Digest of recent discussions on ISSM mail (September

Members continued to contribute generous time and thought to the ongoing discussions on ISSIR List. The main issues discussed included:

The list of topics and responses includes:

Alfuzosin & PDE5 inhibitors
What is sexual satisfaction?
Painful nocturnal erections
Tribulus terrestris!

Alfuzosin & PDE5 inhibitors

Dr. Gerald Brock inquired about trials involving the combination of alfuzosin and a PDE5 inhibitor. Dr. Sidney Glina pointed out a paper by Yassin A presented at EAU 2004 where an improvement in erectile response to Tadalafil was noted when Alfuzosin was added. Dr. Porto Alegre did not note any complications with this combination.

Dr. Pierre Assalian broadened the discussion to include what is the mechanism of action when adding Alfuzosin to a PDE5 inhibitor. Hussein Ghanem suggested that alfuzosin -an alpha adrenergic blocker- might enhance the vasodilatory effect of PDE5 inhibitors. Dr. Ganesh Adaikan noted that Alfuzosin is an alpha1 blocker of higher selectivity and therefore the mechanism of afluzosin combined with a PDE5 inhibitor presumably will be similar to that of phentolamine-sildenafil / other combination including VIP / PGE1, and advised care with such a combination as additive vascular side effects might occur leading to dizziness, headache, postural hypotension etc.

Dr. Raymond Rosen warned that the major limitation of combining alfuzosin, in particular, with any PDE-5 is the current lack of drug interaction data on cardiac function, while Dr. Gregory Broderick pointed that the important clinical issue with this combination is whether the benefit outweighs the potential side-effect of hypotension. Dr. Hartmut Porst also pointed out that there is a label warning on the simultaneous use of PDE 5 inhibitors and alpha-blockers. Dr. Tarek Anis and Dr. Shedeed Ashour added that the blood pressure lowering effect of combining PDE5-inhibitors and alpha-blockers is significant with all alpha blockers except Tamsulosin because of selectivity factors. Dr. Tarek Anis gave a detailed explanation of the various safety issues and advised that further information is available at the FDA website http://www.fda.gov/cder/drug/infopage/cialis/default.htm

Dear All,
I was curious if anyone has had experience in the form of a local trial with the combination of Xatral (alfuzosin) and a PDE5 inhibitor.

Gerry:
There was a paper presented by Yassin AA e Diede HE at EAU 2004 where they showed improvement on erectile response in Tadalafil non-responders (by history)patients when they added Alfuzosin 10mg daily and Tadalafil 20mg on demand.
Sidney Glina

I did not have any problem with this association. In Brazil, we have alfuzosin more than 10 years, then we have a long experience with this drug.

Dear Sidney
What is the mechanism of action when adding Alfuzosin to a PDE5 inhibitor

Pierre Assalian.MD
President,17th World Congress of Sexology
Montreal,july 10-15,2005
www.montrealsexo.com

Dear Dr. Assalian,
Regarding the mechanism of action, alfuzosin -an alpha adrenergic blocker-might enhance the vasodilatory effect of PDE5 inhibitors. This is an idea similar to adding phentolamine to PGE1 for intracavernous therapy. I couldn't find literature about the (alfuzosin + PDE5 inhibitor) combination.
Best regards,

Dear all
In addition to direct antagonism of alpha1 and alpha2 -adrenoceptors, phentolamine has also been shown to relax CC by an indirect effect - via non-adrenergic, endothelium-mediated mechanism through NOS activity (Traish et al, 1998; Vemulapalli & Kurowski, 2001). May be this possibility also exists for alfuzosin?

Some in vitro studies have shown that phentolamine can potentiate relaxation of sildenafil, VIP and also PGE1. These effects appear to be additive & synergistic with phentolamine induced relaxation, which is the result of inhibition of adrenergic tone of the CC. This will increase the efficacy of these relaxants, which act through known pathways. Alfuzosin is a more selective alpha1 blocker and therefore the mechanism of afluzosin combined with a PDE5 inhibitor presumably will be similar to that of phentolamine-sildenafil / other combination including VIP / PGE1.

Indeed, as shown recently, alfuzosin also improved apomorphine induced penile erection in hypertensive rats (Mayoux et al., 2004). However, we should watch out for the additive vascular side effects of such combination leading to dizziness, headache, postural hypotension etc.

In theory, they would be complementary (alpha blockade/PDE-5 inhibition). Alfuzosin does not have the adverse effects on ejaculation often seen with tamsulosin.

The major limitation of combining alfuzosin, in particular, with any PDE-5 currently is the lack of drug interaction data on cardiac function (e.g. BP, HR).

If this is OK, it will be possible to administer the drugs concomitantly. In theory, it should be a good combination.

