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Useful Implications of Low-dose Long-term Use of PDE-5 Inhibitors
Taymour Mostafa, MD
ABSTRACT
Received De
DepartmentUniversity, C
Copyright ªElsevier Inc.http://dx.doi
270
Introduction: Phosphodiesterase type 5 (PDE-5) hydrolyzes cyclic guanylate monophosphate (cGMP) specif-ically to 50 GMP, promoting successful corporeal vascular relaxation and penile erection during sexual stimu-lation. Oral PDE-5 inhibitors such as sildenafil, vardenafil, tadalafil, and avanafil have provided noninvasive,effective, well-tolerated treatment for erectile dysfunction (ED) patients and, at the same time, stimulated bothacademic and clinical interests. Lately, some oral PDE-5 inhibitors were released as low-dose preparations withthe concept of potential daily administration and long-term use.
Aim: To highlight the possible potential implications of low-dose long-term use of PDE-5 inhibitors.
Method: A systematic review was carried out until December 2015 based on a search of all concerned articles inMEDLINE, medical subjects heading (MeSH) databases, Scopus, The Cochrane Library, EMBASE, andCINAHL databases without language restriction. Key words used to assess the outcome and estimates forconcerned associations were: PDE-5 inhibitors; erectile dysfunction; low-dose; long-term; sildenafil; tadalafil;vardenafil; avanafil.
Main Outcome Measures: Demonstrating different implications for low-dose long-term use of PDE-5inhibitors.
Results: Low-dose and/or long-term use of PDE-5 inhibitors was shown to put forth beneficial sound effects indifferent medical implications with potentials that could be extended for different utilities. These implicationsincluded sexual, urogenital, cardiovascular, pulmonary, cutaneous, gastrointestinal, and reproductive, as well asneurological disorders. However, it is evident that most potential appliances were carried out experimentally onpreclinical studies with off-label indications.
Conclusion: Making use of and exploring low-dose and/or long-term use of several PDE-5 inhibitors for theirpossible implications seem to be valuable in different medical disorders. Increased knowledge of the drugcharacteristics, comparative treatment regimens, optimal prescribing patterns, and well-designed clinical trials areneeded before these agents can be recommended for use.
Sex Med Rev 2016;4:270e284. Copyright � 2016, International Society for Sexual Medicine. Published by ElsevierInc. All rights reserved.
Key Words: PDE-5 Inhibitors; Erectile Dysfunction; Low-Dose; Chronic Use; Sildenafil; Tadalafil; Vardenafil;Avanafil
INTRODUCTION
As the first-line treatment for erectile dysfunction (ED), oralphosphodiesterase type 5 inhibitors (PDE-5Is) are used world-wide with confirmed efficacy, tolerability, and couple sat-isfaction.1e3 Eleven groups of PDE isoenzymes were identifiedthat can be grouped into 3 categories based on their substratespecificity. PDE-4, PDE-7, and PDE-8 selectively hydrolyze
cember 5, 2015. Accepted December 24, 2015.
of Andrology, Sexology & STDs, Faculty of Medicine, Cairoairo, Egypt
2016, International Society for Sexual Medicine. Published byAll rights reserved..org/10.1016/j.sxmr.2015.12.005
cAMP, whereas PDE-5, PDE-6, and PDE-9 hydrolyze cyclicguanosine monophosphate (cGMP). PDE-1, PDE-2, PDE-3,PDE-10, and PDE-11 possess dual specificity, acting on bothcyclic adenosine monophosphate (cAMP) and cGMP.4,5
Specifically, PDE-5 hydrolyzes cGMP to 50 GMP. This PDEfamily consists of a single PDE5 gene with 3 alternatively splicedPDE-5 isoforms (PDE-5A1, -5A2, and -5A3), differing only inthe 50 ends of their corresponding mRNAs and N-terminals.PDE-5, which specifically degrades cGMP, is relatively highlyexpressed in the corpus cavernosum. Thus, PDE-5Is, by blockingcGMP hydrolysis, potentiate the effects of cGMP, resulting indecreased intracellular calcium that leads to penile smoothmuscle relaxation, vasodilatation with increased penile bloodflow and erection.6e8
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PDE-5Is: Low-dose Long-term Use 271
Currently, 4 orally effective PDE-5Is are approved by the USFood and Drug Administration (sildenafil, vardenafil, tadalafil,and avanafil), whereas others are under clinical development9e11
(Table 1, Figure 1).
Sildenafil was the first, being released at 1998. It reaches itsmaximal concentration in the plasma (Tmax) at 60 minutes onempty stomach with a duration of action of 4e6 hours.
