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Phosphodiesterase type 5 inhibitors (PDE5i) (e.g., sildenafil, tadalafil, vardenafil, and avanafil) are drugs commonly used to treat erectile dysfunction, pulmonary arterial hypertension, and benign prostatic hyperplasia. PDE5i are not prohibited by the World Anti-Doping Agency (WADA) but are alleged to be frequently misused by healthy athletes to improve sporting performance. In vitro and in vivo studies have reported various effects of PDE5i on cardiovascular, muscular, metabolic, and neuroendocrine systems and the potential, therefore, to enhance performance of healthy athletes during training and competition. This suggests well-controlled research studies to examine the ergogenic effects of PDE5i on performance during activities that simulate real sporting situations are warranted to determine if PDE5i should be included on the prohibited WADA list. In the meantime, there is concern that some otherwise healthy athletes will continue to misuse PDE5i to gain an unfair competitive advantage over their competitors.
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Phosphodiesterase Type 5 Inhibitors,
Sport and Doping
Luigi Di Luigi,MD
1
; Massimiliano Sansone, MD
2
; Andrea Sansone, MD
2
; Roberta Ceci, PhD
3
;
Guglielmo Duranti, PhD
3
; Paolo Borrione, MD
4
; Clara Crescioli, PhD
1
; Paolo Sgro
`, MD, PhD
1
;
and Stefania Sabatini, BiD
3
Abstract
Phosphodiesterase type 5 inhibitors (PDE5i) (e.g., sildenafil, tadalafil,
vardenafil, and avanafil) are drugs commonly used to treat erectile dys-
function, pulmonary arterial hypertension, and benign prostatic hyper-
plasia. PDE5i are not prohibited by the World Anti-Doping Agency
(WADA) but are alleged to be frequently misused by healthy athletes to
improve sporting performance. In vitro and in vivo studies have reported
various effects of PDE5i on cardiovascular, muscular, metabolic, and
neuroendocrine systems and the potential, therefore, to enhance perfor-
mance of healthy athletes during training and competition. This suggests
well-controlled research studies to examine the ergogenic effects of PDE5i
on performance during activities that simulate real sporting situations are
warranted to determine if PDE5i should be included on the prohibited
WADA list. In the meantime, there is concern that some otherwise healthy
athletes will continue to misuse PDE5i to gain an unfair competitive ad-
vantage over their competitors.
Introduction
Phosphodiesterases (PDE) are a family of enzymes (from
PDE1 to PDE11) with different selectivity for cyclic nucle-
otides, sensitivity to inhibitors and activators, physiological
roles, and tissue distributions. PDE catalyze the hydrolysis of
cyclic adenosine monophosphate (cAMP) and cyclic guanosine
monophosphate (cGMP) to the corre-
sponding 5-nucleotide monophosphate,
modulating their intracellular levels and
hence affecting different cell functions
in many tissues. Phosphodiesterase type 5
inhibitor (PDE5i) drugs, such as sildenafil,
tadalafil, vardenafil, and avanafil, have
different pharmacokinetic properties that
preferentially inhibit the PDE5 albeit
PDE6, PDE9, and PDE11 also are in-
hibited to a lesser extent (26,31). PDE5i
are approved for treating erectile dys-
function (ED), pulmonary arterial hyper-
tension, and benign prostatic hyperplasia.
Furthermore, other therapeutic applica-
tions have been proposed (e.g.,heart
failure, cardiomyopathy, stroke, meta-
bolic diseases) because of their cardio-
vascular and metabolic effects (9,26).
PDE5i work by influencing nitric oxide (NO)-related
cardiovascular, endocrine and metabolic pathways. NO
impacts cardiovascular hemodynamics, energy metabo-
lism, hormones, and mitochondrial biogenesis through
cGMP-dependent and -independent mechanisms (e.g.,Ca
++
,
prostaglandins) (13,15,17). PDE5i enhances the cGMP-
dependent effects of NO by increasing the intracellular
levels of NO-induced cGMP in different tissues. Particularly,
PDE5i influences the pathway downstream of NO: (a) NO
activates soluble guanylate cyclase producing cGMP, an in-
tracellular transduction mediator of NO; (b) intracellular
cGMP is physiologically decreased by the degradative action
of intracellular PDE5; (c) PDE5i inhibits the PDE5 action
thus increasing cGMP bioavailability; and (d) increased
cGMP availability amplifies the cGMP-related pleiotropic
effects of NO.
In addition to the widespread therapeutic use of PDE5i for
ED, there appears to be widespread abuse for recreational
purposes in healthy men (7,25,33). Based on anecdotal reports
and ‘‘doping control forms’’ data (36,39), many healthy ath-
letes (not affected by ED) participating in sports requiring en-
durance and/or competing in hypoxic conditions (i.e.,cycling,
running, rowing, and so on) misuse PDE5i to improve sporting
FIMS ARTICLE
www.acsm-csmr.org Current Sports Medicine Reports 443
1
Unit of Endocrinology, Department of Movement, Human and Health
Sciences, Universita
`degli Studi di Roma ‘‘Foro Italico’’, Rome, ITALY;
2
Section of Medical Pathophysiology, Food Science and Endocrinology,
Department of Experimental Medicine, Sapienza-University of Rome,
Rome, ITALY;
3
Unit of Biology, Genetics and Biochemistry, Department
of Movement, Human and Health Sciences, Universita
`degli Studi di
Roma ‘‘Foro Italico’’, Rome, ITALY; and
4
Unit of Internal Medicine, De-
partment of Movement, Human and Health Sciences, Universita
`degli
Studi di Roma ‘‘Foro Italico’’, Rome, ITALY
Address for correspondence: Luigi Di Luigi, MD, Unit of Endocrinology,
Department of Movement, Human and Health Sciences, Universita
`degli
Studi di Roma ‘‘Foro Italico’’, Largo Lauro de Bosis 15, 00135, Rome,
ITALY; E-mail: luigi.diluigi@uniroma4.it.
