BigKNY3 <<I recommend reading the International Journal of Impotence Research article "Sildenafil: an orally active type 5 cyclic GMP-specific phosphodiesterase inhibitor for the treament of penile erectile dysfunction: (1996, 47-52) for a review of its pharmacokinetics and pharmacodynamic properties.>>.
Here is the article; it does not answer all of Gene's questions. More importantly, it does not answer: what are the co-reactions with people suffering from Diabetes, Empysema, Coronary artery disease with coronary stents , hypertension, ulcers, who are taking theophylline, Lasix, potassum chloride, erythromycins, H2 anatagonists, calcium channel blockers, blockers, digitalis; these are the combinations of diseases and drugs COMMONLY present in people with ED who will be popping Viagra. Do you think that they studied
all of the above since Sept? No.
Here is the article you mentioned:
International Journal of Impotence Research (1996) 8, 47-52
C) 1996 Stockton Press.
Sildenafil: an orally active type 5 cyclic GMP-specific
phosphodiesterase inhibitor for the treatment of penile
erectile dysfunction
Mitradev Boolell, Michael f Allen, Stephen A Ballard, Sam Gepi-Attee , Gary J Muirhead,Alasdair M Naylor, Ian H Osterlohl and Clive Ginge
Pfizer Central Research, Sandwich, Kent CT13 9NJ, UK; 2 Urology Department, Southmead Hospital, Bristol, UK
ú
ú Sildenafil (ViagraTm, UK-92,480) is a novel oral agent under development for the treatment of penile erectile dysfunction. Erection is dependent on nitric oxide and its second messenger, cyclic guanosine monophosphate (cGMP). However, the relative importance of phosphodiesterase (PDE) isozymes is not clear. We have identified both CGMP- and cyclic adenosine
monophosphate-specific-- phrsphodiesterases (PDES) in human corpora cavernosa in vitro. The main PDE activity in this tissue was due to PDE5, with PDE2 and 3 also identified. Sildenafil is a selective inhibitor of PDE5 with a mean IC50 of 0.0039 gM. In human volunteers, we have shown sildenafil to have suitable pharmacokinetic and pharmacodynamic properties (rapid absorption, relatively short half-life, no significant effect on heart rate and blood pressure) for an oral agent to be taken, as required, prior to sexual activity. Moreover, in a clinical study of 12 patients with erectile dysfunction without an established organic cause, we have shown sildenafil to enhance the erectile response (duration and rigidity of erection) to visual sexual stimulation, thus highlighting the important role of PDE5 in human penile erection. Sildenafil
holds promise as a new effective oral treatment for penile erectile dysfunction.
Keywords: penile erectile dysfunction; sildenafil; oral treatment; phosphodiesterase type 5
Correspondence Dr M Boolell
Received 25 April; accepted 15 May 1996
Introduction
Penile erectile dysfunction is a common medical disorder. It has an estinaated prevalence of 2% in men aged 40 years, which increases to over 50% in men over the age of 70 years.' Penile erectile dysfunction has been defined as 'the inability to achieve and/or sustain an erection for satisfactory sexual performance .2 Generally, it is accepted that this disorder adversely affects quality of life' Patients often report increasing anxiety, loss of self-esteem, lack of self-confidence, tension and difficulty in the relationship with their partner.2
Penile erection is a haemodynamic event which is dependent upon relaxation of the smooth muscle cells of the corpus cavernosum and of its associated arterioles, with consequential increase in arterial flow into the trabecular spaces of the corpora cavernosa. 3,4 The increased blood flow causes the lacunar spaces or sinusoids to become distended which results in compression of the small venules between the sinusoids and the tunica albuginea. The relative indistensibility of the tunica albuginea results in a veno-occlusive effect such that the penile pressure increases to approach mean arterial pressure and penile rigidity develops.
There is now ample evidence from both animal experiments and in vitro studies with human tissue to suggest that relaxation of the smooth muscle of the corpora cavernosa is mediated by nitric oxide via cyclic guanosine monophosphate (cGNT). 5-8 During sexual stimulation, nitric oxide is released from nerve endings and endothelial cells. Nitric oxide then stimulates the cytosolic enzyme guanylate cyclase to produce CGNT which results in a decrease in intracellular calcium and allows relaxation of smooth muscle cells. Cyclic nucleotide phosphodiesterase (PDE) isozymes, which are distributed in various tissues, specifically hydrolyse cyclic nucleotides, such as cGNM.9 Therefore, a pharmacological agent which inhibits the cGNT-specific phosphodiesterase isozyme, should enhance the action of nitric oxide/cGNT on penile erectile activity and have the potential to enhance penile erections during sexual stimulation.
