementia. Eur. Arch. Psychiatry Clin. Neurosci. 2001; 251 (6): 247-254.

32. Moher D., Pham B., Ausejo M., Saenz A., Hoad S., Barber G. Pharmacological management of intermittent claudicatio: a meta-analysis of randomized trials. Drugs. 2000; 59 (5): 1057-1070.

33. Louis J. C. Effect of naftidrofuryl on metabolism and survival of cultured neurons. Neurochem. Res. 1989; 14 (12): 1195-1201.

34. Takeo S., Tanonaka R., Miyake K., Tanonaka K., Taguchi T., Kawakami K., Ono M., Hiramatsu M., Okano K. Naftidrofuryl oxalate improves impaired brain glucose metabolism after microsphere-induced cerebral embolism in rats. J. Pharmacol. Exp. Ther. 1991; 257 (1): 404-410.

35. Ogawa S., Kameyama T., Nabeshima T. Naftidrofuryl oxalate, nootropic effects on the scopolamineand the basal forebrain lesion-induced amnesia in rats. Pharmacol. Biochem. Behav. 1991; 39 (4): 997-1002.

36. Kieffer E., Bahnini A., Mouren X., Gamand S. A new study demonstrates the efficacy of naftidrofyril in the treatment of intermittent claudication: findings of the Naftidrofyril Clinical Ischemia Study (NCIS). Int. Angiol. 2001; 20: 58-65.

37. Boeijinga P. H., Nedelec J. F., Demazieres A., Souan M. L., Gamand S., Gilles C., Parot P., Staner L., Luthringer R., Macher J.P. Characterization of the CNS effects of naftidrofyril (Praxilene) by quantitative EEG and functional MRI: a study in healthy elderly subjects. Neuropsychobiology. 2003; 48: 160-168.

38. De Backer T., Van der Stichele R., Lehert P., Van Bortel L. Naftidrofuryl for intermittent claudication: meta-analysis based on individual patient data. Br.Med. J. 2009; 338: 603.

39. Borzunov O. I., Korotkikh S. A. [Ophthalmoneuroprotection in open-angle glaucoma and diabetic retinopathy patients]. Osobennosti oftal’moneiroprotektsii u patsientov s otkrytougol’noii glaukomoii i diabeticheskoi retinopatiei. [Ophthalmology]. Oftal’mologiya. 2014: 11 (1): 66-72. (in Russ.).

40. Miller J.W., Le Couter J., Strauss E.C., Ferrara N. Vascular endothelial growth factor a in intraocular vascular disease. Ophthalmology. 2013; 120: 106-114.

41. Sultan M.B., Zhou D., Loftus J., Dombi T., Ice K.S. A phase 2/3, multicenter, randomized, double-masked, 2-year trial of pegaptanib sodium for the treatment of diabetic macular edema. Ophthalmology. 2011; 118: 1107-1118.

42. Stefanini F. R., Arevalo J. F., Maia M. Bevacizumab for the management of diabetic macular edema. World J. Diabetes. 2013; 4 (2): 19-26.

43. Andzhelova D.V. [Current approaches to haemophtalmia treatment]. Sovremennye podkhody k lecheniyu gemoftal’ma. Obzor. [Ophthalmology]. Oftal’mologiya. 2012; 9 (2): 8-10. (in Russ.).

44. Bressler N. M., Silva J. C., Bressler S. B., Fine S. L., Green W. R. Clinicopathologic correlation of drusen and retinal pigment epithelial abnormalities in age-related macular degeneration. Retina. 2005; 25:130-42.

45. Hyun H. J., Sohn J. H., Ha D. W., Ahn Y. H., Koh J.-Y., Yoon Y. H. Depletion of intracellular zinc and cooper with TPEN results in apoptosis of cultured human retinal pigment epithelial cells. Invest. Ophthalmol. Vis. Sci. 2001; 42 (2): 460-465.

46. Klein R., Klein B. E., Jensen S. C., Cruickshanks K. J., Lee K. E., Danforth L. G., Tomany S.C. Medication use and the 5-year incidence of early age-related maculopathy: the Beaver Dam Eye Study. Arch. Ophthalmol. 2001; 119 (9): 1354-1359.

47. Kiseleva T. N., Polunin G. S., Budzinskaya M. V., Lagutina Yu. M., Vorob’eva M. V. [Current approaches to the treatment and prevention of age-related macular degeneration]. Sovremennye podkhody k lecheniyu i profilaktike vozrastnoy makulyarnoy degeneratsii. [Russian Medical Journal]. Russkiy meditsinskiy zhurnal. 2007; 2: 78-79. (in Russ.).

48. Kim S.R., Nakanishi K., Itagaki Y., Sparrow J.R. Photooxidation of A2-PE, a photoreceptor outer segment fluorophore, and protection by lutein and zeaxanthin. Exp. Eye Res. 2006; 82 (5): 828-839.

49. Mirzabekova K.A. [Novel approaches to the correction of metabolic disorders in primary open-angle glaucoma and age-related macular degeneration patients]. Novye vozmozhnosti v korrektsii metabolicheskikh narusheniy setchatki u patsientov s pervichnoy otkrytougol’noy glaukomoy i vozrastnoy makulyarnoy degeneratsiey [Ophthalmology]. Oftal’mologiya. 2014; 11 (4): 4-9. (in Russ.).

50. Mirzabekova K. A. [Age-related macular degeneration: prevention and treatment]. Vozrastnaya makulyarnaya degeneratsiya: profilaktika i lechenie. [Ophthalmology]. Oftal’mologiya. 2014; 11 (2): 41-46. (in Russ.)

51. Achache F., Titze P., Movaffaghy A., Mermoud A. Effect of naftidrofyril (praxilene) on optic nerve head blood flow in the patient with glaucoma. Klin. Monatsbl. Augenkeilkd. 1999; 214 (5): 260-262.

52. Mermoud A., Faggioni R., Van Melle G.D. Double-blind study in the treatment of normal tension glaucoma with naftidrofyril. Ophthalmologia. 1990; 201 (3): 145-151.