1537-890X/1606/443Y447
Current Sports Medicine Reports
Copyright *2017 by the American College of Sports Medicine
Copyright © 2017 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
performance, as PDE5i medications are not prohibited by the
World Anti-Doping Agency (WADA).
Unfortunately, as is true for other substances already
prohibited by WADA, there are no studies documenting a
specific performance-enhancing effect of PDE5i at either
therapeutic or supratherapeutic doses during real sporting
competitions. However, in vitro and in vivo studies de-
scribing the effects of PDE5i related to physical perfor-
mance enhancement provide a stronger case for prohibiting
PDE5i than some of the currently prohibited drugs. PDE5i
have great potential to enhance exercise capacity due to
their cardiovascular and vasodilatory effects increasing ox-
ygen transport to the exercising muscles, in addition to the
numerous neuroendocrine, muscular, and metabolic effects
summarized below.
PDE5i and Exercise Performance in Healthy Individuals
The capacity of PDE5i to enhance exercise tolerance in
humans affected by cardiovascular diseases is well-documented
(9,23,28,47). However, there is a paucity of information on the
effects of different PDE5i in either normoxia or hypoxia on
maximum aerobic (V
˙O
2max
) and anaerobic capacity in healthy
individuals of different ages (i.e., older humans might have a
reduced PDE5i-related sympatholytic effect) (42). This includes
athletes involved in different sports.
In normoxia, a single dose of tadalafil (20 mg) in a healthy
athlete did not substantially influence performance indicators,
such as the ventilatory threshold, V
˙O
2max
, exercise tolerance,
or the cardiopulmonary response, during a maximal stan-
dardized exercise test (12). Moreover, the same dose of
tadalafil did not influence the mean and peak power output
values during a 30-s Wingate anaerobic power test, but did
significantly decrease the time to peak power and increased
blood lactate concentrations during recovery. The observed
association between a reduced time to peak power and higher
blood lactate concentration (24) could be related to a possible
effect of PDE5i in stimulating anaerobic glycolysis (46), and
this may benefit performance in sports requiring a rapid at-
tainment of maximum power output.
Sildenafil is one of the first drugs to show increased ex-
ercise capacity in healthy individuals during severe hypoxia
both at sea level and at high altitude at therapeutic doses. In
healthy cyclists and triathletes at simulated high altitude,
sildenafil (50 mgY100 mg) increased stroke volume, cardiac
output, and arterial oxygen saturation (SaO
2
) during set-
work-rate exercise and significantly lowered 6-km time-
trial time by 15% in a double-blind study versus placebo
(27). In the same study, there were subjects who appeared to
be sildenafil responders and nonresponders with improved
time-trial performances of 39% (P G0.05) and 1.0%, re-
spectively (27). If confirmed, these individual differences
in PDE5i response could explain the observed discrepancies
in the studies evaluating PDE5i-related effects. In healthy
mountaineers and trekkers breathing a hypoxic gas mixture
with 10% fraction of inspired oxygen at low altitude (Giessen,
155-304 m), sildenafil (50 mg) significantly increased SaO
2
during exercise and reduced systolic pulmonary artery pres-
sure at rest and during exercise (20). Sildenafil also signifi-
cantly increased maximum workload and maximum cardiac
output compared with placebo (20). At the Mount Everest
base camp (elevation 5380 m), sildenafil (50 mg) reduced
systolic pulmonary artery pressure (at rest and during ex-
ercise) and increased maximum workload and cardiac
output (20). Other studies have been unable to replicate
these effects on performance. During acute exposure to
hypobaric hypoxia (elevation, 4000 m) at rest and during
maximal and submaximal (60% V
˙O
2max
) exercise, silden-
afil (100 mg) did not impact performance in healthy men or
women (53). Moreover, no effects of sildenafil (50 mg)
were observed on cardiovascular hemodynamics, arterial
oxygen saturation, peak exercise capacity, and 15 or 6 km
time-trial performance in endurance-trained subjects of
either sex at simulated moderate altitude (~2100 and3900 m)
(30,34). These negative findings may be due to methodo-
logical factors, such as altitude (i.e., PDE5i may have greater
effects above 4000 m), duration of exposure to acute or chronic
hypoxia, possible variability of individual response to PDE5i,
or individual hormonal status (i.e., in men affected by ED, se-
rum testosterone levels influence the responsiveness to PDE5i)
(5,32,49).
Alveolar hypoxia, either natural (e.g., high altitude) or
artificial (e.g., hypoxic tents), may negatively influence ex-
ercise capacity, because hypoxia reduces alveolar partial
oxygen pressure (pPO
2
) and SaO
2
, increases pulmonary ar-
terial pressure and enhances the right heart. PDE5i may in-
crease exercise capacity in hypoxic conditions due to the
vasodilatory function and modulatory effects on central ner-
vous system and sympathetic system (i.e., functional sympa-
tholytic effects), heart rate, myocardial contractility, and
alveolar-capillary membrane conductance (23,29,35,42,45,51).