Raymond C. Rosen, Ph.D
Professor of Psychiatry and Medicine
Robert Wood Johnson Medical School

The more important clinical issue is not whether systemic alpha-blockade enhances oral PDE5-I therapy, but whether the benefit outweighs the potential side-effect of hypotension?

Greg Broderick
Professor of Urology
Mayo Clinic College of Medicine
Jacksonville, Florida
Residency Program Director
President Elect-Sexual Medicine Society NA

Dear all,
as all of you should be aware there is a principal warning or even contraindication on the simultaneous use of PDE 5 inhibitors and @-blockers. I am wondering very much on that debate regarding that all 3 PDE 5 inhibitors except tamsulosin, are not recommended or even contraidicated in patients on @ blockers. It is true that there was one clinical paper from Yassin on the simultanous use of doxazosin and tadalafil but once more this guy was not aware on these label- issues, which of course bear also liability issues if they are not considered.

At present no data are available on alfuzosin whether there are interactions with this @blocker and PDE 5 inhibitors or not. And as long as these data are not generated we have to consider alfuzosin as an @-blocker with a potential risk of cardiovascular side-effects if given simultaneously with a PDE 5 inhibitor.

Dr. Yassen presented the same results of the simultaneous use of tadalafil and doxazosin (and not alfuzosin as Dr Porst indicated earlier) during the 4th Asian and oceanic congress of Andrology, in Malaysia, last May. After his presentation I draw his attention to the safety issue indicating that both the Consumer drug Information Sheet and Patient Package Insert (both available at the FDA website http://www.fda.gov/cder/drug/infopage/cialis/default.htm) clearly indicate that Tadalafil is contraindicated with alpha-blockers with the exception of tamsulosin 0.4 mg daily. The answer of Dr. Yassen was that this label warning exists only in the States and not in Europe, and that he did not see any vascular side effect. The difference in label information was later confirmed by Dr. Sharlip in his presentation about tadalafil during the same congress.

At present no data are available on alfuzosin whether there are interactions with this alpha blocker and PDE 5 inhibitors or not, however data are available for interaction between tadalafil and other alpha blockers. When tadalafil 20 mg was administered to healthy subjects taking the alpha - blocker doxazosin 8 mg daily, there was significant augmentation of the BP-lowering effect of doxazosin. In studies that investigated the hypotensive effects of tadalafil (20 mg) combined with 0.4 mg once-daily tamsulosin, a selective alpha-blocker, subjects did not experience any clinically meaningful reductions in BP. These differences in hypotensive effects between tadalafil and doxazosin compared with tadalafil and tamsulosin may be related to the different actions of the alpha-blockers. The alpha1A -adrenergic receptors that are selectively targeted by tamsulosin comprise about 70% of the alpha1A -adrenergic receptors in human prostate, while doxazosin (and also alfuzosin) acts on alpha1 -adrenergic receptors located on both vascular and nonvascular smooth muscle throughout the body.

ALFUZOSIN PACKAGE INSERT warns that postural hypotension with or without symptoms (e.g., dizziness) may develop within a few hours following administration of UROXATRAL (alfuzosin HCl extended-release tablets). As with other alpha-blockers, there is a potential for syncope. Patients should be warned of the possible occurrence of such events and should avoid situations where injury could result should syncope occur. Care should be taken when UROXATRAL is administered to patients with symptomatic hypotension or patients who have had a hypotensive response to other medications.

Till more data become available, we should consider that all PDE5 inhibitors can augment the hypotensive effects of alpha-blockers. It is a precaution that sildenafil (>25 mg) not be administered within 4 hours of receiving an alpha blocker; vardenafil is contraindicated with all alpha-blockers; tadalafil is contraindicated with alpha-blockers except once-daily tamsulosin 0.4 mg.

Dear All
The issue of alpha blockers and PDE5 inhibitors can be simplified, only for practical purposes but not for academic research point as follows:
1- The BP lowering effect of this combination is obvious with all alpha blockers except Tamsulosin 0.4 mg because of selectivity issue ( it is the most selective on the prostate and bladder neck but not acting on the Blood Vs.), and this why is the most studied with ejaculatory disturbances.
2- Other alpha blockers are relatively less selective and well affect both the bladder neck and vessels.
3- All PED5 inhibitors can induce a low Bl Pr if combined with the alpha blockers; the effect that is most obvious with vardenafil and to lesser extent with Tadalafil (+ the fact that tadalafil has the longest halflife 17.5 Hrs)
4- Some studies demonestrated a high degree of safety if combing 2 or three antihypertensive classes of medicines with PDE5 inhibitors in treating ED. i.e the lowering effect on Bl Pr. is insignificant.
5- the conclusion is that this combination if ever wanted has to be individualized and tailored for every patient as needed.