To date, pharmacological therapy for penile erectile dysfunction has been largely based on the use of intracavernosal injections of vasoactive agents. Though efficacious, this form of therapy is associated with a high dropout rate for a variety of reasons.10 Recent insights into the mechanism of penile erection have, however, led to the development of sildenafil (Viagra ; 1-[4-ethoxy-3-(6,7dihydro-l-methyl-7-OXO-3-propyl-lH-pyrazolo f4,3cl] pyrimidin-5-yl) phenylsulphonyl]-4-methyl-piperazine, Pfizer Central Research) a novel, orally_efficacious drug for the treatment of penile
erectile dysfunction.
This review focuses on in vitro studies relating to the mode of action of sildenafil, pharmacokinetic studies in human volunteers, and an early clinical study in patients with erectile dysfunction.
Methods
Isolation of soluble phosphodiesterase activities from human tissues
Frozen human corpus cavernosal tissue (obtained from IIAM, Exton, Pennsylvania; donor age range 48-64 years) was thawed on ice, coarsely chopped, and then homogenised in approximately 4 volumes of ice cold HEPES buffer (20 n-lM, containing 0.25M sucrose, ImM EDTA, imM phenylmethyl sulphonylfluoride [PMSF], pH 7.2) using an Ultra Turrax homogeniser at high setting. The homogenate was filtered through two layers of surgical gauze to remove any undispersed tissue and fibrous material. The filtrate was centrifuged at 100 000 g for 60 min at 4'C. The supernatant was filtered through a 0.2 pM filter and either used directly (see below) or stored in liquid nitrogen prior to analysis. A similar procedure was used for preparation of soluble fractions from samples of human cardiac ventricle and human skeletal muscle (also obtained from IIAM).
Phosphodiesterase activities in the soluble fractions prepared from human tissues were separated using a Pharmacia FPLC system (Pharmacia Ltd, Milton Keynes, UK) with a Mono Q anion exchange column (imL bed volume, Pharmacia Ltd). The Mono Q column was pre-equilibrated with HEPES buffer (2OmM, containing lmM EDTA, 0.5niM PMSF, pH 7.2), before loading tissue soluble fractions (2-5mL). The column was then washed with 5 ml of the buffer and the phosphodiesterase isozymes were eluted using a cntinuous gradient of 0-5OOmM NaCl in the same buffer (total volume 55 mL) at a flow rate of 1 ML/ min, and 2mL fractions were collected. Fractions comprising the main peaks of phosphodiesterase activity were pooled and stored at -80'C for use in characterisation and inhibition studies.
Determination of phosphodiesterase activity and isozyme characterisation
The cyclic nucleotide phosphodiesterase activity in FPLC fractions was determined using a modification of the two step radioisotopic procedure of Thompson and Appleman." The reaction mixture (total volume 100 @LL) contained column fraction (10 to 25 @tL), [3 HI-CGNT or [3 H]-CAMP (500 nM, 2 @LCi/mL), bovine serum albumin (0.5 mg/mL) and MgC'2 (5 mM) in Tris HC1 buffer (15 mM, pH 7.4). Reaction -was initiated by addition of the radiolabelled substrate, and the samples incubated in a water bath at 300C for 30min. The reaction was stopped by immersing the sample tubes in boiling water for 2 min. The 5'-mononucletides formed by hydrolysis of cyclic nucleotides were determined after their further conversion to nucleosides using snake venom (Ophiophagus hannah) nucleotidase activit as described by Thompson and Appleman. 17
For inhibitor studies, test compounds were added to incubation mixtures in dimethyl sulphoxide (DMSO, final concentration 2% v/v). The hydrolysis of cyclic nucleotides did not exceed 15% and under these conditions, product formation increased linearly with time and amount of enzyme. lC50 values were determined from sigmoidal curves, fitted to plots of enzyme activity vs log compound 12 concentration using a curve fitting programme.
Phosphodiesterase activities in FPLC fractions were characterised based on their substrate specfficities, effects of calcium cabnodulin, the effect of CGMP on CAMP hydrolytic activity and the inhibitory potency of known selective inhibitors of the PDE isozyrnes (Table 1).13-16 Human cardiac ventricle was used as a source of soluble PDE1 and human skeletal muscle (gluteus maximus) for PDE4.