It is likely that the improvement in exercise capacity and
cardiac output observed in healthy subjects during exercise
under hypoxic conditions after PDE5i administration is
due to the blunting effect of PDE5i on pulmonary hyper-
tensive response to hypoxic exercise and to reduced right
ventricular afterload, which is a critical factor limiting ex-
ercise capacity in hypoxia (20,27). Moreover, the possible
presence of responders and nonresponders to PDE5i
may explain the variability in pulmonary hemodynamic,
pPO
2
and SaO
2
responses, and in the adaption to acute or
chronic hypoxic conditions.
The reported effects of PDE5i on human physiology un-
der hypoxic conditions could explain the mechanism(s) by
which PDE5i can enhance athletic performance at very high
altitude and/or the response to exercise training performed
in natural or artificial hypoxia.
Intriguingly, PDE5i (e.g., sildenafil) could be a prophylactic
medication for swimming-induced pulmonary edema (SIPE) in
swimmers (38,40). SIPE occurs during immersed exercise, in
susceptible healthy individuals, because of higher pulmonary
artery and wedge pressures, and sildenafil (50 mg) adminis-
tration may reduce the pulmonary pressures and prevent the
hemodynamic pulmonary edema (38,40).
Although the existing data are contradictory, NO donors
per se (e.g., beetroot juice, and so on) could mitigate the
ergolytic effects of hypoxia on cardiorespiratory endurance
(18,19,37,41,44,50). Unfortunately, there is no adequate
information regarding the possible role of other drugs and/or
supplements increasing NO availability and influencing the
individual responses to PDE5i in athletes (1,6,11,16).
444 Volume 16 &Number 6 &November/December 2017 FIMS Article
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PDE5i and Hormones Adaptation to Exercise
In animals, prolonged sildenafil administration increases
testosterone production by stimulating Leydig cell steroido-
genesis (3). In humans with ED, chronic PDE5i administra-
tion also has been shown to increase serum testosterone and
the testosterone to estrogen ratio, due to increased sexual in-
tercourse, PDE5i-related antiestrogen effects, and/or to direct
effect at testicular levels (8,22,43,52). In healthy men, a single
dose of tadalafil (20 mg) amplified the physiological cortisol
and testosterone responses to a maximal exercise-related stress
in normoxia (Fig. 1), decreasing the testosterone to corti-
sol ratio (13). Interestingly, when compared with placebo,
a slightly prolonged tadalafil administration (20 mgId
j1
for 2 d) reduced the ACTH, cortisol, corticosterone, and
free cortisol index responses to a maximal exercise and in-
creased beta-endorphin and dehydroepiandrosterone sul-
fate (DHEAS) to cortisol ratio during recovery by influencing
the 11b-hydroxysteroid dehydrogenases activity (14,17). In
fact, after tadalafil (20 mgId
j1
for 2 d), higher postexercise
tetrahydrocortisol-to-cortisol ratio and tetrahydrocortisone-
to-cortisone ratio were observed (14). Recently, chronic ad-
ministration of vardenafil reduced dehydroepiandrosterone
(DHEA) levels and increased DHEAS to DHEA ratio in men
with type 2 diabetes, confirming a PDE5i-related modulation
of steroidogenic enzymes by tissue changes in cAMP and
cGMP (48). The fact that there were no effects on cardiore-
spiratory and performance parameters in these studies does
not exclude potential endocrine effects of PDE5i during a spe-
cific competition and/or training. A laboratory exercise can-
not reproduce all the factors influencing the final result
during real competition and many confounding factors exist
makingthelinktoperformanceenhancement and PDE5i dif-
ficult to confirm. Based on the available studies (13,14,17,48),
we believe in athletes that a) acute tadalafil administration
could amplify the positive psychophysical effects of acutely
increased endogenous cortisol and testosterone during sport
competition (e.g., the response to exercise-stress is increased by
tadalafil) (13) and b) chronic tadalafil administration, by
decreasing the adrenal steroids response to exercise-stress,
could be useful during training because of reduced cortisol-
related protein catabolism, increased testosterone-related an-
abolic effects, improved recovery from exercise, and reduced
risk of overtraining (14,17,48).
PDE5i, Muscle, and Metabolism
PDE5i also may act directly on skeletal muscle cells.
In vitro, an acute tadalafil exposure influenced the metabo-
lism of murine C2C12 skeletal muscle cells (46), indicating
that cGMP signaling may play a role also in the regulation of
energy homeostasis. Specifically, acute treatment with 0.5
KM tadalafil improved glucose metabolism through the in-
duction of anaerobic glycolysis with an accompanying de-
crease of aerobic metabolism (46). Studies performed using
isolated human skeletal muscle cells, either myoblasts or
myotubes, showed that tadalafil did not affect lactate, but en-
hanced citrate synthase activity involved in Krebs cycle while
simultaneously increasing free fatty acid release. At the same
time, tadalafil was able to activate the main insulin-dependent
intracellular steps dedicated to cell metabolism regulation,
such as Ras-Raf mitogen-activated protein kinase, protein ki-
nase B/Akt, glycogen synthase kinase 3-A(downstream target
of phosphatidylinositol 3-kinase), and the transcription
factor c-Myc (downstream target of glycogen synthase kinase
3-A), all paths directly engaged in the control of intracellular
nutrient fate and utilization (10). Tadalafil, like insulin, seems
to target and potentiate part of the energy management and
metabolic control in human skeletal muscle cells (Fig. 2).