Vardenafil was approved at 2003 with Tmax of 60 minutes onempty stomach with a duration of action extending up to 7hours. It has also an oral-dispersible tablet (ODT) formula thatdissolves in the mouth in seconds.12 Lately, vardenafil incorpo-rated into a nano-sized lipid vesicular matrix as a transdermalfilm was thought to avoid first-pass metabolism in the liver, todecrease the erectogenic dose and to reduce adverse effects.13
Tadalafil was released at 2003 with Tmax of 120 minutes andcharacterized with longer duration of action, reaching up to 36hours and not being affected with food.14
Avanafil was approved in 2012. It is formulated as self-nano-emulsifying drug delivery system, reaching Tmax within 30 to 45minutes on an empty stomach and 1.25 hrs if a high-fat meal wasingested.15 Successful sexual attempts were established as early as10 minutes, making it preferable for ED patients with multiplecomorbiditiesl.16,17
PDE-5Is’ extensive achievement in treating ED has led toincreased interest in investigating their effects as potential ther-apeutic agents in diverse medical conditions apart from theirfamed erectogenic action. This spectrum includes cardiotonics,vasodilators, smooth muscle relaxants, antidepressants, antith-rombotics, antiasthmatics, and agents for improving learning andmemory, etc.18,19
Lately, the concept of low-dose use of PDE-5Is was intro-duced first for treating ED as an extra administration optioncloser to the couples preference for spontaneous rather thanplanned sexual activity.20e22 In this context, accumulated dataindicated that low-dose use of PDE-5Is or their long-term use
Table 1. Chemical and Pharmacokinetic Data of FDA-approved PDE-5
Sildenafil Vardenafi
Trade name Viagra LevitraFDA approval Mar 27, 1998 Aug 19,Available doses (mg) 25, 50, 100 2.5, 5, 10Chemical data
Formula C22H30N6O4 C23H32NMolecular mass 474.600 g/mol 488.604
Pharmacokinetic dataProtein binding 90% 95%Metabolism CYP3A4, CYP2C9 (liver) CYP3A4Biological half-life 3e4 hours 4e5 houExcretion Feces (80%), urine (13%) Biliary
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could provide additional potential benefits and/or improvedtreatment responses in diverse medical implications (Table 2).
SEXUAL IMPLICATIONS
1. EDSeveral studies demonstrated that low-dose tadalafil, once
daily, is both effective and well tolerated compared withon-demand use. It allows the patients and their partners todisconnect its administration from sexual activity, therebyenabling them to return to the sex life they had before the onsetof ED.23,24 Wrishko et al25 predicted that 5 mg tadalafil oncedaily maintained therapeutic concentrations throughout the 24-hour dosing interval based on pharmacodynamic and pharma-cokinetic data.
In this context, McMahon26 reported on daily tadalafil open-label, flexible-dose (10 or 20 mg) in 112 ED men who failed torespond to 20 mg tadalafil on at least 6 occasions. These subjectsexhibited substantial improved International Index of ErectileFunction-Erectile Function (IIEF-EF) domain scores from 10.3at baseline to 14.9 after the 4-week on-demand treatment and to23.1 after 12 weeks of daily dosage. Also, McMahon27 carriedout an open-label crossover trial comparing 12 weeks of tadalafil(10 mg daily vs 20 mg on-demand) in 145 men with ED, inwhich the baseline IIEF-EF score 14.6 was increased to 23.3 inthe on-demand arm and 26.4 in the daily dose arm.
Porst et al28 evaluated the efficacy of 5 mg or 10 mg oftadalafil daily in a multicenter, randomized, double-blinded,placebo-controlled study on 293 men for 12 to 15 weeks.Both doses significantly improved EF, with a mean change inIIEF-EF domain scores of 9.7, 9.4, and 0.9 for the 5 mg, 10 mg,and placebo groups, respectively. Porst et al29 also reported thattadalafil 5 mg daily for up to 2 years is tolerated and effective inmen with ED, with improved mean IIEF domain, intercoursesatisfaction, and overall satisfaction. Positive responses were re-ported for 95.7% of the global assessment question 1 (GAQ,
Is
l Tadalafil Avanafil
Cialis Stendra2003 Nov 21, 2003 April 27, 2012, 20 2.5, 5, 10, 20 50, 100, 200
6O4S C22H19N3O4 C23H26CIN7O3
g/mol 389.404 g/mol 483.951 g/mol
94% 99%(liver) CYP3A4 (liver) CYP3A4 (liver)rs 17.5 hours 5 hours
Feces (>60%),urine (>30%)
Feces (>62%), urine (>21%)
Table 2. Different Impacts of Low-dose Long-term Use of PDE-5Is
Sexual implications Pulmonary implications
1. Erectile dysfunction 1. Pulmonary arterialhypertension
2. Sexual quality of life 2. Eisenmenger syndrome3. Combined PDE-5I medication Cutaneous implications4. ED, no sexual life 1. Raynaud’s phenomenon5. Psychogenic ED 2. Digital ulcers6. Avoid PDE-5I side effects 3. Palmar-plantar
erythrodysesthesia7. Anejaculation 4. Diffuse cutaneous systemic
sclerosis8. ED post bone marrow
transplantation5. Wound healing
9. Female sexual dysfunction 6. Pressure ulcer10. Recurrent priapism 7. Skin flap survival11. Morning erection Gastro-intestinal implications12. Experimental cavernous
effects1. Esophageal spasm
Urogenital implications 2. Chronic anal fissure1. Benign prostatic hyperplasia 3. Congenital diaphragmatic
hernia2. Penile rehabilitation 4. Liver regeneration3. Prostate brachytherapy Reproductive implications4. Testicular torsion 1. Uterus5. Chronic renal disease 2. Recurrent miscarriage6. Ovarian torsion 3. Poor ovarian response7. Interstitial cystitis 4. Sperm functions8. Peyronie’s disease Neurological implicationsCardiovascular implications 1. Peripheral neuropathy1. Heart failure 2. Cognitive functions2. Congenital heart disease 3. Hepatic encephalopathy3. Cardioprotection4. Flow-mediated dilatation5. Orthotopic heart
transplantation6. Allograft vasculopathy
272 Mostafa
improved erection) and 92.1% of GAQ2 (improved ability toengage in sexual activity).