----------------------------------------------------------------
Table1 Classification of PDE isoenzymes
ISOZYME Substrate Effectof CGMP on Effect of standard
family specificity on cAMP hydrolysis calcium inhibitor
calmodulin
PDE1 cAMP/cGMP N.A. stimulationvinpocetinel6
PDE 2 cAND/cGW stimulation no effect vinpocetinel6
PDE 3 CANT inhibition no effect milrinonel6
PDE 4 CANT no effect no effect rolipraml6
PDE 5 CGNW N.A. noeffect zaprinastl6, E4021"
--------------------------------------------------------------------
Pharmacokinetic studies
The following studies have been conducted to
investigate the single oral dose pharmacokinetics
of sildenafil.
(i) A single-blind, escalating single oral dose
study, in which solution doses ranging from
1.25 to 90mg were administered to two
groups (n = 9 and n = 10) of healthy male
volunteers, with random insertion of placebo.
Each subject received three active doses and
placebo.
(ii) An extension of the first study in which a
group of 10 healthy male volunteers received
single oral solution doses of sildenafil (100,
150 and 200mg) with random insertion of
placebo.
(iii) An open, randomised, two-way cross-over study to
investigate the pharmacokinetics of sildenafil
after oral administration (50mg
capsule) and intravenous administration
(50 mg) to a group of 12 healthy male volun-
teers.
In all studies blood samples were taken pre-dose
and at intervals up to 72 h post-dose for determi-
nation of the plasma concentrations of sildena:ral.
Plasma and urine samples were assayed using a
sensitive and specific HPLC assay following solid
phase extraction.
Clinical study
The efficacy of sildenafil on penile erectile activity
was evaluated in 12 patients who had a history of
penile erectile dysfunction of at least six months
duration. On clinical evaluation there was no
obvious organic cause for penile erectile dys-
function. Patients were excluded from the study if
there was evidence of neurovascular disease on
Clinical evaluation, diabetes, drug or alcohol
abuse, or other established causes for their penile
erectile dysfunction.
The study was a double-blind, placebo-
controlled, randomised, four-way crossover design. .
A period of at least three days was allowed
between consecutive treatment periods to ensure
that there was adequate clearance of sildenafil
from the circulation. On each dosing period,
patients were admitted to a hospital bed with
complete privacy. They received a single dose of
sildenafil (10, 25 or 50mg) or placebo. Each dose
was followed by visual sexual stimulation (VSS)
starting 30min post-dose and lasting for two
hours. VSS was provided by viewing of sexually
explicit material chosen from a selection of videos
and magazines. Drug efficacy on penile erectile
activity was evaluated by measurement of penile
rigidity at the base and tip of the penis by penile
plethysmography (RigiScan, Dacomed Corpora-
ion). The study was approved by the local ethics
committee.
Mean duration of rigidity of greater than 60% at the base and tip of the penis was analysed by analysis of variance (ANOVA).
Results
Phosphodiesterase activities in human corpus cavemosum
Two major peaks demonstrating CGMP hydrolytic activity and one peak demonstrating CAMP hydrolytic activity were resolved by anion exchange chromatographic analysis of soluble fractions from human corpus cavernosilm (Figure 1). Peak 1, which had the greatest PDE activity, was found in soluble fractions prepared from three separate samples of human corpus cavernosum. The PDE activity in the peak was specific for CGNT as substrate and unaffected by calcium calmodulin.
-----------------------------------------
( shows graph, which could not be duplicated )
Figure 1 Separation of PDE isoenzymes from human corpus cavernosum by fast protein liquid chromatography on a Mono-Q column. Panel (a) shows hydrolysis of CGNT (0.5 JIM) in the presence and absence of loorun sildenafil. Panel (b) shows hydrolysis of CAMP (0.5pM) in the presence and absence of loo nm sildenafil. Each point represents the mean of three replicate assays.
-----------------------------------------------------
In addition it was inhibited by zaprinast, a standard PDE5 inhibitor with a mean IC50 ñ SEM of 0.86 ñ 0.11 PM (n = 4), which is similar to values previously reported for PDE5 from rat lung (0.76pM)17 and porcine aorta (0.5lpM).15 These data indicated that peak I comprised predominantly PDE5. Peak 2 and peak 3 were identified as PDE2 and PDE3, respectively.