Recent studies have shown that prolonged tadalafil admin-
istration improved free fatty mass content in nonobese men,
probably via enhanced insulin secretion and estradiol reduc-
tion (4,10,22). PDE5i also may amplify the action of endog-
enous NO on muscle satellite cells (2). Furthermore, after
prolonged tadalafil administration, the endothelial function
increased and correlated directly with insulin and inversely
with estrogen serum levels (4). Moreover, the exposure of
C2C12 cells to increasing tadalafil concentrations (10
j7
to
10
j6
M) significantly increased total androgen receptor (AR)
mRNA and protein expression as well as myogenin protein
expression after 24 and 72 h, suggesting a translational action
of PDE5i on AR and on muscle cells (4). After 24-h treatment
with upregulation of AR expression, a significant increase
Figure 1: Box plot of salivary testosterone and cortisol concen-
trations before (Pre-Ex), at the end (Post-Ex), and 30 min after (30-Rec) a
maximal exercise test on cycle ergometer after placebo (open box)and
tadalafil (20 mg; dark box) administration in healthy male athletes.
Lower and upper edges of each box represent the first and third quartile
of observed data. The line-partitioning box corresponds to median
observation and whiskers give range of data. *PG0.05 vs respective
Pre-Ex; PG0.05 vs placebo (Adapted from Di Luigi L et al., J Clin
Endocrinol Metab. 2008;93:3510Y4).
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of testosterone concentrations in the supernatant of 10
j6
M
tadalafil-treated cells (2.3 T0.5-fold) compared with untreated
cells was found (PG0.05) (4).
Conclusions
PDE5i administration-related effects on cellular and body
physiology, observed both in animal models and in some
healthy individuals and specific circumstances (e.g., hypoxia),
could potentiate sport performance. The possible effects of
PDE5i on exercise physiology are related both to the type of
PDE5i use (e.g., molecules, doses and length of administration)
and to various individual factors (e.g., age, hormone status,
individual responsiveness, oxygen availability, and so on). In
our opinion, PDE5i should be included in the list of prohibited
substances for athletes, rather than waiting for challenging in-
vestigations on the possible performance enhancing effects of
PDE5i during real-life sporting competition (i.e., in different
sports and experimental conditions), for the already observed
effects of PDE5i on exercise physiology/performance and pos-
sible serious health risk related to their misuse (21).
The authors declare no conflict of interest and do not
have any financial disclosures.
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... Probably due to its long half-life among blood circulation (~ 24 hours), the PDE5i tadalafil is the most well studied PDE5i for what concerns metabolic implications. Particularly, tadalafil, as well as the other PDE5i sildenafil [17] may influence cellular physiology and endocrine-metabolic pathways in skeletal muscles [18][19][20]. In particular it has been demonstrated that by activating the cell signaling linked to the insulin-related metabolic pathways, tadalafil improves beta cell function in patient with metabolic syndrome, and reduces the hemoglobin A1c (HbA1c) in patients with diabetes [21], modulates the endocrine responses, protein catabolism and hormone-related anabolism/catabolism during and after physical exercise-related stress [5,22]. ...
... In their studies the authors demonstrated that the overexpression of PDE5 (isoform A) in cultures of mice muscle cells, negatively regulates the insulin signaling, altering the insulin activation pathways, and inhibiting glucose uptake [33,34]. Moreover, studies on murine C2C12 and primary human skeletal muscle cells demonstrated that tadalafil improves glucose metabolism through the initiation of anaerobic glycolysis with an accompanying decrease of aerobic metabolism, enhanced citrate synthase activity and increases free fatty acids release [18,35,36]. At the same time, tadalafil activated the main insulin-dependent intracellular steps dedicated to cell metabolism regulation, such as Ras-Raf mitogen-activated protein kinase (MAPK), protein kinase B/AKT (PKB/AKT), glycogen synthase kinase3-A (GSK3-A), a downstream target of phosphatidylinositol 3-kinase, and the transcription factor c-Myc (downstream target of GSK3-A), all pathways directly engaged in the control of intracellular nutrient outcome and consumption [5,35]. ...
... The main information regarding the possible relationships between PDE5i activity, steroid hormones, and skeletal muscles in vivo, come from experimental evidence in male athletes and in patients affected by ED and/or metabolic disorders (table 2) [18,27,44,45]. Indeed, since to its long half-life, tadalafil can provoke marked and prolonged outcomes interfering with endocrine system status at rest and/or as adaptation during physical exercise [22,27]. ...
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Beside its mechanical roles in controlling posture and locomotion, skeletal muscle system, the largest insulin and steroid hormones target tissue, plays a key role in influencing thermoregulation, secondary sexual characteristics, hormones metabolism, and glucose uptake and storage, as well as energetic metabolism. Indeed, in addition to insulin, several hormones influence the skeletal muscle metabolism/function and/or are influenced by skeletal muscles activity (i.e., physical exercise). Particularly, steroid hormones play a key role in modulating many biological processes in muscles, essential for overall muscle's function and homeostasis, both at rest and during all physical activities (i.e., physical exercise, muscular work). The phosphodiesterase type 5 (PDE5) is the enzyme engaged to hydrolyze cGMP in inactive 5'- GMP form. Therefore, through the inhibition of this enzyme, the intracellular level of cGMP increases, and the cGMP-related cellular responses are prolonged. Different drugs inhibiting PDE5 (PDE5i) exist, the main of which commercially available are sildenafil, vardenafil, tadalafil, and avanafil. The PDE5i tadalafil may influence cellular physiology and endocrine-metabolic pathways in skeletal muscles and exerts its functions both by activating the cell signaling linked to the insulin-related metabolic pathways and modulating the endocrine responses, protein catabolism and hormone-related anabolism/catabolism during and after physical exercise-related stress. Based on recent in vivo and in vitro findings, in this narrative review we summarized the available evidence describing the interactions between the PDE5i tadalafil and steroid hormones in skeletal muscle tissue and physical exercise adaptation, focusing our interest on their possible synergistic or competitive action(s) on muscle metabolism and function.