In their work, Rajfer et al30 reported that both 2.5 mg or 5 mg oftadalafil daily in EDmen over 24 weeks were superior to placebo, asthe mean IIEF-EF score was increased by 6.1 with 2.5-mg tadalafiland by 7.0 with 5mg tadalafil compared to 1.2 points with placebo.Shabsigh et al31 pointed thatEDmenondaily tadalafil experienced ahigh rate of reliable efficacy with successful attempts. Also, Kanget al32 concluded that 5 mg of tadalafil daily over 8 weeks is effectivein improving EFwithout adverse effects in EDmen, in whom IIEF-5 scores significantly increased from 11.3 at baseline to 16.9.Similarly, udenafil (not approved yet by FDA) showed significantlyimprovedEF amongEDpatients when administered at 50mg or 75mg/day for 12 weeks.33
Porst et al34 demonstrated that daily tadalafil (2.5 and 5 mg) isboth effective and well-tolerated even after failure of on-demand use
because of its longer efficacy, allowing a more spontaneous sexuallife. Also, Huang et al35 showed that daily tadalafil 5 mg for 6 to 8weeks improved endothelial function and erectile hardness with aneffectiveness rate of 96.1% in treating ED patients and significantlyimproved IIEF-5 scores compared with pretreatment scores.
Likewise, Xu et al36 showed obvious increase in IIEF-5 scoresand peak systolic velocity (PSV) of the cavernosal artery on 43arterial ED on tadalafil 5 mg after supper on alternate days for4 weeks. Li et al37 demonstrated significant increases in theself-esteem and relationship questionnaire and IIEF-5, withimproved nocturnal penile tumescence after 5 mg/day tadalafilfor 12 weeks compared with the baseline. In their study, Chenet al38 concluded that oral tadalafil improved PSV and penileerection in ED patients, where the patients with PSV >15 cm/scan be medicated at 5 mg dose, and those with PSV <15 cm/s at10 mg dose or more on alternate days. Goldfischer et al39
demonstrated that tadalafil 5 mg daily significantly improvedsexual function in men with partial response to on-demandPDE-5Is therapy vs placebo irrespective of testosterone (T)levels. Also, Kim et al40 showed that tadalafil 2.5 mg or 5 mg/dayis a feasible alternative to as-needed therapy in ED men.
2. Sexual Quality of LifeTadalafil 5 mg daily as ED treatment was demonstrated to
improve overall satisfaction for both partners with high concor-dance among couples in their responses to the man’s ED treat-ment. In addition, significant improvement in sexualrelationship, confidence, self-esteem, and overall relationshipwere correlated with EF improvement.41e43
3. Combined PDE-5I MedicationIt is suggested that combined PDE-5I medication can better
improve EF, especially for patients with severe ED. Cui et al44
evaluated the efficacy of long-term low-dose tadalafil combinedwith sildenafil in the early stage of ED treatment; 1:1 to tadalafil5 mg/day or once daily combined with sildenafil 50 mg asneeded. Total IIEF-5 scores of patients with severe ED andQuestion 2 scores of patients with moderate and severe ED incombined medication group were significantly higher than in thetadalafil alone group. The percentage of “yes” responses to SEP4,SEP5, and partner’s SEP3 were improved significantly in thecombined medication group without adverse events.
4. ED-No Sexual LifeED-no sexual life (ED-NS) is the inability to have enough
penile erection hardness and duration for enough confidence inattempting coitus for more than 6 months. Zhang et al45 inves-tigated 35 ED-NS patients (17 to 35 years of age) on oral tadalafil5 mg/day for 3 months who were followed for another 3 months.The patients’ Self-estimation Index of Erectile Function-No Sex-ual Life scores were 43.2 after medication and 42.1 at 3 monthsafter drug withdrawal compared with 21.2 before treatment.
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Figure 1. Chemical formulae of FDA-approved PDE-5 inhibitors.
PDE-5Is: Low-dose Long-term Use 273
5. Psychogenic EDHuang et al46 investigated the effect of low-dose daily
de-escalatory administration of tadalafil on 84 psychogenic EDpatients for 2 months compared with on-demand medicationas controls. The rate of therapeutic effectiveness was signifi-cantly higher in the observation group than controls (95.2% vs86.5%).
6. Avoid PDE-5Is’ Side EffectsAbout 25% of ED patients on sildenafil experience headaches,
including cluster headaches that could be resolved by prescribinglow-dose vardenafil or tadalafil instead.47 Also, sildenafil shouldbe used as single dose 25 mg/48 hr with protease inhibitors,especially ritonavir, as anti-retrovirals reduce metabolismof sildenafil in the liver, resulting in abnormally high levels inthe body.48 In addition, low-dose PDE-5Is appear to be effica-cious and well tolerated in patients on renal dialysis or hepaticfailure.
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7. AnejaculationJin et al49 assessed anejaculation (AE) in 55 patients ran-
domized on Yangjing capsule (once 5 pills, tid) and low-dosetadalafil (5 mg, qd alt, 1 h before bedtime) compared with oralephedrine (25 mg before bedtime) as controls for 1 to 3 months.The patients were advised to do sexual stimulation, to reduce thefrequency of sexual intercourses and to quit masturbation. Thetotal effectiveness rate was 83.34% compared with 40% incontrols, demonstrating that Yangiing capsule plus low-dosetadalafil are effective for treating functional AE.
