Stesura Seveso Archivio Italiano di Urologia e Andrologia 2020; 92, 4326 LETTER TO EDITOR No conflict of interest declared. DOI: 10.4081/aiua.2020.4.326 Erectile disfunction medical treatment with phosphodiesterase 5 inhibitors (PDE5i) in patients with retinitis pigmentosa and side effects KEY WORDS: Erectile dysfunction; Medical treatment; Side effects. Submitted 29 April 2020; Accepted 10 June 2020 To the Editor Retinitis pigmentosa represents a heterogeneous group of degenerative hereditary pathologies of the retinal photocep- tors, some forms mainly affect the cones and others the rods (1). The prevalence of the disease is of 1 case per 3000- 5000 inhabitants (1), in 80-90% of cases these are forms with prevalent involvement of the rods (RCD) and in 10-20% of cases of forms with prevalent involvement of the cones (CRD) (2). In 85% of the cases these are isolated forms, while in 15% of syndromic forms (2), the most common syndromic form is Usher's syndrome, in which retinitis pigmentosa is associated with neurosensory deafness (3). An extensive search of Medline, Embase and Scopus databases was con- ducted to retrieve English-language articles published up to 31 Dec 2019, assessing side effect of PDE5i. The protocol was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. All studies have been included. Congress meetings, editorial comments and review papers were excluded: Further exclusion criteria were full texts not available in English. Two reviewers (G.I.R. and A.C.) independently assessed the eligibility of the identified papers and any disagreements were discussed with a third reviewer (G.M.). In the early stages of RCD disease patients show predominantly decreased night and peripheral vision, associated with photophobia. Patients with CRD complain of photophobia and reduced central vision. In both cases, disease evolution and specific symptoms are difficult to predict and depend on genetic and environmental factors. PDE-6 Phosphodiesterase 6 is an isoenzyme of PDE that is found in the retina and is involved in the transduction of the sig- nal, some forms of retinitis pigmentosa are related to mutations on this enzyme (4). PDE5 is the molecular target of sev- eral drugs used in the treatment of erectile dysfunction, but some of these drugs have off-target actions on PDE6 and may therefore be contraindicated (2). PDE5 Inhibitors (5-7) Phosphodiesterase is an enzyme responsible for the hydrolysis of cGMP, a molecule that allows the erection of the penis thanks to its vasodilatory action on smooth vasal muscle cells. The smooth muscle cells of the corpora cavernosa of the penis express the isoenzyme PDE5. Inhibitory drugs specific to PDE5 are used for the treatment of erectile dysfunction: by inhibiting the enzyme they stop the hydrolysis of cGMP and thus promote vasodilation and erection. Off-target action of PDE5 inhibitors can result in several adverse reactions. Of particular interest are the adverse reactions related to the action on retinal PDE6, which may contraindicate treatment in patients with retinitis pigmentosa, where the func- tioning of the photoceptors is already impaired (Tables 1, 2). Sildenafil Sildenafil is the most used inhibitor of PDE5, its action is not entirely specific for PDE5 but has a slight affinity for PDE6 retinal, in fact 9% of patients report among the adverse reactions, photosensitivity and alterations in color vision (5, 8). The intake of sildenafil may cause transient alterations in the electroretinogram, so it is not recommended for patients with retinitis pigmentosa (4, 5). Verdenafil Verdenafil is a molecule similar to sildenafil but more potent (7) and more selective than sildenafil, so higher doses are needed for adverse reactions related to the action on PDE6 to occur, which are therefore very rare. Tadalafil Tadalafil has a chemical structure different from that of sildenafil and verdanafil, it has very little action on PDE6 so it does not cause adverse reactions for off-target effect on that isoenzyme (9). Avanafil Avanafil has recently been approved for the treatment of erectile dysfunction, it is a very selective pyrimidine derivative Cocci Letter_Stesura Seveso 14/12/20 20:40 Pagina 326 327Archivio Italiano di Urologia e Andrologia 2020; 92, 4 Retinitis pigmentosa and PDE5i for PDE5, which therefore does not cause adverse reactions related to the action on PDE6 (10, 11). Following a single 200 mg dose of Avanafil, no changes in colour perception were detected, however, the observation was made in a small