... Phosphodiesterase type 5 inhibitors (PDE5Is) (e.g., avanafil, sildenafil, vardenafil, tadalafil), represent a class of drugs routinely consumed worldwide, because of their great therapeutic role for the treatment of erectile dysfunction (ED) (avanafil, sildenafil, vardenafil, tadalafil), and pulmonary arterial hypertension (sildenafil and tadalafil), and for the management, in men, of moderate to severe lower urinary tract symptoms (LUTS) secondary to benign prostatic obstruction with or without ED (tadalafil) acting mainly via the nitric oxide (NO) and cyclic guanosine monophosphate (NO-cGMP) pathways [1][2][3][4][5][6][7][8]. ...
... Finally, plasma's total antioxidant capacity, which expressed the reactivity of plasmatic antioxidant compounds in counteracting radicals, also remained unchanged. In vitro analysis of the scavenger capacity of tadalafil showed modest activity (Table 7) and, therefore, although the molecule may act for longer than other PDE5 inhibitors [6], its contribution to the plasma total antioxidant capacity may be not significant. There are few studies evaluating the effects of tadalafil on healthy athletes [27,[53][54][55]. ...
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Background: The phosphodiesterase type 5 inhibitor (PDE5I) tadalafil, in addition to its therapeutic role, has shown antioxidant effects in different in vivo models. Supplementation with antioxidants has received interest as a suitable tool for preventing or reducing exercise-related oxidative stress, possibly leading to the improvement of sport performance in athletes. However, the use/abuse of these substances must be evaluated not only within the context of amateur sport, but especially in competitions where elite athletes are more exposed to stressful physical practice. To date, very few human studies have addressed the influence of the administration of PDE5Is on redox balance in subjects with a fitness level comparable to elite athletes; therefore, the aim of this study was to investigate for the first time whether acute ingestion of tadalafil could affect plasma markers related to cellular damage, redox homeostasis, and blood polyamines levels in healthy subjects with an elevated cardiorespiratory fitness level. Methods: Healthy male volunteers (n = 12), with a VO2max range of 40.1–56.0 mL/(kg × min), were administered with a single dose of tadalafil (20 mg). Plasma molecules related to muscle damage and redox-homeostasis, such as creatine kinase (CK), lactate dehydrogenase (LDH), total antioxidant capacity (TAC), reduced/oxidized glutathione ratio (GSH/GSSG), free thiols (FTH), antioxidant enzyme activities (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx)), as well as thiobarbituric acid reactive substances (TBARs), protein carbonyls (PrCAR), and polyamine levels (spermine (Spm) and spermidine (Spd)) were evaluated immediately before and 2, 6 and 24 hours after the acute tadalafil administration. Results: A single tadalafil administration induced an increase in CK and LDH plasma levels 24 after consumption. No effects were observed on redox homeostasis or antioxidant enzyme activities, and neither were they observed on the oxidation target molecules or polyamines levels. Conclusion: Our results show that in subjects with an elevated fitness level, a single administration of tadalafil induced a significant increase in muscle damage target without affecting plasma antioxidant status.
... 159 Besides, natural compounds like phytoekdysteroids or PDE5 inhibitors are also used in sports and PDE5 inhibitors are alleged to be frequently misused by healthy athletes to improve sporting performance. 160 Finally, the implementation of gene doping constitutes a great threat of major concern about the future of human performance manipulation. ...
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The use of substances and medications with potential cardiovascular effects among those practicing sports and physical activity has progressively increased in recent years. This is also connected to the promotion of physical activity and exercise as core aspects of a healthy lifestyle, which has led also to an increase in sport participation across all ages. In this context, three main users' categories can be identified, (i) professional and amateur athletes using substances to enhance their performance, (ii) people with chronic conditions, which include physical activity and sport in their therapeutic plan, in association with prescribed medications, and (iii) athletes and young individuals using supplements or ergogenic aids to integrate their diet or obtaining a cognitive enhancement effect. All the substances used for these purposes have been reported to have side effects, among whom the cardiovascular consequences are the most dangerous and could lead to cardiac events. The cardiovascular effect depends on the type of substance, the amount, the duration of use, and the individual response to the substances, considering the great variability in responses. This Position Paper reviews the recent literature and represents an update to the previously published Position Paper published in 2006. The objective is to inform physicians, athletes, coaches, and those participating in sport for a health enhancement purpose, about the adverse cardiovascular effects of doping substances, commonly prescribed medications and ergogenic aids, when associated with sport and exercise.
... Inhibitors of phosphodiesterase type 5 (PDE5-Is), including tadalafil, are the first-line ED-treating drugs [7]. Besides its role in the treatment of ED, tadalafil, like insulin, appears to regulate many metabolic risk factors by directing part of the energy produced from metabolic body' processes under the control of skeletal myocytes [8]. ...
