RC
`
`n
`
`CONTENTS
`
`page
`
`Opportunities for the Treatment of Erectile Dysfunction bjr
`Modulation of the NO Axis.- Alternatives to Sildenafil Citrate.
`Christian de Mey
`
`Comparison of Buccal and- Oral Prochlorperazine_ in the Treatment
`of Dizziness Associated with Nausea and/or Vomiting.
`C. M. Bond
`
`Current Experience with Tacalcitol Ointment in the Tieatment of
`Psoriasis. H. Gollnick and T. Menke
`
`Is Chloral Hydrate/Hydroxyzine a Good Option for Paediatric
`Dental Outpatient Sedation'? VerOnica Avd!Os-Arenas,
`Diana Moyao-Garcfa> Alejandro A. Nava-Ocampo,
`Rodo E. Zayas-Carranza and Rodolfo Fragoso-Rios
`
`A Multi-centre, General Practice Compitdson _of Ispaghula Husk
`with Lactulose and Other Laxatives in-the 'J'reatment of Simple
`Constipation. Peter W. Dettmar and] ohn Sykes
`
`Comparative Responses to Three Different TyPes of Interferon-a:
`in _Patients with C~ronic _Hepatiti~ _G. Q_. Montalto, 'M. Soresi,
`A. Carroccio, Gc Anastasi,.R Campagna, F. Vasile, L. DiPrima,
`A. Cartabellotta, L. Giannitrapan.i and M. Fulco
`
`A Double-blind, Placebo-controlled Evaluation of the Effects
`of RW94 on the Body Weight of Both Overweight and Obese
`Healthy Volunteers. A. R. Williams
`
`187
`
`203
`
`213
`
`219
`
`227
`
`235
`
`243
`
`~: ,.~, '
`
`ltJBJECT
`?s:--
`ll}ecrile- dysfunction;' NO;
`lfitroglycerin; Sildenafil; cGMP
`)(;',",; I::
`.
`
`;m~ccal prochlorperazme; Otal
`lf~pchlorperazine; Dizziness; Nausea;
`~'I'(Qmiting
`if!J;:
`
`Q1~riasis; Vitamin D~ _analogues;
`
`~acalcitol
`
`1~-onscious- sedation;-Arnilgesla;
`~-€linical investigation
`
`~~~paghuia hu_sk;-Lactulose; Laxatives;
`~~onstipation
`-~E:
`"&;>
`~Chronic hep4titis C; Efficacy;
`f~uman_ leUk~cyte interferon-a;_
`~~~ecowbinant_itvterfe-ron,...~;
`~ymphqblastoid interferon-<X
`~W94; Body weight; Obesity
`
`ATI 1029-0001
`
`ATI v. ICOS
`IPR2018-01183
`
`

`

`General information
`
`Cnrrent Medical Research and Opinion is an international journal devoted to publishing, in the English language,
`the results of original research and clinical investigation of pharmaceutical preparations used in medical treatment,
`and other topics of general medico-scientific interest. Studies carried out anywhere in the world will be
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`
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`
`Notes for Contributors
`Sec inside back over.
`
`Copyright
`© LibraPharm Limited. All rights reserved. None of the contents of this publication may be reproduced in whole
`or in part, translated, stored in a retrieval system, or transmitted or distributed in any form or by any means
`(electronic, mechanical, photocopy, recording or otherwise) without the prior written permission of the
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`
`Editorial Advisers
`Prof. G. E. Ehrlich (Chairman) (Philadelphia, USA); Prof. A. Atkinson (Salisbmy, UK); Prof. N. Bellamy
`(Hamilton, Ontario, Canada); Prof. G. R. D. Cat to (Aberdeen, UK); Dr W M. Chong (Kuala Lumpur, Malaysia);
`Dr P. Dawes (Wilmslow, UK); Prof. B. M. Hegde (Mangalore, India); Prof. R. Marks (Cardiff, UK); Prof. E.
`Szabadi (Nottingham, UK); Prof. W Watson Buchanan (Hamilton, Ontario, Canada); Dr D. Whynes
`(Nottingham, UK); Dr K. C. Wong (Kuala Lumpur, Malaysia).