What is sexual satisfaction?

Dr. Ruben Hernandez inquired about what is sexual satisfaction in the personal view of List members. Dr. John Dean expressed his view quite elegantly, as an experience for two that varies with the environment, mood and circumstances of both partners. We might have different expectations but the experience needs to be mutually enjoyable. It will range between a shared feeling of intense emotional and spiritual intimacy, accompanied by a pleasurable physical sensation, and an intense, passionate physical experience, more visceral than emotional, more “animal” than spiritual. Being male, this would involve orgasm and, usually, intercourse.

I would like to receive your personal view in 3 lines about describing what is sexual satisfaction for you ? Thanks

Wow! This is a question that you don’t get asked every day! There’s nothing like holding a public airing of your own sexuality to get the day off to a good start. Still, it’s all in the cause of science.

“For me, it is an experience for two that varies with the environment, mood and circumstances of both partners. We might have different expectations but the experience needs to be mutually enjoyable. It will range between a shared feeling of intense emotional and spiritual intimacy, accompanied by a pleasurable physical sensation, and an intense, passionate physical experience, more visceral than emotional, more “animal” than spiritual. Being male, this would involve orgasm and, usually, intercourse.”

Painful nocturnal erections

Dr. Edgardo Becher presented the case of a 29 years-old young man with a history of painful nocturnal erections which wakes him up 2 to 3 times per night, for the past 4 months. He treated him using Digoxin 0.25 mg/day 5 days a week with only a partial improvement. Dr. Betcher explained –and provided references- that digoxin has been reported to interfere with normal erectile function by inhibition of corporeal smooth muscle sodium/potassium ATP ase pump activity, impeding relaxation. Dr. Hartmut Porst advised a trial of the antiandrogen Casodex 50 mg/day for 2 of months. Dr. Guillermo Gueglio had good results in three cases using alpha receptor agonists while Dr Fernando Ugarte advised adding muscle relaxants to decrease perineal muscle tone induced by pain. Dr. Sidney Glina advised finasteride use. Dr. Shedeed Ashour suggested a trial of ketoconazole based on its antiandrogenic effect.

Dr. Ihab Osman contributed a concise review and references about current pharmacologic treatment options for recurrent priapism. He advised that Baclofen -a GABA (gamma-aminobutyric acid) agonist used in treatment of spasticity- succeeded not only in managing Recurrent Priapism, but also preserved erectile function. He suggested adding Rivotril (Clonazepam) in resistant cases and reported 4 successfully treated cases.

This is a 29 years-old young gentleman with a history of painful nocturnal erections which wakes him up 2 to 3 times per night, every night, for the past 4 months. He says the erections are very firm, painful without glans tumescence. The erection disappears a few minutes after he wakes up.

This events doesn't happen during the day and he has normal sexually-induced erections.

He has no history of substances abuse, hematologic disorders or trauma. I gave him Digoxin 0.25 mg/day 5 days a week with only a partial improvement.

Dear Edgardo,
I have made good experiences in those cases with the antiandrogen Casodex 50 mg/day for a couple of months.

Dear Carlos,
Digoxin has been reported to interfere with normal erectile function. It's mechanism has been explained by inhibition of corporeal smooth muscle sodium/potassium ATP ase pump activity, impeding relaxation (1). It has been reported its use to treat nocurnal priapism although it frequently requires high doses (2).

Edgardo: is funny to answer you through this way but this is the world today! I�ve had 3 cases like yours and I solved them by using an alpha-agonist such as fenilpropanolamine (25 mg before going to bed, Rome Laboratories). Good luck, Guillermo Gueglio.

I agree with Guillermo, but I also use muscle relaxants, because this patients increase perineal muscle tone during painful erections and increase intracavernosal presure.

Edgardo:
It seems to be a stuttering priapism, although he has no hematologic disorders. You could try finasteride 5 mg for a period

Current pharmacological therapy of recurrent priapism consists of [alpha]-adrenergic agonists, antiandrogens and smooth muscle inotropic agents. Therapy with antiandrogens should be used only in patients who are not sexually active or do not wish to remain potent, which is actually not the case in most patients & this form of therapy is not ideal for young patients with recurrent priapism. Digoxin has been shown to have an inhibitory effect on penile rigidity and it has been proposed as a treatment for recurrent priapism. However, this inhibitory effect occurs at the upper end of therapeutic concentrations and it can be difficult to maintain these high serum levels.

Treatment failure often leads to a decreased quality of life compounded by the risk of permanent erectile dysfunction.

We followed 4 cases of refractory and recurrent idiopathic nocturnal priapism that were successfully treated with oral baclofen, either alone or with Rivotril or Abitryl.