sam- ple and the data may not be significant. Similar results were also obtained in larger studies with larger doses of medica- tion (12). Other adverse reactions Other side effects were headache, dyspepsia, skin flush for sildenafil (4); headache, dyspepsia, skin flush, rhinitis, lengthening of QT for verdenafil (13, 14); headache, dyspepsia, back pain for tadalafil (5); headache, skin flush, nasal congestion, muscle cramps, postural hypotension for avanafil (10, 11). Although there is no evidence in the literature that the administration of PDE5i in patients with retinitis pigmentosa may or may not lead to an aggravation of the disease, in the light of the knowledge on the pharmacodynamics of PDE5i and on the etiopathogenesis of retinitis pigmentosa, it seems appropriate, as a precaution, to avoid administering to these patients the least selective drugs for PDE5 and opt instead for the most selective ones. In case of patient presenting retinitis pigmentosa and organic or post-operative erectile dysfunction, the possibility of PDE5i treatment should not be excluded. This kind of patient should be analyzed and should undergo specific genetic tests to assess the presence or absence of mutations in gene coding for PDE6 expressed at retinal level. In conclusion the presence of PDE6 muta- tion allows us to avoid oral treatment with PDE5i. REFERENCES 1. Pagon RA. Retinitis pigmentosa. Surv Ophthalmol. 1988; 33:137-77. 2. Parmeggiani F, Sato G, De Nadai K, Romano MR, Binotto A, Costagliola C. Clinical and rehabilitative management of retinitis pigmentosa: Up-to-Date. Curr Genomics. 2011; 12:250-9. 3. Boughman JA, Vernon M, Shaver KA. Usher syndrome: definition and estimate of prevalence from two high-risk populations. J Chronic Dis. 1983; 36:595-603. 4. Basu A, Ryder REJ. New treatment options for erectile dysfunction in patients with diabetes mellitus. Drugs. 2004; 64:2667-88. 5. Hakky TS, Jain L. Current use of phosphodiesterase inhibitors in urology. Turkish J Urol. 2015; 41:88-92. 6. Setter SM, Iltz JL, Fincham JE, Campbell RK, Baker DE. Phosphodiesterase 5 inhibitors for erectile dysfunction. Ann Pharmacother. 2005; 39:1286-95. 7. Kuthe A. Phosphodiesterase 5 inhibitors in male sexual dysfunction. Curr Opin Urol. 2003; 13:405-10. 8. Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD, Wicker PA. Oral sildenafil in the treatment of erectile dysfunction. Sildenafil Study Group. N Engl J Med. 1998; 338:1397-404. 9. Eardley I,Cartledge J. Tadalafil (Cialis) for men with erectile dysfunction. Int J Clin Pract. 2002; 56:300-4. 10. Limin M, Johnsen N, Hellstrom WJG. Avanafil, a new rapid-onset phosphodiesterase 5 inhibitor for the treatment of erectile dysfunction. Expert Opin Investig Drugs. 2010; 19:1427-37. 11. Alwaal A, Al-Mannie R, Carrier S. Future prospects in the treatment of erectile dysfunction: focus on avanafil. Drug Des Devel Ther. 2011; 5:435-43. 12. Wang R, Burnett AL, Heller WH, Omori K, Kotera J, Kikkawa K. Selectivity of avanafil, a PDE5 inhibitor for the treatment of erectile dysfunction: implications for clinical safety and improved tolerability. J Sex Med. 2012; 9:2122-9. 13. Hellstrom WJG, Gittelman M, Karlin G, Segerson T, Thibonnier M, Taylor T. Vardenafil for treatment of men with erectile dysfunction: efficacy and safety in a randomized, double-blind, placebo-controlled trial. J Androl. 2002; 23:763-71. 14. Carson CC. Cardiac safety in clinical trials of phosphodiesterase 5 inhibitors. Am J Cardiol. 2005; 96:37M-41M. Correspondence Andrea Cocci, MD Andrea Romano, MD (Corresponding Author) - romano.andrea7895@gmail.com Department of Urology, University of Florence - San Luca nuovo padiglione 16/settore C/Piano II - Largo Brambilla 3-50134 Firenze (Italy) Girolamo Morelli, MD Davide Frediani, MD Department of Surgery, Urology Section, University of Pisa, Pisa (Italy) Andrea Sodi, MD Department of Surgery, Ophthalmology Section, University of Florence, Florence (Italy) Giorgio Ivan Russo, MD Department of Surgery, Urology Section, University of Catania, Catania (Italy) Andrea Cocci 1, Andrea Romano 1, Girolamo Morelli 2, Davide Frediani 2, Andrea Sodi 3, Giorgio Ivan Russo 4 1 Department of Surgery, Urology Section,University of Florence, Florence, Italy; 2 Department of Surgery, Urology Section, University of Pisa, Pisa, Italy; 3 Department of Surgery, Ophthalmology Section, University of Florence, Florence, Italy; 4 Department of Surgery, Urology Section, University of Catania, Catania, Italy. 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