`
`Managing Editor: P. L. Clarke, MA, PhD
`
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`
`Listed in Current Contents/Clinical Practice and indexed in EMBASE/Exce1pta Medica
`
`ATI 1029-0002
`
`

`

`Current Medical Ri!sem-d! and Opi!lioll, J!o!. 14, No.1, 1998, 187-202 \!(
`© 1998 UbmPI111rm Limited
`-~
`
`Opportunities for the Treatment of Erectile
`Dysfunction by Modulation of the NO Axis -
`Alternatives to Sildenafil Citrate
`
`Christian de Mey
`
`>(cid:173)
`
`E c = -::li -... u
`
`ifi
`u
`Applied Clinical Pharmacologj; Services, Philippsring II, D-55252 Mainz-Kastel, Germ~
`::
`!::::>
`:5
`
`Key words: Erectile dysfunction- NO- Nhrog/ycerin- Sildenafil- cCMP
`
`%
`
`Summary
`
`Erectile function in man depends upon a complex interaction of psychogenic, neurologic,
`hormonal and vascular factors, and therefore the management of erectile dy-"function
`(RD) reflects this complexity of control. Therapeutic options include p.1ychological and
`non-pharmacological approaches as well as drug treatments. The effectiveness of the
`type-5 cGMP phosphodiesterase inhibitor sildena.fil citrate (Viagra®) confirms the pivotal
`role of the NO-cGMP axis in promoting and maintaining erection. Although t<videly
`acclaimed, sildenafil leaves many questions unanswered, especially regarding its
`susceptibility to pharmacokinetic drug interactions, and its safety in patients with
`ischaemic heart disease and those taking nitrates. Tn view of the epidemiological/ink
`between erectile dysfunction and cardiovascular disease in the elderly, this limitation
`m(qht have much broader implications. The presently avaUable scientzfic documentation,
`although less extensive, indicates that NO donors, such as topically applied nitroglycerin
`(GTN; for example, 1-2 puf{1 ~fan ordinary GTN spray applied to the shaft of the
`penis), might be a reasonable alternative. Further larger-scale research on the efficacy
`and tolerability of topical GTN is needed to establish its full therapeutic potential in
`the treatment of erectile dysfunction.
`
`Introduction
`
`Penile erection is the major functional
`expression of sexua1 arousal in man and
`therefore plays a key role in hun1an sexual
`behaviour. Historically, the ten11 'impotence'
`has been used for a wide range of male
`sexual dysfunctions, including low sexual
`desire, retarded ejaculation, and difficulties
`in achieving and sustaining erections 1
`•
`Owing to pejorative connotations and lack
`of specificity it has now mostly been replaced
`by 'erectile dysfunction' or 'erectile disorder'
`(ED) to signify a persistent or recurrent
`inability to attain and/or n1aintain an
`adequate erection to pern1it satisfactory
`
`sexual intercourse (highlighting penile
`erection as a part of the multifaceted process
`of 1nale sexual function) 1 • In 1992, the NIH
`Consensus Statement on Impotence
`estimated 10-20 million U.S. males to be
`affected, with a 5% prevalence at the age of
`40 increasing to 15-25% at the age of 65
`and older2
`; later surveys indicate an overall
`prevalence of 52 (Yo of In en aged 40-70 years
`in the Massachusetts Male Aging Study'.
`Undoubtedly, ED
`is not a mere
`inconvenience, but the source of important
`distress and social isolation 4 as it may be
`perceived by the ego-threatened 1nale as a
`vital 'insult to his manhood's often
`experienced with both shame and guilt6
`
`•
`
`Address for correspondence: PD Dr. med. Ch1istian de Mey, Applied Clinkal Pham1acology Services, Philipps1ing I J,
`D-55252 Mainz-Kastrl, Germany. Tel: +49 6134180-467; Fax: +49 6134 180-468; email: CileMcy@T-online.de
`Accepted: 17th September 1998
`
`ATI 1029-0003
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`
`n·eatment of Erectile Dysfunction by Modulation of the NO Ax6·
`Christian de Mey
`
`Until recently, the lack of simple definitions,
`appropriate wording and convenient
`therapeutic options may have discouraged
`both health-care providers and patients to
`consider ED as a legitimate medical issue
`rather than as an embarrassing psycho-social
`oddity: only a few patients sought medical
`help, which then often consisted of lengthy
`psychological counselling, complex medical
`devices, painful local intracavernous
`injections or surgery, etc.