Effects of sildenafil on human phosphodiesterase
activities
Sildenafil (100 13m) completely inhibited the cGW hydrolytic activity of the PDE5 peak from human corpus cavernosilm, but had no significant effect of the PDE2 or PDE3 peaks (Figure 1). Moreover, sildenafil was found to be a potent inhibitor of PDE5 activity from human corpus cavernosum with a mean IC50 Of 0 . 0039 pM (Table 2). Sildenafil had low activity against PDE2 and PDE3 from corpus cavernosum and PDE4 from skeletal muscle (IC50 values > 7.3 pM; Table 2). It had moderate activity against PDE1 from human cardiac ventricle (IC50, 0.29pM). These data showed that sildenafil was at lest 70-fold selective for PDE5 relative to isozymes from PDE families
1-4.
Pharmacokinetics of sildenafil in human
volunteers
The results from the single-blind escalating single oral dose (studies and [ii] under pharmacokinetic method) demonstrate that sildenafil is rapidly absorbed with maximum observed plasma concentrations occurring within one hour after oral dosing. Plasma concentrations decline in a biexponential manner with a mean terminal half life of 3 to 5 h. Pharmacokinetic simulations predict no significant accumulation of the drug after repeated once-daily dosing.
The pharmacokinetics of sildenafil were approximately dose proportional after administration of solution formulations in the range 1.25mg to 200 mg. The maximum plasma concentration and the area under the plasma concentration-time curve increased linearly with
dose. (Figures 2 and 3). ( cannot be duplicated).
The absolute bioavailability (study[iii]above) revealed that sildenafil has a mean plasma clearance of 41 L/h and a mean steady state volume of
-----------------------------------------------------------
(Figure 3 [ not shown]Mean maximum plasma concentration values
(Cmax) of sildenafil following single oral administration to
healthv male volunteers. Each point represents mean ñ SD from 4'or 10 subjects
-----------------------------------------------------------
distribution of 105 L. The mean absolute bioavailability after oral dosing of a 50mg capsule was 41%.
There were no clinically significant effects on pulse rate, blood pressure and laboratory safety tests (haematology and biochemistry profiles) following administration of single oral doses of up to 200mg to healthy volunteers. The main adverse events reported following doses of 90mg and
-------------------------------------------------------------
(Figure 3 [ not shown]Mean area under the plasma concentration - time curve (AUC) values for sildenafil following single oral admin-
istration to health male volunteers. Each point represents y
mean ñ SD from 9 or 10 subjects
-------------------------------------------------------------
(Table 2 [ not shown ] TCSO values for inhibition of human PDE isozymes by sildenafil. PDE2, 3 and 5 were isolated from corpus cavernosum, PDE1 from cardiac ventricle and PDE4 from skeletal muscle. IC50 values were determined using cGW (0.5 W) as substrate foK PDE1, 2 and 5 and cAW (0.5 pM) as substrate for PDE3 and 4. Data shown are means + S.E.M.
---------------------------------------------------------------
Compound ICSO (PM)
PDE1 PDE2 PDE3 PDE4 PDE5
Sildenafil 0.29 0.03 >30 17 + 3 7.3 + 0.8 0.0039 + 0.009 (n 7) (n 4) (n 4) (n 3) (n 15)
PDE = phosphodiesterases
cGI" = cyclic guanosme monophosphate
cAw = cyclic adenine monophosphate
-------------------------------------------------------------
There were no clinically signifiicant effects on pulse rate, blood pressure and laboratory safety tests ( haematology and biochemistry proiles ) following asministration of single oral doses of up to 200 mg to healthy volunteers.The main adverse effects reported following doses of 90 mg and above were headache and facial flushing. These adverse events were of mild to moderate severity and resolved spontaneously after a few hours. There were no treatment-related discontinuations.
Clinical efficacy
For the 12 patients entering the clinical study, the mean age was 48 years (range 36 to 63) and the mean duration of penile erectile dysfunction 3.4years (range 1.5 to 10).
Two patients were excluded from the ANOVA analysis of mean duration of rigidity of greater than 60% at the base and tip of the penis. One
patient had an erection of greater than 60% rigid-
ity which started prior to VSS in the period when
he received 25 mg of sildenafil. The second patient
was excluded because penile plethysmography
was not recorded due to technical difficulties.