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Exercise (Ex) shares the first-line approach with pharmacological inhibitors of phosphodiesterase type 5 (PDE5-Is), including tadalafil, in the treatment of erectile dysfunction (ED) in obese men. The effect of elliptical training (ET) on ED was not questioned in the literature. This study aimed to clarify the effect of adding a 2-month consequent continuous and interval ET to once-daily 5-mg tadalafil administration on ED in obese men. Sixty obese men aged 34–56 years with ED were randomly assigned to the Ex group (n = 30) and the non-Ex group (n = 30). Both groups received 8-week oral tadalafil administration (five-milligram tablet, one time/day). Ex group only received a 1-h concurrent interval and continuous ET (three times/week for 2 months). Homeostasis model assessment of insulin resistance (HOMA-IR), insulin, body mass index (BMI), the circumference of the waist (WC), systolic blood pressure (SBP), high-density lipoprotein (HDL), diastolic blood pressure (DBP), triglycerides (TG), Five-Item Version of International Index of Erectile Dysfunction (IIEF-5), and fasting blood glucose (FBG) were screened before and after the trial. A significant statistical difference of all measures was ascertained from the within-Ex-group comparison (P < 0.05) while this significance was not achieved from the within-comparison of the non-Ex group (except IIEF-5 which showed a significant difference, P < 0.05). The established post-intervention comparison between Ex and non-Ex groups exhibited a non-significant difference in BMI, HDL, and WC while other variables exhibited a statistically-significant difference in favor of the Ex group. Adding 1-h consequent continuous and interval ET to tadalafil drug is a highly efficient procedure in improving ED than tadalafil alone in obese men.
... In recent years, PDEs have been attracting increased attention as new therapeutic targets and have become a new research hotspot. The clinical research of selective PDE4 and PDE5 inhibitors has also received significant attention (9,10). PDE4 has multiple isozymes, which are divided into four subtypes: PDE4A, B, C and D (11). ...
... 122 Another instance of misuse is to improve athletic performance. 36 There have been numerous reports of use of sildenafil in cardiovascular diseases, Raynaud phenomenon, cystic fibrosis, cancer, diabetes, and neurological disorders such as Alzheimer disease. 34 , 140 , 59 , 65 In terms of mechanism of action, selective inhibition of PDE5 by sildenafil results in elevated concentration of c-GMP in the tissues that potentiates the vasodilatory action of nitric oxide (NO) through relaxation of smooth muscles. ...
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Sildenafil citrate is a selective oral phosphodiesterase 5 (PDE5) inhibitor, a widely used drug for erectile dysfunction that acts by elevating cGMP levels and causing smooth muscle relaxation. It also has 10% activity against PDE6, a key enzyme in phototransduction cascade in the retina. Recent ocular imaging developments have further revealed the influence of sildenafil on ocular hemodynamics, particularly choroidal perfusion. Choroidal thickness is increased, and choroidal perfusion is also enhanced by autoregulatory mechanisms that are further dependent on age and microvascular abnormalities. Studies demonstrating high intraocular pressure via a "parallel pathway" from increased choroidal volume and blood flow to the ciliary body have challenged previous concepts. Another new observation is the effect of sildenafil on bipolar cells and cyclic-nucleotide gated (CNG) channels. We discuss potential deleterious effects (central serous chorioretinopathy, glaucoma, ischemic optic neuropathy, and risks to recessive carriers of retinitis pigmentosa), potential beneficial effects (ameliorate choroidal ischemia, prevent thickening of Bruch membrane, and promote recovery of the ellipsoid zone) in macular degeneration, as well as potential drug interactions of sildenafil.
... Potent ABCC5 inhibitors like compound #8 and #16 could therefore have a potential in treatment of cardiovascular disorders. In healthy athletes, vardenafil and sildenafil reduce systolic pulmonary pressure and enhance cardiac output during exercise [32] and in patients with chronic systolic heart failure, sildenafil improves cardiac index [33]. ...
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Background Clinical studies have reported overexpression of PDE5 and elevation of intracellular cyclic GMP in various types of cancer cells. ABCC5 transports cGMP out of the cells with high affinity. PDE5 inhibitors prevent both cellular metabolism and cGMP efflux by inhibiting ABCC5 as well as PDE5. Increasing intracellular cGMP is hypothesized to promote apoptosis and growth restriction in tumor cells and also has potential for clinical use in treatment of cardiovascular disease and erectile dysfunction. Vardenafil is a potent inhibitor of both PDE5 and ABCC5-mediated cGMP cellular efflux. Nineteen novel vardenafil analogs that have been predicted as potent inhibitors by VLS were chosen for tests of their ability to inhibit ATP- dependent transport of cGMP by measuring the accumulation of cyclic GMP in inside-out vesicles. Aim In this study, we investigated the ability of nineteen new compounds to inhibit ABCC5- mediated cGMP transport. We also determined the Ki values of the six most potent compounds. Methods Preparation of human erythrocyte inside out vesicles and transport assay. Results Ki values for six of nineteen compounds that showed more than 50 % inhibition of cGMP transport in the screening test were determined and ranged from 1.1 to 23.1 μM. One compound was significantly more potent than the positive control, sildenafil. Conclusion Our findings show that computational screening correctly identified vardenafil-analogues that potently inhibit cGMP efflux-pumps from cytosol and could have substantial clinical potential in treatment of patients with diverse disorders.