`albeit not
`The overwhelming
`unequivocal - public acclaim of the
`introduction of sildenafil citrate (Viagra®),
`the first peroral treatment of ED with an
`adequately proven efficacy claim, redefines
`ED as a lifestyle rather than as a
`(conventional) medical issue: very many
`males appear to be unsatisfied with their
`sexual (erectile) performance - although
`they would probably not consider
`themselves 'impotent' - and are eager to
`seek pharmacological help for it, provided
`it can be achieved conveniently.
`However, sildenafil citrate has important
`drawbacks. Safety concerns exclude an
`important fraction of the affected population
`-
`those with cardiovascular diseases and
`those taking nitrates, in particular. Against
`this background of well-documented
`experience with sildenafil citrate, which
`confirms the NO-cGMP hypothesis, it is
`appropriate to evaluate further options for
`the managen1ent of erectile dysfunction.
`
`Physiology
`
`Anatomically, the erectile system of the
`human male penis consists of the corpus
`cavernosum (two chambers adjacent to the
`urethra which runs on the underside of the
`corpora) and the corpus spongiosum
`(composed of large venous sinuses which
`contain little blood when the penis is flaccid,
`but which become very dilated when
`
`engorged with blood)'.
`Penile erection is a vascular event initiated
`by neuronal action and maintained by a
`critical interplay between vascular and
`neurological processes. Psychogenis
`stin1ulation (perception, desire, etc) and/or
`tactile (reflexogenic) st:iJ11ulation initiate the
`process. Centrally mediated erection ll11pulses
`reach the penis via the thoracolumbar
`syn1pathetic outflow and hypogastric plexus.
`The afferent fibres in the pudendal nerve
`carry the tactile iinpulses to the erection
`centre in the sacral cord, which returns
`efferent signals through parasympathetic
`nerve fibres. Full erection requires input from
`both central and reflex pathways.
`In the flaccid penis, the blood pressure in
`the cavernosal sinuses is near to venous
`pressure and the smooth n1uscles of the
`penile arteries and the trabeculae of the
`corpus cavernosu1n are contracted in order
`to maximise the impedance against arterial
`inflow; this tone is kept by the excitatory
`adrenergic
`innervation
`although
`spontaneous n1yogenic activity 1nay play an
`ancillary roles. Relaxation of the corpus
`cavernosum smooth muscle is the pivotal
`physiological event responsible for erection.
`Increased inflow fills the cavernous lacunar
`spaces increasing the pressure within the
`spaces so that the penis becomes erect9
`
`•
`
`Pharmacology
`
`Although confounded by methodological
`constraints and species heterogeneity,
`experiments 'in vitro and in vivo conducted
`in man, anin1als and cultured cells, allow
`definition of several working hypotheses to
`identify suitable approaches to therapeutic
`intervention in ED.
`Tumescence depends on the changing
`balance between neuronal and humoral
`messengers
`that
`affect
`1nyosin
`dephosphorylation and sn1ooth muscle cell
`
`ATI 1029-0004
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`

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`189
`
`tone: filling of the sinusoidal spaces with blood
`due to smooth muscle cell relaxation results
`from an increased efferent parasympathetic
`tone (and probably simultaneous withdrawal
`·>f the efferent adrenergic drive), with nitric
`oxide (NO) as the main proerectile
`neurotransmitter and noradrenaline as the
`major anti erectile agent 10- 12 •
`
`Central Nervous Control
`
`Centrally, apomorphine, a D,- and D,(cid:173)
`dopaminergic agonist, facilitates erection
`through stimulation of the D,-receptors in
`the hypothalamic medial preoptic area,
`while higher doses inhibit erection by
`• Oxytocinergic
`stimulation of D 2 -receptors 13
`14
`·
`nerves appear to enhance erection both
`directly and by modulating limbic
`• Serotonin modulates
`doparninergic activity 15
`spinal reflex activity in the spinal cord, with
`5-HT 2 -receptor stimulation inhibiting
`erection and facilitating ejaculation, while
`5-HT 1c-agonists (such as trazodone 16
`)
`augment erectile responses by amplifying
`the efferent parasympathetic drive. NO
`synthase (nNOS or Type I) has been co(cid:173)
`localised with various central nervous
`neurotransmitters in selective parts of the
`brain and spinal cord, including the
`paraventricular nucleus;
`although
`predominantly a peripheral modulator (see
`below), central nervous NO might act as a
`long-term synaptic modulator following its
`release from presynaptic neurones 17
`•
`
`Peripheral Nervous Modulation
`
`Penile erection relies on stimulation of the
`pelvic (nervi errigentes) and cavernous
`nerves. The latter originate from the pelvic
`plexus, which
`is modulated by
`parasympathetic (pelvic nerve), sympathetic
`(hypogastric nerve) and somatic (pudendal
`nerve) axons.