8. ED Post Bone Marrow TransplantationED is a recognized complication of bone marrow trans-
plantation (BMT). Chatterjee et al50 studied 8 male recipients ofBMT presented with hypogonadism, ED, diminished libido, andejaculatory disorders. All patients received intramuscular testos-terone cypionate (250 mg 4 weekly) for 6 months and 50to 100 mg sildenafil orally, 1 to 2 times/week. All patients
274 Mostafa
responded favorably, suggesting that this combined therapy is aneffective approach in recipients of high-dose therapy presentingwith ED after transplant.
9. Female Sexual DysfunctionAngulo et al51 concluded that potentiating the NO pathway
by vardenafil improves vascular sexual responses and overcomesthe inhibitory effects of acutely administered antidepressants onfemale genital vascular responses. van der Made et al52,53 inves-tigated the combination of T and vardenafil on increased sensi-tivity for sexual cues and physiological sexual responding inwomen with hypoactive sexual desire disorder. In women whodid not suffer childhood sexual abuse (CSA), T appears to acti-vate central sexual mechanisms resulting in higher vaginal pulseamplitude under the combination of T and vardenafil. However,women who suffered CSA showed no alterations in their phys-iological sexual responses.
10. Recurrent PriapismBurnett et al54e56 demonstrated that long-term, continuous
PDE-5Is therapeutic regimen in recurrent ischemic priapism issuccessful in alleviating, controlling. and resolving recurrenceswith unchanged erectile function.
11. Morning ErectionAversa et al57 indicated that long-term use of tadalafil
improved endothelial function with dramatic increase in morn-ing erections and sustained effects after its discontinuation thatdetermines better oxygenation to the penis.
12. Experimental Cavernous EffectsMostafa et al58,59 pointed to the pronounced antiapoptotic
and antioxidant effects of frequent low-dose sildenafil and/ortadalafil combined with T for 12 weeks on the cavernous tissuesof aged diabetic rats, where alternate sildenafil/tadalafil with/without T showed further improvement. Also, Helmy andSenbel60 concluded that low-dose sildenafil (5 mg/kg/day) resultsin antioxidant properties in long-term use being increased ifcombined with vitamin E (80 IU/day) in age-associated ED.
Mostafa et al61 associated tadalafil (0.09 mg/200 g) daily for 2months in induced diabetic rats with substantial improvedstructure of penile cavernous tissue, increased smooth musclesand elastic tissue, decreased fibrous tissue, and functionalenhancement of the erectile function. Also, Wu et al62 concludedthat a continuous low dose of tadalafil can improve the functionand structure of cavernous vascular endothelium. Similarly,Hotta et al63 determined that long-term vardenafil couldameliorate impaired penile hemodynamics and maintainednormal smooth muscle/collagen ratio in cavernous tissues foracute arteriogenic ED in rats induced by ligating bilateral internaliliac arteries from 1 week after ligature.
UROGENITAL IMPLICATIONS
1. Benign Prostatic HyperplasiaPDE-5Is have a favorable impact in patients with lower uri-
nary tract symptoms (LUTS) due to benign prostatic hyperplasia(BPH).64e66 The similarities between the pathophysiologicalmechanisms of LUTS and ED include NO/cGMP pathway,RhoA/Rho-kinase signaling, pelvic ischemia, and autonomicadrenergic overactivity.67 Ying et al68 indicated that treatment ofED with LUTS due to BPH by sildenafil could improve urinarysymptom scores, whereas Zhang and Park69 pointed to PDE-5Isefficacy for improving LUTS in BPH patients with/without ED.Also, Porst et al70 showed meaningful reduction in total Inter-national Prostate Symptom Score (IPSS) on BPH symptoms asearly as 1 week with achieved significance at 4 weeks by daily 5mg tadalafil in a double-blind, placebo-controlled study for 12weeks. Egerdie et al71 also demonstrated the efficacy of daily 5mg tadalafil on both ED and BPH.
Regarding concomitant use of PDE-5Is and alpha blockers,Kloner et al72 reported that tadalafil augmented the hypotensiveeffects of alpha-blocker doxazosin but had little hemodynamicinteraction with tamsulosin. Kaplan et al73 showed that thecombination of alfuzosin 10 mg and sildenafil 25 mg is safe andmore effective than monotherapy with either agent to improvevoiding in ED men with LUTS suggestive of BPH. Becharaet al74 showed that tamsulosin 0.4 mg/day plus tadalafil 20 mg/daywas more effective than tamsulosin 0.4 mg/day alone to improveLUTS and ED. Liguori et al75 verified that combined therapy ofalfuzosin 10 mg and tadalafil 20 mg for 12 weeks could improveED and LUTS with significant upgrading in uroflowmetrymeasures and in IPSS, IIEF-EF scores, and quality of life as-sessments. Jin et al76 indicated that combined therapy with sil-denafil and doxazosin for ED and BPH/LUTS is safe andeffective compared to sildenafil monotherapy. Lee et al77
demonstrated that tadalafil 5 mg/day combined with alphablockers have few adverse effects on hypotensive events and canimprove LUTS and restore sexual function. Gacci et al78 showedthat the combination of tamsulosin and vardenafil for 12 weekswas well tolerated and more effective in improving both LUTSand erectile function compared with tamsulosin alone.
However, Tuncel et al79 showed that the combination oftamsulosin only and sildenafil only was not superior to tamsu-losin only to enhance voiding symptoms. Also, sexual functionimprovement was similar for both the combination and sildenafilonly treatments. In their study, Goldfischer et al80 illustrated atrend for increased hemodynamic signs and symptoms in mentaking nonuroselective a-blockers, most notably those takingdoxazosin in these cases.