The duration of rigidity of greater than 60% at
the base and tip of the penis during VSS was sig-
nfficantly higher in each treatment group com-
pared with placebo (Figure 4). The geometric mean
duration (in min) of rigidity of greater than 60%
the base of the penis was 3.2 (95% confidence interval 1.1 to 7.9) on placebo, 25.9 (11.7 to 56.8, P = 0.001) on 10 mg, 24.1 (10.3 to 55.8, P = 0.003) on 25 mg and 31.8 (14.4 to 69.6, P = 0.001) on 50mg of sildenafil. The corresponding values at the tip of the penis were 3.0 (95% confidence interval 1.3 to 6.4) on placebo, 19.1 (9.8 to 36.8, P = 0.001) on 10 mg, 26.3 (13.0 to 52.7, P = 0.001) on 25 mg and 26.5 (13.7 to 50.8, P = 0.001) on 50mg of sildenafil. The onset of penile tumescence in all the patients was within the first few minutes of commencing VSS or approximately 30 to 40min post-dosing with sildenafil, corresponding approximately with the peak plasma concentration of the compound.
Four patients (two at 25 mg and two at 50mg) reported mild headache. There was no discontinuation from the study due to these adverse events, which were mild and transient. Importantly, there were no significant changes in pulse rate, blood pressure or laboratory safety data in these patients.
Discussion and conclusion
During recent years it has become increasingly
clear that the nitric oxide-cGNT system plays a
key role in the local mechanism of penile erec-
tion. 5-8 We have demonstrated the presence of
PDE2, 3 and 5 in human corpora cavernosa, and
shown that sildenafil is a potent selective inhibi-
tor of hilmqn PDE5. Furthermore, the clinical data
obtained with sildenafil highlight the iiiaportant
role of PDE5 in human penile erection.
Our finding that cGNT-specific PDE5 was the
major CGNT phosphodiesterase activity isolated
from human corpus cavernosum and that CGNT-inhibited PDE3 was also present is in agreement with the report of Stieff et al.18 In general, tissues such as corpus cavernosal smooth muscle, in
which CGNV and cAlvT appear to have similar
physiological effects, express PDE3 in addition to
the cGNT-specifac phosophodiesterase.19, 20 This
allows CGMP and CAMP to work synergistically in
the tissue. 2 0 We have previously demonstrated
that sildenafil potentiates relaxation of
phenylephriiae-contracted human corpus caver-
nosilm elicited by electrical field stimulation,21
and endothelium-dependent relaxation of rabbit
cavernosal tissue induced by the muscarinic
agonist, methacholine 22.In both cases the effects
of sildenafil were dependent on activation of the
nitric oxide-cGMP mediated relaxation pathway.
This may explain why Stieff et al. 18, who exam
ined relaxation of cavernosal tissue without
stimulation by nitric oxide, found that the selec-
tive PDE5 inhibitor, zaprinast, was a weaker and
less effective elaxant of human cavernosal tisues
than PDE3 selectiveagents.
By selectively inhibiting the type 5 CGMP specific phosphodiesterase, sildenafil improves
penile erectile activity in patients with erectile
dysfunction during sexual stimulation. Experimental evidence indicates that this is a local action of sildenafil on the corpus cavernosal smooth muscle cells where it enhances nitric oxide mediated relaxation. 21,22 We believe that under conditions of nitric oxide drive, type 5 PDE is the
most important regulator of CGMP levels in the corpus cavernosal smooth muscle cell. The mechanism of action of sildenafil suggests that it will induce or enhance erections during sexual stimulation, but will not provide erections in the absence of any physiological or sexual stimulus.
Sildlenafil demonstrates ideal pharmacokinetics for an oral agent to be taken, as required, prior to sexual activity for the treatment of penile erectile dysfunction. It is rapidly absorbed when adminis-tered orally, and has an onset of action of less than one hour. Furthermore, the drug has a relatively short plasma half life of approximately 4 h and is not expected to accumulate on repeated single daily administration. In the dose range studied, sildenafil is generally well tolerated and has no significant effects on pulse rate and blood pressure.
Sildenafil represents a new class of orally active
and peripherally acting drug for the treatment of
penile erectile dysfunction. The RigiScan study
demonstrates that sildenafil enhances the erectile
response to erotic stiinuli under standardised con-
ditions. The results are reported in terms of mean
duration of rigidity of greater than 60%. Although
There is considerable debate as to the threshold
degree of rigidity which correlates with sufficient hardness for penetrative intercourse, previous
studies indicate that the vast majority of patients
who achieve 60% rigidity will have an erection
that is sufficient for sexual intercourse. 23,24 its
efficacy in enhancing erections during stimulation
in the natural and private setting and its safety on
long-term adminstration are currently being inves-
tigated in large-scale clinical trials.