`
`Treatment of Erectile Dysfunction by Modulation of the NO iLYis
`Christian de Mey
`
`Although cholinergic nerves have been
`identified in the penile effector system,
`muscarinergic blockade does not appear to
`alter nerve-evoked penile smooth muscle
`relaxation 1
`R; acetylcholine has dual, mainly
`indirect, effects by stimulating endothelial
`NO release and by releasing noradrenaline
`via stimulation of prejunctional muscarinic
`receptors.
`Increased cavernosal smooth muscle tone
`and penile flaccidity is controlled by
`postjunctional a 1-adrenoceptors and
`increased a-adrenoceptor sensitivity has
`been suggested to play a role in ED".
`Physiologically the main peripheral
`neurotransmission pathway to induce penile
`erection seems to be non -cholinergic, non(cid:173)
`adrenergic and mediated by the EDRF(cid:173)
`analogue NO'". NO
`is synthesised
`endogenously during the conversion of L(cid:173)
`arginine to L-citrulline as catalysed by NO
`synthase (NOS). NO activates guanylate
`cyclase which then catalyses the formation
`of guanosine 3 ', 5' -cyclic monophosphate
`(cGMP) from guanosine s·, -triphosphate. As
`a secondary messenger, cGMP inhibits
`myosin phosphorylation and reduces
`intracellular calcium concentrations via
`activation of cGMP kinase". NOS has been
`localised in the penile effector system in
`neurones (nNOS, Type I), endothelium
`(eNOS, Type III) and smooth muscle
`(inducible iNOS, Type II)". Experimentally,
`penile NOS was found to be reduced in
`several conditions associated with ED (such
`as senescence, castration, diabetes,
`adrenalectomy, hypophysectomy and
`androgen receptor blockade), while
`substitution of the respective hormones
`prevented ED and loss of NOS". NO(cid:173)
`mediated relaxation is impaired by excess
`prolactin 23
`. Neurogenic penile smooth
`muscle cell relaxation can be blocked by
`inhibitors of NO biosynthesis and by
`substances that reduce cGMP or bind directly
`to NO, while NO-donors, such as GTN and
`nitroprusside, have potent relaxant effects
`
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`TI-eatment of Erectile Dy:.function by Modulation of the NO Axis
`Christian de Mcy
`
`1
`
`• Low oxygen
`on cavernosal smooth muscle 2
`'
`tension (as in the flaccid penis) may be an
`important inhibitor of NO-mediated
`relaxation, while the early blood flow
`increase by penile nerve stimulation may
`rapidly increase NO release to 1naintain
`erection25 • Recent observations suggest that
`both the non -adrenergic non -cholinergic
`neurogenic and the endothelial-dependent
`relaxation of the small penile (helicine) arteries
`that regulate the blood flow between the
`arterial systemic circulation and the cavernous
`sinusoids rely on NO mediation, although not
`exclusively26
`• This latter point is important as
`agents p1imarily acting via adenosine 3',5'(cid:173)
`cyclic monophosphate (cAMP), such as
`papaverine and PGE 1, also prove to be quite
`
`potent relaxants- even nwre potent than NO
`donors such as linsidomine27
`
`•
`
`Pathophysiology
`
`ED occurs if penile arterial inflow is
`insufficient or if the corporal vena-occlusive
`system fails. The fanner requires relaxation
`of the trabecular smooth muscle and
`dilatation of the helicine arteries, while the
`latter requires the con1pression of the
`outflow venules against the tunica albuginea
`by corporal engorgement. Because adequate
`arterial supply is critical for erection, any
`disorder that impairs blood flow and its
`dynamic regulation may be implicated in the
`aetiology of erectile failure. Most vascular
`disorders resulting in ED appear to affect the
`arterial rather than the vena-occlusive
`system, although both appear to be affected
`by atherosclerotic aorto-fe1noral discase 28
`•
`Damage to the autonomic nen;ous control of the
`vascular effector system resulting from
`somatic pathway lesions llnpair reflexogenic
`erections and may impede tactile sensations
`needed to maintain and amplify primarily
`psychogenically mediated erections. Such
`lesions may be the result of trauma but also
`
`of peripheral neuropathies. Androgens appear
`to play an important role in regulating sexual
`interest but also play a role in the vascular
`1nodulation of the erectile response as a
`consequence of their impact on NO.