2. Penile RehabilitationBannowsky et al81,82 and Mevcha et al83 reported that low-
dose sildenafil (25 mg) at night for rehabilitation after nerve-sparing radical prostatectomy (NSRP) led to a significant
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PDE-5Is: Low-dose Long-term Use 275
improvement/acceleration of EF recovery. Also, Nakano et al84
analyzed the post-NSRP EF with 10 or 20 mg vardenafil atleast once weekly for 12 months. The proportion of patients thatrecovered EF in those undergoing penile rehabilitation wassignificantly greater than those without penile rehabilitation(60% vs 38.2%). Later, Bannowsky et al85 reported that dailylow-dose vardenafil (5 mg/day) escalation had improved recoveryof EF after unilateral NSRP, whereas doubling the dosage didnot. Similarly, Tang et al86 reported that tadalafil 5 mg/day for12 weeks in ED treatment following pelvic fracture-inducedurethral injury helps penile rehabilitation, and that the earlierthe medication is initiated, the better the effect will be. In theirstudy, Montorsi et al87 demonstrated that tadalafil once daily wasmost effective on drug-assisted EF in men with ED after NSRPprovided early use after surgery.
Conversly, Pavlovich et al88 showed that erectile recovery upto 1 year after NSRP did not differ between previously potentmen who use sildenafil nightly compared with on-demand.
Experimentally, Kovanecz et al89 concluded that lower-dosecontinuous long-term sildenafil maintained reversed corporalveno-occlusive dysfunction (CVOD) in a bilateral cavernosalnerve resection rat model. Kovanecz et al90 added that long-termsingle daily oral tadalafil has a similar effect to that of sildenafil orvardenafil in preventing corporal fibrosis and CVOD caused bycavernosal nerve damage in rats through a cGMP-relatedmechanism independent of inducible NOS induction.
3. Prostate BrachytherapyPahlajani et al91 reported that early use of sildenafil after
prostate brachytherapy maintained EF at 6 and 12 months,where ED can be a side-effect within the first 12 months aftertreatment. Pugh et al92 reported that periprocedural tadalafil10 mg twice/week and prostate brachytherapy gave high rates ofsexual potency preservation. At 24-months follow-up, 72% ofthese men reported erections firm enough for coitus and 56%were potent. Of men with potency at baseline, 89% had erectionfirm enough for coitus and 76% remained potent 24 monthsafter treatment.
4. Testicular TorsionYildiz et al93 showed that intraperitoneal low-dose sildenafil was
beneficial in reducing testicular injury after unilateral testiculartorsion/detorsion (T/D) in rats created by rotating the right testis720� in a clockwise direction for 2 hours. Yíldíz et al94 added thatlow-dose sildenafil before detorsion prevents ischemia/reperfusion(I/R) cellular damage through reduced reactive oxygen species andsupported antioxidant enzymes. Yíldíz et al95 reported that low-dose sildenafil in these cases prevents increased MDA and NOlevels and decreased glutathione peroxidase activity, whereas high-dose sildenafil had no effect. Also,Wu et al96 reported that tadalafil0.5 and 2 mg/kg/day can alleviate testicular I/R injury in a time-and dose-dependent manner.
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5. Chronic Renal DiseaseRodríguez-Iturbe et al97 reported that sildenafil treatment pre-
vented hypertension and deterioration of renal function, reducedhistologic damage, inflammation and apoptosis, delayed the onsetof proteinuria, and preserved renal capillary integrity. Delayedsildenafil treatment failed to improve proteinuria and glomerulo-sclerosis but ameliorated hypertension and azotemia with potentialclinical value in the treatment of chronic renal disease.
6. Ovarian TorsionYurtcu et al98 concluded that low- and high-dose vardenafil
are effective in attenuating induced I/R ovary injury.
7. Interstitial CystitisChen et al99 showed that interstitial cystitis (IC) symptom
indices scores and urodynamic index were significantly improvedon daily low-dose (25 mg) sildenafil for 3 months compared withplacebo at baselines at weeks 4, 6, 8, 10, and 12, and 3 monthsafter treatment.
8. Peyronie’s DiseaseChung et al100 assessed the efficacy of tadalafil 2.5 mg/day for
6 months in remodeling isolated septal scar with higher IIEF-5scores in 69% of their patients, compared with 10% in thecontrols.
CARDIOVASCULAR IMPLICATIONS
Low dose and long term uses of PDE-5Is demonstrateddiverse cardiovascular implications.
1. Heart FailureBotha et al101 showed that intravenous PDE-5Is in patients
with end-stage congestive heart failure (HF) had reduced sys-temic and pulmonary vascular resistance with a suitable hemo-dynamic profile. In chronic HF, Bussotti et al102 demonstratedthat sildenafil increases exercise performance, improves lungmechanics and gas diffusion, and prevents exercise-inducedpulmonary edema formation, probably by restoring NOpathways.
2. Congenital Heart DiseaseZeng et al103 reported that sildenafil (25 mg, 3 times daily) is
effective and safe for pulmonary arterial hypertension (PAH)secondary to atrial septal defects, ventricular septal defects, orpatent ductus arteriosus. Fraisse et al104 showed that intravenoussildenafil reduced PAH and shortened time to extubation forimmediate postoperative pediatric patients undergoing congen-ital heart surgery. Zhang et al105 added that iloprost combinedwith low- dose tadalafil effectively reduced pulmonary vascularresistance, increased 6-minute walking test and improved
276 Mostafa
cardiopulmonary function in adult congenital heart disease pa-tients with severe PAH.