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1, 2, 3, 4-Tetrahydro-β-carboline (THβC) scaffold is widespread in many natural products (NPs) and synthetic compounds which show a variety of pharmacological activities. In this article, we reviewed the design, structures and biological characteristics of reported synthetic THβC compounds, and structure and activity relationship (SAR) of them were also discussed. This work might provide a reference for subsequent drug development based on THβC.
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The presented review of modern literature on Avanafil in the treatment of erectile dysfunction and its accompanying certain pathologies of the male reproductive system indicates the promise of the use of this drug in sexological patients, given its high efficiency and safety.
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A number of high profile revelations concerning anti‐doping rule violations over the past 12 months has outlined the importance of tackling prevailing challenges and reducing the limitations of the current anti‐doping system. At this time, the necessity to enhance, expand and improve analytical test methods in response to the substances outlined in the World Anti‐Doping AgencyꞋs (WADA) Prohibited List represents an increasingly crucial task for modern sports drug testing programs. The ability to improve analytical testing methods often relies on the expedient application of novel information regarding superior target analytes for sports drug testing assays, drug elimination profiles, and alternative sample matrices, together with recent advances in instrumental developments. This annual banned‐substance review evaluates literature published between October 2017 and September 2018 offering an in‐depth evaluation of developments in these arenas and their potential application to substances reported in WADAꞋs 2018 Prohibited List.
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Nitrate supplementation appears to be most ergogenic when oxygen availability is restricted and subsequently may be particularly beneficial for swimming performance due to the breath-hold element of this sport. This represents the first investigation of nitrate supplementation and swimming time-trial (TT) performance. In a randomized double-blind repeated-measures crossover study, ten (5 male, 5 female) trained swimmers ingested 140ml nitrate-rich (∼12.5mmol nitrate) or nitrate-depleted (∼0.01mmol nitrate) beetroot juice. Three hours later, subjects completed a maximal effort swim TT comprising 168m (8 × 21m lengths) backstroke. Preexercise fractional exhaled nitric oxide concentration was significantly elevated with nitrate compared with placebo, Mean (SD): 17 (9) vs. 7 (3)p.p.b., p = .008. Nitrate supplementation had a likely trivial effect on overall swim TT performance (mean difference 1.22s; 90% CI -0.18-2.6s; 0.93%; p = .144; d = 0.13; unlikely beneficial (22.6%), likely trivial (77.2%), most unlikely negative (0.2%)). The effects of nitrate supplementation during the first half of the TT were trivial (mean difference 0.29s; 90% CI -0.94-1.5s; 0.46%; p = .678; d = 0.05), but there was a possible beneficial effect of nitrate supplementation during the second half of the TT (mean difference 0.93s; 90% CI 0.13-1.70s; 1.36%; p = .062; d = 0.24; possibly beneficial (63.5%), possibly trivial (36.3%), most unlikely negative (0.2%)). The duration and speed of underwater swimming within the performance did not differ between nitrate and placebo (both p > .30). Nitrate supplementation increased nitric oxide bioavailability but did not benefit short-distance swimming performance or the underwater phases of the TT. Further investigation into the effects of nitrate supplementation during the second half of performance tests may be warranted.
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Background and objective Dietary beetroot juice (BR) supplementation has been shown to reduce the oxygen (O2) consumption of standardized exercise and reduce resting blood pressure (BP) in healthy individuals. However, the physiological response of BR in chronic obstructive pulmonary disease (COPD) remains controversial. The objective was to test exercise performance in COPD, supplementing with higher doses of BR for a longer duration compared to previous trials in this patient group. Methods Fifteen COPD patients consumed concentrated BR (2×70 mL twice daily, each containing 300 mg nitrate) or placebo (PL) (2×70 mL twice daily, nitrate-negligible) in a randomized order for 6 consecutive days. On day 7, participants consumed either BR or PL 150 min before testing. BP was measured before completing 6-minute walk test (6MWT) and two trials of submaximal cycling. The protocol was repeated after a minimum washout of 7 days. Results Plasma nitrite concentration was higher in the BR condition compared to PL (P<0.01). There was no difference between the BR and PL conditions regarding the covered distance during the 6MWT (mean ± standard error of the mean: 515±35 m (BR) vs 520±38 m (PL), P=0.46), O2 consumption of submaximal exercise (trial 1 P=0.31 vs trial 2 P=0.20), physical activity level (P>0.05), or systolic BP (P=0.80). However, diastolic BP (DBP) was reduced after BR ingestion compared to baseline (mean difference: 4.6, 95% CI: 0.1–9.1, P<0.05). Conclusion Seven days of BR ingestion increased plasma nitrite concentrations and lowered DBP in COPD patients. However, BR did not increase functional walking capacity, O2 consumption during submaximal cycling, or physical activity level during the intervention period.