`Psychological processes, such as depression,
`anxiety and relationship problems, can impair
`erectile performance by reducing erotic focus
`or reducing awareness of sensory experience.
`From a pharmacological point of view,
`il1adequacy of NO-mediated s1nooth muscle
`cell relaxation has been implicated as one
`of the main pathogenic pathways 12·24 and
`one of the most promising opportunities for
`therapeutic intervention.
`
`Diagnosis
`
`There is a wide variety of diagnostic
`approaches and techniques, n1any of which
`require expensive equipment and special
`training. There is in1proved understanding
`of their benefits and lllnitations29 but there
`is no evidence that an extensive diagnostic
`work up (including nocturnal penile
`tumescence,
`somatosensory-evoked
`potentials, bulbocavernous reflex latency,
`corpus cavernosum EMG, evaluation of
`penile haemodynamics by plethysmography,
`selective pudendal pharmacoangiography,
`duplex Doppler sonography, dynamic
`infusion
`cavernosometry
`and
`cavernosography, intracavernous injection
`of vasoactive agents and PGE 1, etc) improves
`the subsequent therapeutic outcon1e. The
`fear of diagJ?-ostic procedures, their
`inconvenience and discomfort may be an
`ilnportant reason why patients are reluctant
`to seek medical help. There is therefore
`reasonable justification for a therapeutic trial
`with drugs such as sildenafil citrate or
`nitrates (after exclusion of their eventual
`concon1itant usage). Therapeutic failure
`should then indicate a need for a more
`detailed investigation.
`
`ATI 1029-0006
`
`

`

`Therapeutic Options
`
`Psychological Treatment
`
`Psychogenic components are likely to play
`a role in every form of ED, affecting both
`partners. Multiple factors may contribute to
`a loss of 'sexual chemistry' between
`partners. Psychological treatments have
`typically emphasised
`
`and
`
`reduction
`(i) Anxiety
`desensitisation.
`(ii) Cognitive manipulation and fantasy
`training.
`(ill) Increased sexual stimulation.
`(iv) Assertiveness
`and
`couple's
`communication training, eventually
`endorsed by systematic training to
`prevent relapse"0
`
`•
`
`Both the acceptance and the outcome of
`these approaches remain disappointing.
`Increasing
`'medicalisation',
`i.e.
`conceptualisation of ED and its treatment
`as a merely biomedical problem, serves as a
`welcome and ready excuse not to consider
`emotional and interpersonal conflicts as an
`inherent part of the issue. There is need to
`develop an appropriate therapeutic climate
`which accounts for these psychogenic
`components in any kind of treatn1ent of ED.
`The ultimate success (and benefit) of newer
`pharm~cotherapeutic options (such as
`si1denafil citrate and nitrates) 1nay well
`depend on how this challenge is met.
`
`Non-pharmacological
`Treatment
`
`In spite of their increasing sophistication,
`surgical treatments (e.g. semi-rigid surgical
`prosthesis, inflatable prosthesis, venous
`ligation, etc) and mechanical devices
`(constriction rings and external vacuu1n
`pumps) are not generally well accepted
`
`Treatment of Em:lilc Dy:ojimction by Modulatiou of the NO Axis
`Christian de Mcy
`
`r
`
`191
`
`because of their irreversible (for surgery) or
`highly intrusive (for devices) nature, and
`their 'artificiality'; they are best reserved for
`patients unresponsive to pharmacotherapy.