3. CardioprotectionIn isolated rat heart model, Das et al106 reported that sildenafil
pretreatment within a narrow dose range (0.001 mg to 0.5mg/kg) provided significant cardioprotection from I/R injuryevidenced by improved ventricular recovery, reduced incidenceof ventricular fibrillation and decreased myocardial infarction. duToit et al107 showed that pretreatment with low-dose sildenafil(20 to 50 nM) could increase myocardial cGMP levels andprotect the heart against I/R injury with decreased infarct size.Similarly, Elrod et al108 demonstrated that treatment with 0.06mg/kg sildenafil 5 minutes before reperfusion significantly re-duces myocardial infarct size. Also, Kolettis et al109 showedexperimentally that sildenafil regimen effect on left ventricularfunction after I/R is strongly evident after acute pretreatmentwith a low dosage.
4. Flow-mediated DilatationImpaired flow-mediated dilation (FMD) is partly attributable
to hyporesponsiveness of cGMP-mediated vasorelaxation effectormechanisms in the vascular smooth muscle.110 Katz et al111
demonstrated that acute effect with sildenafil 25 mg singledose increased endothelium-dependent FMD in the brachialartery of patients with chronic HF compared with placebo afterrelease of transient arterial occlusion. In their study, Desouzaet al112 assessed the acute and prolonged effects of a low-dosesildenafil (25 mg) on FMD in ED patients with type 2 dia-betes. After 1 hour, FMD increased the brachial artery dilatationby 15% without change in the placebo group. After dailytreatment for 2 weeks, the mean FMD was increased to 14% vs9% in the placebo group and persisted for at least 24 hours afterthe last dose.
5. Orthotopic Heart TransplantationMaruszewski et al113 performed a short-term outcome analysis
of orthotopic heart transplantation in 6 patients with PAHtreated perioperatively with oral sildenafil 50 mg followed by 50or 25 mg t.i.d after transplantation, then discontinued 10 to 14days with stepwise reduction. Perioperative sildenafil was asso-ciated with good short-term outcomes in the majority of patients(4/6), reducing pulmonary resistance and pressure with a low rateof hemodynamic instability.
6. Allograft VasculopathyZiqiang et al114 explored the effects of tadalafil on allograft
vasculopathy in male Brown-Norway rats that supplied aortagrafts for male Lewis rats divided into 3 groups; saline placebocontrols, low-dose tadalafil (0.5 mg/kg/day), and high-dosetadalafil (1.0 mg/kg/day) for 8 weeks. Treatment with tadalafilsignificantly alleviated the neointimal thickness and attenuatedgraft arteriosclerosis of aortas compared with the controls.
PULMONARY IMPLICATIONS
1. Pulmonary Arterial HypertensionPAH is a chronic and disabling condition characterized by
elevated pulmonary vascular resistance and mean pulmonaryarterial pressure. Current treatment guidelines recommendtadalafil for patients with WHO functional class II or III PAH.In a placebo-controlled clinical trial, tadalafil demonstratedimproved exercise capacity, as measured by the 6-minute walkingdistance, decreased incidence of clinical worsening, increasedquality of life, and improved cardiopulmonary hemody-namics.115 Kothari et al116 reported that low-dose sildenafil is ofclinical benefit in 14 patients with severe PAH in improvingclinical condition and exercise performance. Similarly, Vidaet al117 evaluated the efficacy of a low dose of 0.5 mg/kg sil-denafil in 10 PAH patients daily for 3 months with improvedfunctional capacity in 9/10 patients. Blanco et al118 added thatsildenafil 20 mg and 40 mg doses in patients with chronicobstructive pulmonary disease (COPD)-associated PAH reducedthe mean PAH pressure, and improved pulmonary hemody-namics at rest and during exercise with inhibited hypoxicvasoconstriction.
In younger age, Barst et al119 randomized 235 children(�8 kg) with PAH for low-, medium-, or high-dose sildenafil orplacebo orally 3 times/day for 16 weeks and reported hemody-namic improvement with medium and high doses. Also, Shahand Ohlsson120 reported the efficacy and safety of sildenafil intreating persistent PAH in neonates, with a steady improvementafter the first dose with reduced mortality.
2. Eisenmenger SyndromeThis syndrome comprises pulmonary vascular disease associ-
ated with intra-cardiac shunting, cyanosis, and polycythemia.Mukhopadhyay et al121 treated 16 cases with tadalafil (1 mg/kg)daily for 12 weeks with decreased mean pulmonary vascularresistance and improved mean systemic oxygen saturationimmediately and for 12 weeks.
CUTANEOUS IMPLICATIONS
1. Raynaud’s PhenomenonRaynaud’s phenomenon (RP) is excessively reduced blood
flow in response to cold or emotional stress, causing discolorationof the fingers or toes. In a randomized controlled trial in RPpatients unresponsive to other vasodilators, Fries et al122 reportedthat sildenafil (50 mg) twice daily for 4 weeks reduces the meanfrequency, duration of Raynaud attacks and increases capillaryblood flow velocity. Baumhaekel et al123 showed that tadalafiluse in RP is an effective option if not responding to sildenafil.Caglayan et al124 pointed that patients with primary or secondaryRP on vardenafil (10 mg) twice daily exhibited significant in-crease after 2 weeks in digital blood flow at room temperatureand during cold exposure test with reduced total daily duration,number, and severity of attacks.