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Background Previous studies suggested that phosphodiesterase 5 inhibitors (PDE5i) have a beneficial effect in patients with heart failure (HF), although the results were inconsistent. We performed a meta-analysis to evaluate the effect of PDE5i in HF patients, and investigated the relationship between PDE5i effects and pulmonary hemodynamics. Method We searched PubMed, EMBASE and the Cochrane Library for randomized controlled trials (RCTs) that compared PDE5i with placebo in HF with reduced ejection fraction (HFrEF) or HF with preserved EF (HFpEF). PDE5i effects were interpolated according to baseline pulmonary arterial pressure (PAP) or according to changes in PAP after PDE5i treatment. Results Thirteen RCTs enrolling 898 HF patients, and two sub-analysis studies with different study outcomes, were included in the meta-analysis. Among patients with HFrEF, PDE5i improved peak VO2 (mean difference [MD], 3.76 mL/min/kg; 95% confidence interval [CI], 3.27 to 4.25; P < 0.00001), VE/VCO2 slope (MD, −6.04; 95% CI, −7.45 to −4.64; P < 0.00001), LVEF (MD, 4.30%; 95% CI, 2.18 to 6.42; P < 0.0001), and pulmonary vascular resistance (MD, −80.74 dyn·sec/cm⁵; 95% CI, −110.69 to −50.79; P < 0.00001). The effects of PDE5i in patients with HFpEF were heterogeneous. Meta-regression analyses indicated that the beneficial effect of PDE5i was related to the baseline PAP as well as the extent of PDE5i-mediated PAP decrease. Conclusion PDE5i improved pulmonary hemodynamics and exercise capacity in patients with HFrEF, but not in HFpEF. The relationship between the benefits by PDE5i with the baseline PAP and the changes in PAP indicates the therapeutic potential of PDE5i in HF according to pulmonary hemodynamics. Electronic supplementary material The online version of this article (doi:10.1186/s12872-017-0576-4) contains supplementary material, which is available to authorized users.
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It has been shown that nitrate supplementation can enhance endurance exercise performance. Recent work suggests that nitrate ingestion can also increase intermittent type exercise performance in recreational athletes. We hypothesized that six days of nitrate supplementation can improve high-intensity intermittent type exercise performance in trained soccer players. Thirty-two male soccer players (age: 23 ± 1 years, height: 181 ± 1 m, weight: 77 ± 1 kg, playing experience: 15.2 ± 0.5 years, playing in the first team of a 2nd or 3rd Dutch amateur league club) participated in this randomized, double-blind cross-over study. All subjects participated in two test days in which high-intensity intermittent running performance was assessed using the Yo-Yo IR1 test. Subjects ingested nitrate-rich (140 mL; ~800 mg nitrate/day; BR) or a nitrate-depleted beetroot juice (PLA) for six subsequent days, with at least eight days of wash-out between trials. The distance covered during the Yo-Yo IR1 was the primary outcome measure, while heart rate (HR) was measured continuously throughout the test, and a single blood and saliva sample were collected just prior to the test. Six days of BR ingestion increased plasma and salivary nitrate and nitrite concentrations in comparison to PLA (p < 0.001), and enhanced Yo-Yo IR1 test performance by 3.4 ± 1.3% (from 1574 ± 47 to 1623 ± 48 m; p = 0.027). Mean HR was lower in the BR (172 ± 2) vs. PLA trial (175 ± 2; p = 0.014). Six days of BR ingestion effectively improves high-intensity intermittent type exercise performance in trained soccer players.
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Sildenafil citrate (Viagra®) is a vasoactive agent available worldwide since 1998 for the treatment of male erectile dysfunction. It is a selective phosphodiesterase type 5-enzyme inhibitor able to potentiate the downstream effects of nitric oxide on smooth muscle relaxation and vasodilation through its effects on the cyclic guanosine monophosphate (c-GMP) pathway in the erectile tissue of the penis. When sildenafil is orally administered, it is rapidly absorbed with a maximum plasma concentration achieved within 1 h and has a terminal half-life of between 3 to 6 h. The drug is extensively and rapidly metabolized by the liver, primarily by the CYP3A4 enzyme. Although the drug is well tolerated, specific adverse events have been observed, like flushing, headaches, dyspepsia, and visual disturbances. Liver toxicity related to sildenafil consumption has been considered a very rare event. However, in the last decade, some cases of sildenafil-associated hepatotoxicity have been reported. Furthermore, some hepatic intoxications have been reported after the intake of “natural” or “herbal” aphrodisiac supplements sold through Internet, sex shops, social media, and by word-of-mouth found to contain sildenafil and other phosphodiesterase type 5 (PDE-5) inhibitors. Studies investigating a possible link between sildenafil use and liver damage are limited, and the underlying mechanism responsible for hepatotoxicity is still missing. Studies in animals evidence that the hematopoietic function of the liver may have severely been affected as a result of a probable toxic effect of sildenafil. Here, the studies reporting liver toxicity by sildenafil in humans and in animals are reported and discussed.
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Swimming-induced pulmonary edema (SIPE) occurs during swimming and scuba diving, usually in cold water, in susceptible healthy individuals, especially military recruits and triathletes. We have previously demonstrated that pulmonary artery pressure (PAP) and pulmonary artery wedge pressure (PAWP) are higher during immersed exercise in SIPE-susceptible individuals vs. controls, confirming that SIPE is a form of hemodynamic pulmonary edema. Oral sildenafil 50 mg 1 hour before immersed exercise reduced PAP and PAWP, suggesting that sildenafil may prevent SIPE. We present a case of a 46-year old, female ultra-triathlete with a history of at least five SIPE episodes. During a study during exercise submerged in 20°C water, physiological parameters before and after sildenafil 50 mg orally were: O2 consumption 1.75, 1.76 L.min-1; heart rate 129, 135 bpm; arterial pressure 189/88 (mean 121.5), 172/85 (mean 114.3) mmHg; mean pulmonary artery (PA) pressure 35.3, 28.8 mmHg; PA wedge pressure 25.3, 19.7 mmHg. She has had no recurrences during 20 subsequent triathlons while taking 50 mg sildenafil before each swim. This case supports sildenafil as an effective prophylactic agent against SIPE during competitive surface swimming.