`
`Main Pharmacotherapeutic
`Strategies
`
`the various
`reviews on
`Excellent
`pharmacotherapeutic options which
`preceded the introduction of sildenafil citrate
`have been published30
`37
`-
`•
`
`Hormonal Agents
`
`Hypogonadism is relatively uncommon but
`is a specific and distinct pathogenic entity
`which is preferably treated by androgen
`supplements
`either
`administered
`intramuscularly (testosterone enanthate or
`propionate) or transdermally". The efficacy
`of androgen supplemen.ts in eugonodal men
`is controversial.
`Hyperprolactinaemia is usually associated
`with ED, possibly as a consequence of
`depressed NO neurotransmission and
`reduced LH and testosterone production. It
`is often iatrogenic (owing to the use of
`dopaminergic antagonists
`such as
`domperidone, oestrogens, methyldopa,
`cimetidine, phenothiazines, reserpine,
`opiates, etc). In those (relatively rare) cases
`of hyperprolactinaen1ia that relate to
`pituitary tumours, peripherally acting
`dopaminergic
`agonists
`such
`as
`bromocriptineJ9 and apomorphine 40 may be
`useful.
`
`Central Nervous Acting Drugs
`
`Dopaminergic agonists such as subcutaneous
`or sublingual apomorphine (stimulating
`hypothalamic medial preoptic area D,(cid:173)
`receptors)41,
`central nervous
`a
`
`-
`
`2
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`Treatment of Erectile Dy~function by Modulation of the NO Axis
`Christian de Mcy
`
`adrenoceptor antagonists such as yohimbine
`(suggested to facilitate stimulated erections
`by increasing central nervous sympathetic
`drive) 42
`, serotonin~reuptake inhibitors such
`as trazodone (which amplifies the efferent
`parasympathetic drive and also has
`peripheral vasodilatory a-blocking
`properties) 16
`, opiate antagonists such as
`3
`A
`naltrexone (amplifying the release of
`endogenous gonodatrophin- releasing
`hormone and reducing central nervous
`sexual inhibition) 44.4 5
`, have all been used
`with varying degrees of success.
`
`Intracavernous Vasoactive Injection
`Therapy
`
`Before the introduction of sildenafil,
`intracavernous injections with single or
`multiple agents were often considered as the
`treatment of first choice 31
`AM7, e.g. with the
`cAMP phosphodiesterase
`inhibitor
`papaverine 48
`the
`a-adrenoceptor
`,
`antagonists phentolamine and moxisylyte 49
`,
`PGE, ( alprostadil 50
`), calcitonin gene(cid:173)
`51
`·
`related peptide (which has smooth muscle
`relaxing, potassium channel activating and
`cAMP stimulating properties"·"), the NO
`donator 1insidomine54
`, vasoactive intestinal
`polypeptide (VIP)" and low doses of
`atropine (which diminishes the cholinergic
`inhibition of the autonomic excitation of
`non -cholinergic non -adrenergic neurogenic
`corporeal sn1ooth muscle relaxation 56
`).
`However, major adverse effects, such as
`priapism, corporeal pain and the formation
`of nodules or plaques in the corpora
`cavernosa, represent an important limitation
`especially in less severe forms of ED.