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PDE-5Is: Low-dose Long-term Use 277
In their study, Kamata et al125 assessed RP in 3 patients withmixed connective tissue disease and 3 patients with systemicsclerosis on sildenafil, vardenafil, or tadalafil measuring fingertiptemperature by thermography before and 120 minutes afteradministration. For longer effects, vardenafil was administereddaily for 12 weeks. Compared with preadministration of sildenafil,vardenafil, and tadalafil, the mean fingertip temperature increasedby 2.17�C, 3.47�C, and 3.59�C in 120 minutes, whereas in thevardenafil 12-week trial, the mean fingertip temperature increasedby 3.04�C, 7.96�C, and 3.32�C from baseline.
2. Digital UlcersDigital ulcers in progressive systemic sclerosis are often re-
fractory to therapy where chronic aggressive course can lead toloss of involved acral limbs. Ambach et al126 described a 73-year-old woman with dramatic worsening of her ulcerations despitemaximum conventional therapy. Switching therapy to bosentan(endothelin receptor antagonists) and sildenafil in low-dose reg-imens yielded complete healing of these ulcers. Also, Wollinaet al127 reported improved chronic leg ulcers by combining sil-denafil 20 mg 3 times/day and repeated application of a porcinesmall intestinal submucosal acellular matrix.
3. Palmar-Plantar ErythrodysesthesiaMeadows et al128 evaluated the efficacy of sildenafil cream for
treating palmar-plantar erythrodysesthesia (PPE) on 9 subjectsrandomized to receive 0.5 mL of 1% topical sildenafil creamtwice daily to the left or right extremities and placebo cream onthe opposite extremity. Improved foot pain was reported in 5/9subjects and in 3/8 subjects for hand pain.
4. Diffuse Cutaneous Systemic SclerosisGheita et al129 presented a case of a 40-year-old female patient
with diffuse cutaneous systemic sclerosis who presented withprogressive dyspnea, choking sensation, cough, abdominaldistension, constipation and dysphagia to solids, reduced musclepower, and multiple purpuric eruptions on the legs. Sildenafil50 mg/day resulted in marked improve of dyspnea, skin tight-ness, small vessel vasculitic rash, with dramatic improved PAH.
5. Wound HealingFarsaei et al130 demonstrated the beneficial effects of sildenafil
in wound healing in 15 animal studies, 7 case reports, and 2clinical studies in various conditions of skin flaps, grafts andanastomosis. In this context, Samy et al131 studied the possiblebenefit of combining biodegradable polymers with sildenafil inwound healing, showing that the spray-dried chitosan/sildenafilpowder and its gel form are promising wound healing promoters.
6. Pressure UlcerPressure ulcer (PrU)-related hospitalization and mortality are
critical issues in medical and surgical patients. Farsaei et al132 was
Sex Med Rev 2016;4:270e284
the first to evaluate effects of topical sildenafil (10%) ointmentdaily on PrU healing in humans. Decreases in PrU grades weresignificantly higher and their surface areas in sildenafil groupwere significantly reduced compared with controls at day 14compared with placebo group. These effects were attributed toimproved microvascular reperfusion in the skin and soft tissue.
7. Skin Flap SurvivalBrewer et al133 investigated oral tadalafil on random flap
survival measured 8 cm � 2.5 cm raised on the backs of 37 malerats divided into controls, low-dose (10 mg/kg), and high-dose(20 mg/kg) groups once preoperatively and every day post-operatively for 7 doses. Average flap survival at 7 days and 14days was 77% and 77% in controls, 82% and 81% in the low-dose-group, and 81% and 80% in the high-dose group,respectively.
GASTROINTESTINAL IMPLICATIONS
1. Esophageal SpasmEsophageal spasm is presented with dysphagia and chest pain.
Fox et al134 provided open-label sildenafil treatment for 2patients with severe, treatment-resistant symptoms associatedwith esophageal spasm. Dysphagia and chest pain were resolvedduring this therapeutic trial and the efficacy was preserved onmaintenance treatment of 25 to 50 mg sildenafil b.i.d. withoutside effects.
2. Chronic Anal FissureHypertonicity of the internal anal sphincter (IAS) is involved
in the pathogenesis of anal fissure. Sildenafil was shown to relaxaugmented tone of human IAS in vitro.135,136 Torrabadellaet al137 showed that topical 10% sildenafil significantly reducesanal sphincter pressure in these patients, whereas Marino andBottalico138 pointed that tadalafil 5 mg/day improves thesymptoms of chronic anal fissure.
3. Congenital Diaphragmatic HerniaKeller et al139 described a case of chronic pulmonary hyper-
tension in a 7-week-old infant with congenital diaphragmatichernia who was mechanically ventilated from birth and depen-dent on low-dose inhaled NO but still unstable, with systemicright ventricular pressures leading to oxygen desaturation.Continued oral sildenafil 0.3 mg/kg/12 hr led to successfuldiscontinuation of the inhaled therapy and improvement. Simi-larly, Rocha et al140 reported an improved survival rate forcongenital diaphragmatic hernia due to the use of high-frequencyoscillation ventilation and sildenafil.
4. Liver RegenerationYardimci et al141 concluded that sildenafil accelerates hepatic
regeneration after 70% partial hepatectomy in young female ratsdivided into controls (G1) on intraperitoneal saline; 10 mg/kg
278 Mostafa
sildenafil low-dose (G2), and 100 mg/kg high-dose sildenafil(G3). Hepatic regeneration and mitosis rate were significantlygreater in G2 and G3 than the controls.