1 Furlow WL. Prevalence of Impotence in the United States. 24 Med Aspects Hum Sexuality 1985; 19: 13-16.
2 NIH. Consensus Development Panel on bnpotence. JAMA 1356-
1359.1993;280:83-90.
3 Lue TF, et al. Haemodynamics of erection in the monkey. J
Urol 1983; 130'.1237-1241. of penile erection.
4 Anderson KE, Wagner G. Physiology
Physiol Rev 1995; 75 -.191-236. eview of erectile dYs-
5 Lerner sE, Melman A, Christ Gj. A r estions. J Urol 1993;
function. New insights and more quESTIONS149 -. 1246-1255.
6ú Bush PA, Aronson Wj, Rajfer j, ignatro Lj. The L-arginine
neurotransmission in the corpus cavernosum of human
and rabbit. Circulation 1993; 87 (SUPI)L V): V3o-V32.
7 Kim N, Azadzoi KM, Goldstein Irwin, De Teiada IS. A nitric
oxide-like factor mediates non-adrenergi@, non-cholinergic
relaxation of penile corpus cavernosum smooch muscle.
neurogenic JClin Invest 1991; 88: 112-
8 Burnett AL, et al. Nitric oxide,. a phy
penile erection. Science 1992; 257 -. 401-403. cleo-
ú Lugnier C, Komas N. Modulation of vascular cyclic nu tide -phosphodiesterases by cyclic GNW: role in vasoclilata-
141-148.
tion. Eur I-leart j 1993; 14 (SUPPI 11' self-adm-linistration of
lo Levine SB, et al. Side effects al laniine for the treat-
intracavernous papaverine and phento
ment of impotence. i Urol 1989; 141: 54-57. leotide
son Wj, Appleman IVDA. Multiple cvclic nuc
1-1 Thomp t bra" . Biochemistry
phosphodiesterase activities from ra in
USA 1971; lo-. 311-316. simultaneous analysis
12 De Lean A, Munson A, Rodbard D.
of families of si9moidal curves: application to bioassay,
raclioligand assay and physiological dose-response curves.
Am I Physiol 1978; 235: E97-ElO2.
13 Beavo J,@,, Conti M , Heaslip Rj. Multiple cyclic nucleotide phosphodiesterases. Mol Pharmacol 1994; 46: 399-405.
cyclic GNW potentiation by WIN 58237, a 14 Silver Pj, et al. oticle phosphodiesterase inhibitor. J novel cyclic nucle - 271:1143-1149.
Pharinacol Exp Ther 1994; inhibi-
ctive type V Phosphodiesterase
15 Saeki T, et al. Sele porcine large coronary artery. J Phartor, E4021, dilates
macol Exp Ther 1945; 272-.825-831. of cyclic
der DH. Priinarv sequence
16 Beavo JA, Reifsny . s a-@Ld the design of
nucleotide phosphodiesterase enzyme ; ji: 150-
selective inhibitors. Trends PharamCC)l Sci 1990
155.
17 Gillespie PG, Beavo JA. inhibition and stimulation of photoreceptor phosphodiesterases by dipyridamole and M
& B 22,948. Mol Pharrnacol 1989; 36: 773-781. e of the
18 Stieff CG et al. Phorophodiesterase isoenzym nificance. human cavernous tissue and its functional sig
Akt Ural 1995; 26: 22-24.
ic nucleotide phosdhodiesterases: function-
19 Beavo JA. Cycl s. Physiol Rev 1995; 75: al implications Of multiple isoform
725-748. lic GNV and regulation of
20 Son-nenburg WK, Beavo JA. Cyc cyclic nucleotide hydrolysis. Adv Pharmacol 1994; 26:
87-114. 1. In vitro profile of UK-92,480, an inhibitor
21 Ballard SA et a
of cyclic GNM specific phosphodiesterase 5 for the treat-
155:676A.
ment of male erectile dysfunction. I Urol 1996;
22 Tang K, Ballard SA, Turner LA, N'avlor AM. Effects of the
sildenafil, oil
novel phosphodiesterase type 5 inhibitor, bbit corpus
methacholine induced relaxation of isolated ra cavernosum. Br j Pharmacol 1996 (in press).
WE. Evaluation ol erectile dysfunction
23 Kaneko S, Bradley rol 1986; with continuous monitoring of penile rigidity- J U
136: 1026-1029.
ogrinc FG, Linet 01. Evaluation of real-time RigiScan
24 monitoring in pharmacological erection; J Urol 1995; 154: 1356-1359.
TA |