`
`Transurethral Application
`
`Under certain conditions, the transurethral
`application (MUSE) of PGE, (alprostadil)
`proved successful in treating ED when used
`
`58 or in combination with the
`either alone 57
`•
`a-adrenoceptor antagonist prazosin60
`• Pilot
`observations with the transurethral
`application of PGE, (dinoprostone) were
`considered encouraging60
`61
`
`•
`
`•
`
`Systemic a-Blockers
`
`Systemic a-adrenoceptor blocking agents
`such as phentolamine (Vasomax®) 62 have
`been shown to improve ED, but their use is
`possibly limited by systemic cardiovascular
`adverse effects, orthostatic hypotension in
`particular. a-Blockers, on the other hand,
`have been implicated in iatrogenic
`ejaculation disturbances (dry ejaculation
`and retrograde ejaculation) possibly as a
`consequence of
`inhibition of
`the
`sympathetic thoracolumbar stimulation of
`the vas deferens and epididymis, and
`prevention of adequate closure of the
`internal urethral sphincter63-
`65
`•
`
`Systemic ?DE-Inhibitors: Sildenafil
`Citrate
`
`Sildenafil citrate (Viagra®) is the first oral
`cGMP phosphodiesterase type 5 (PDE,)
`inhibitor developed for the treatment of
`erectile dysfunction. It was approved in the
`U.S. in less than six months after regulatory
`submission and has been the subject of
`impressive lay press coverage and media
`campaigns66
`• In contrast, little data have yet
`been published67
`- 73 ; data on several relevant
`issues (interaction with nitrates, interaction
`with CYP3A4 'enzyme systems, etc - see
`below) although available, have not been
`subject to scientific review and debate.
`Fortunately the FDA bas granted access to
`its detailed clinical review of the studies on
`the internet74 • A summary of the main
`highlights is presented here below:
`General Pharmacology Sildenafil citrate
`has no direct smooth muscle relaxant
`
`ATI 1029-0008
`
`

`

`Treatmml of Rn:cti!e Dysfunction by Modulation of the NO Axis
`Christian de Mey
`
`r
`
`193
`
`properties, but amplifies the pro-erectile
`effect of NO by reducing the degradation of
`cG.MP in the corpus caven1osun1 by blocking
`PDE,. Sildcnafil at recommended doses has
`no effect in the absence of sexual stimulation
`and depends on the functional integrity of
`the NO-generating pathways. Studies in vitro
`have shown that sildenafil is relatively
`selective for PDE, and PDE, (10-fold lower
`affinity) with a> 80-fold lower affinity for
`PDE, and a > 1000-fold lower affinity for
`PDE,, PDE, and PDE,,. The N-desmethyl
`metabolite (UK I 03,220) has PDE-inhibiling
`properties with a sinillar selectivity profi1c
`but 50% lower in vitro potency. The
`inhibition of PDE(,, which is involved in
`phototransduction in the retina, may cause
`a mild, transient, dose-related in1pairment
`of colour discrimination (blue/green),
`resulting in visu31 disturbances, described as
`colour tinge or light sensitivity. This is
`observed in about 3<X) of patients on
`sildenafil in flexible titration studies of 4 to
`26 weeks' duration.
`Phannacoldnetics and Metabolism Maximu1n
`plasma concentrations (Cm~J occur after a
`n1edian t.,~x of about 60 minutes (range: 30-
`120 min). Sildenafil is readily absorbed after
`oral administration but is subject to
`extensive pre-syste1nic biotransformation
`(first pass) resulting in an absolute
`bioavailability of about 40%. The rate of
`absorption is delayed when sildenafil is
`taken with a fatty rneal: mean t,,.,x is delayed
`by 60 niinutes and mean C"'"x is reduced by
`about 29%. Its pharmacokinetics are
`proportional with dose over
`the
`recommended dose range. Although highly
`protein bound (about 96%), sildenafil's
`mean volume of distribution ( V:~s) of about
`105 litrcs indicates extensive tissue
`distribution, but only 0.001 <X> of the dose
`administered appears in the se1nen.
`Sildenafil is cleared predominantly non(cid:173)
`renally by the CYP3A4 (major route) and
`CYP2C9
`(minor route) microsomal
`isozyn1es. The main circulating metabolite,
`
`N-desmethyl sildena!il, achieves about 60%
`lower concentrations and contributes about
`20% to the overall pharmacological action
`in view of its 50°/o lower potency for PDE5
`•
`Both sildenafil and the metabolite have
`apparent terminal half lives of about 4 h.
`Elderly healthy volunteers (65 years or over)
`had a reduced clearance of sildenafil, with
`free (i.e. active) plasma concentrations
`approximately 40% greater than those seen
`in healthy younger volunteers ( 18-45
`years). Total exposure in terms of both the
`AUC and Cm" almost doubled with creatinine
`clearance :::; 30 m1/min cmnpared with age(cid:173)
`matched volunteers with normal renal
`function. In hepatic cirrhosis (Child-Pugh A
`and B) the clearance was reduced, resulting
`in increases in AUC and Cm~x of 84% and
`47°/o, respectively.