REPRODUCTIVE IMPLICATIONS
1. UterusSher et al142 demonstrated enhanced endometrial thickness in
70% of patients on vaginal sildenafil (25 mg, 4 times/day) for 3to 10 days in infertile women with poor endometrial develop-ment. Hale et al143 investigated uterine volumetric blood flow(UVF) and vascular impedance in nonpregnant, nulliparouswomen on placebo or sildenafil (25 or 100 mg) during the lutealphase. Sildenafil showed increased UVF and decreased resistanceindex over a 3-hour monitoring period. Also, Malinova et al144
investigated the role of 25 mg sildenafil vaginally plus 100 to150 mg Serophene orally on endometrial thickness and uterinevolume in anovulatory infertility with increased mean endome-trial thickness and endometrial volume.
2. Recurrent MiscarriageJerzak et al145 evaluated the effect of sildenafil (25 mg intra-
vaginal, 4 times/day) for 36 days on peripheral natural killer(NK)-cell activity in 38 women with a history of recurrentmiscarriage (RM) and 37 healthy women. NK-cell activity wassignificantly decreased and endometrial thickness was signifi-cantly increased.
3. Poor Ovarian ResponseThe use of sildenafil as an adjunct to controlled ovarian hy-
perstimulation (COH) protocols was shown to enhance ovarianresponse in women with poor ovarian response. Trakakis et al146
presented a case of a 37-year-old woman not responding toCOH with the sole use of gonadotropins as a part of intra-cytoplasmic sperm injection cycle, with the combination of re-combinant follicle stimulating hormone and human menopausalgonadotropins for 13 days, without follicular growth. Addition oforal sildenafil 50 mg/day for 5 doses was shown to improveovarian response and retrieval of 10 oocytes then 3 embryos thatwere transferred with successful pregnancy.
4. Sperm FunctionsMany studies demonstrated a significant increase in sperm
motility and viability both in vivo and in vitro at low concen-trations, which was reduced at high concentrations.147e149
NEUROLOGICAL IMPLICATIONS
1. Peripheral NeuropathyPeripheral neuropathy (PN) is a common complication of
diabetes. Hackett150 reviewed 5 patients with diabetic PN orsevere peripheral vascular disease reporting improved symptomson regular or daily dosing with PDEIs. The authors attributed
that improvement to the action of these drugs on endothelialdysfunction via improved blood supply to the vasa nervorum.
2. Cognitive FunctionsOzbeyli et al151 investigated the effects of sildenafil pretreat-
ment and chronic exercise on anxiety and cognitive functions.Sildenafil pretreatment or exercise exerts a protective effect againstacute stress and improves cognitive functions by decreasingoxidative damage. Also, several reports have demonstrated thatcognitive function can be restored in mouse models of Alzheimer’sdisease after administration of sildenafil or tadalafil, which arecapable of passing the blood-brain barrier.152,153
3. Heptaic EncephalopathyAmmonia is a byproduct of protein metabolism in the body
that can cross the blood-brain barrier. Elevated ammonia levelsare toxic to the brain. Arafa et al154 reported that sildenafil has aprotective effect on the brains of hyperammonemic rats due tocytoprotective, antioxidant and antiapoptotic effects, increasedcGMP, and enhanced proper metabolism of fats that suppressesoxygen radical generation and prevents brain oxidative damage.The authors shed a light on the therapeutic modulation of theNOecGMP pathway that might have clinical applications toimprove brain functions in patients with hyperammonemia orclinical hepatic encephalopathy.
4. Antinociception EffectsGediz et al155 investigated the peripheral antinociception ef-
fects of vardenafil on carrageenan-induced nociception in rats,and the role of calcium besides the L-arginineeNOecGMPpathway in these effects. Local administration of vardenafilproduced a dose-dependent antinociceptive effect. The authorssuggested that vardenafil may offer a new therapeutic tool to treatpain that probably result from L-arginineeNOecGMP pathwayactivation and involved Ca2þ channels.
Nevertheless, it should be noted that PDE-5Is have been impli-cated in a number of neurological problems, such as intracerebralhemorrhage, migraine, seizure, transient global amnesia, non-arteritic anterior ischemic optic neuropathy, macular degeneration,branch retinal artery occlusion, and ocular muscle palsies.47,156,157
CONCLUSION
Low-dose and long-term use of different PDE-5Is in differentformulations might pave the way to numerous beneficial medicalimplications for the welfare of the human beings withoutstanding overall efficacy and tolerability. However, it isevident that most potential appliances were carried out experi-mentally in preclinical studies with off label indications. There-fore, increased knowledge of the drug characteristics,comparative treatment regimens, optimal prescribing patterns,and well-designed clinical trials are needed before these agentscan be recommended for use.
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PDE-5Is: Low-dose Long-term Use 279
Corresponding Author: Taymour Mostafa, MD, Departmentof Andrology & Sexology, Faculty of Medicine, Cairo Univer-sity, Cairo 11562, Egypt; E-mail: [email protected]
Conflict of Interest: The authors report no conflicts of interest.
Funding: None.
STATEMENT OF AUTHORSHIP
Category 1
(a) Conception and Design
Sex
Taymour Mostafa
(b) Acquisition of DataTaymour Mostafa
(c) Analysis and Interpretation of DataTaymour Mostafa
Category 2
(a) Drafting the Article
Taymour Mostafa(b) Revising It for Intellectual Content
Taymour MostafaCategory 3
(a) Final Approval of the Completed Article
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