`Pharmacokinetic Interactions Single doses
`of antacid (magnesium hydroxide/
`aluminium hydroxide) did not affect the
`bioavailability of sildenafil. A single dose of
`800 mg cimetidine, 0 non-specific CYP
`inhibitor, caused a 56% increase in plasma
`sildenafil concentrations when sildenafil (50
`mg) was administered concomitantly.
`Repeated doses of 500 mg b.i.d.
`erythromycin, a specific CYP3A4 inhibitor,
`for 5 days, led to a 182% increase in the
`overall systemic exposure to sildenafil
`(AUC). Stronger CYP3A4 inhibitors, such as
`ketoconazole, itraconazole or mibefradil
`ought to be expected to have still greater
`exposure-increasing effects. No interaction
`studies were conducted with grapefruit
`juice, a notorious inhibitor of CYP3A4 and
`no warnings or recommendations in this
`regard are contained in the patient
`information.
`The
`concomitant
`administration of CYP3A4 inducers, such as
`rifampicin, is likely to decrease plasma levels
`of sildenafil. The AUC of N-desmethyl
`sildenafil was increased by 62% by loop and
`potassium-sparing diuretics, and by 102%
`hy non-specific P-blockers. Sildenafil itself
`is a weak inhibitor of the cytochrome P450
`
`ATI 1029-0009
`
`

`

`r
`
`194
`
`Trea/mml of .b'rectile Dysjimclion by Modulation of the NO Axis
`Christian de Mey
`
`isoforms IA2, 2C9, 2Cl9, 2D6, 2El and 3A4
`(IC, > !50 mM). But it is unlikely that
`sildenafil will alter the clearance of
`substrates of these isoenzymes. There was
`no significant interaction with the CYP2C9
`substrates tolbutamide or warfarin.
`Cardiovascular Actions and Interactions
`Single oral doses of sildenafil up to 100 mg
`produced no clinically relevant changes in
`the ECGs of normal 1nale volunteers.
`Sildenafil reduces systolic and diastolic blood
`pressure by about 10 mmHg in healthy
`volunteers, silnilar to the effect in patients
`with ischaenric heart disease given 40 1ng
`sildenafilll1travenously.
`Sildenafil (50 mg) did not potentiate the
`hypotensive effect of alcohol in healthy
`volunteers with mean maximum blood
`alcohol levels of 0.08%.ln hypertensives, the
`blood-pressure-reducing effect of sildenafil
`(I 00 mg) is additive to that of a baseline
`therapy with amlodipine. The combination
`with nitrates in· contrast is synergistic:
`sildenafil amplifies the otherwise moderate
`blood-pressure-reducing effects of sublingual
`nitroglyce1in and oral isosorbide mononitrate
`both in tern1s of extent and duration.
`Unfortunately no studies have been
`conducted to evaluate the effects of
`nitroglycerin (or nitroprusside) when patients
`having taken sildenafil suffer an angina attack
`or 1nyocanlial infarct during intercourse. In
`vitro studies with human platelets indicate
`that sildenafil potentiates the antiaggregatory
`effect of sodium nitroprusside.
`Indication-related Phannacodynamics
`In
`double-blind, placebo-controlled crossover
`studies sildenafil iinproved erections
`(assessed by penile plethysmography) upon
`sexual sthnulation in patients with either
`organic or psychogenic erec1ile dysfunction.
`This effect generally increased with dose and
`plasma concentration. Effects peaked at 1
`h, but usually lasted up to 4 h (although
`diminished vs. 2h).
`Clinical Studies - Efficacy Sildenafil was
`evaluated primarily at doses of 25, 50 and
`
`100 mg in 21 randomised, double-blind,
`placebo-controlled trials of up to 6 months
`in duration, using a variety of study designs
`(fixed dose, titration, parallel, crossover). In
`these studies n1ore than 3000 patients aged
`19-87 years, with ED of various aetiologies
`(organic, psychogenic, mixed) and a n1ean
`duration of ED of 5 years, were investigated.
`Sildenafil proved statistically superior to
`placebo in all21 studies. The main criterion
`was the outcon1e