All cases had history of recurrent nocturnal priapism. Priapism episodes occurred several times a night and caused severe sleep deprivation. Medical history, physical examination and metabolic evaluation were unremarkable. Several trials of [alpha]-adrenergic agonist therapy offered only temporary relief and caused further disruption of the sleep cycle.

A trial of oral baclofen was initiated at a dose of 10 mg, taken at bedtime, which succeeded in 2 patients.

In the 2 remaining cases, we increased the dose by 10 mg tablet until improvement occurred by 30mg/day in one patient & 40mg/day in the other, in addition to Rivotril (Clonazepam) 0.5mg tab at bedtime. On attempts of withdrawal of baclophen, recurrent priapism occurred.

Normal erectile function was preserved in 3 cases & the forth case did not come for follow up yet.

Baclofen, a GABA (gamma-aminobutyric acid) agonist used in treatment of spasticity succeeded not only in managing Recurrent Priapism, but also preserved erectile function. The idea of its use originated when intrathecal baclofen inhibited erection, & on the other hand, sudden stoppage of intrathecal baclofen resulted in priapism. Many studies in rats & man proved the inhibitory effect of baclofen on erection. Some forms of priapism may be primarily a neurological disorder.

That's why baclofen is considered a new therapeutic modality for treating recurrent nocturnal priapism & other investigators postulated its validity in treating episodic priapism in sickle cell disease patients.

Steiger A and Benkert O (1989): Examination and treatment of sleep-related painful erections: a case report. Arch Sexual Behav 1989; 18: 263-7 Rourke KF, Fischler AH and Jordan GH (2002): Treatment of Recurrent Idiopathic Priapism With Oral Baclofen [CLINICAL UROLOGY: Case Reports]. Journal of Urology. Volume 168(6): pp 2552-2553. December 2002

Dear all,
Inputs are all very nice but what i want to add is the trial of Ketoconazole in these cases is of a rewarding results. ketoconazole has an antiandrogenic effect . there was a recent publication in the IJIR regarding the same issue." the role of oral ketoconazole in inhibiting postoperative painfull erections".

Tribulus terrestris!

Dr. Fragas Ramiro requested information about a product named tribulus terrestris. Dr. Poosha mentioned that this product is also present in India. Dr. Pierre Assalian warned about the placebo effects of products that claim to cure all sexual dysfunctions! Dr. Ganesh Adaikan explained that –in Asia- there are many agents of plant origin historically claimed as aphrodisiacs without scientific documentation. Dr. Adaikan also referred to a study reporting an androgen increasing property of this product as well as its ability to increase the levels of both cAMP and cGMP. He noted that further studies are necessary to evaluate its clinical efficacy

Dear friends, I need to know if somebody has had experience with a product natural Vietnamese that They call himself TRIBELUS that say to be effective in the treatment of the sexual deficiency. We don't know it and we have received in our Hospital 5 400 capsules.

The only information that we have is:
COMPOSITION:
- Tribelus terrestris L. ext ........250 mg.
- Excipients (Lactose, manioc amidon, Mg stearat)....s.q. for............1 capsule.
INDICATIONS: Use in cases:
- Sexual deficiency.
- Erectile Dysfunction.
- Fragidity.
CONTRAINDICATION:
- Do not use in person under 18 years of age.
DOSAGE AND ADMINISTRATION:
- Take 3 capsules after a meal, 2 times daily, and continue the treatment for 40 - 60 days.
* AS directed of physician.

(According to the quantity that we have and the recommended dose could use it in 22 patients).

If they have some information, Please, you to communicate with us.

Ramiro
I do not know this product. Anything can be effective, do not forget PLACEBO effect. I always doubt a product that can cure all sexual deficiency? what that mean defiency????40 to 60 days and the patient is CURED? you are a doctor ,do you believe this?

It's "Tribulus" terrestris - recognized in Ayurveda an Indian System of Medicine to have mild aphrodisiac properties.

In Asia, there are many agents of plant origin historically claimed as aphrodisiacs without scientific documentation. One such compound that was studied in my laboratory is Tribulus terrestris (TT-with about 50% of protodioscin extract as active ingredient); we have published this work. We have shown that TT increased the proerectile relaxant effect and nitrergic neurotransmission in the rabbit corpus cavernosum and improved sexual behaviour in rats. We showed these effects to be due to its androgen increasing property and the ability to increase the levels of both second messengers cAMP and cGMP (it also increased DHEA level in man). Apart from its receptoral affinity, it also compared well with the effects of testosterone in these studies (hence TT may mimic testosterone in its latency for therapeutic effect - 40 to 60 days?). Apart from our publications on this, limited studies elsewhere showed that TT improved seminal parameters and fertility in man.

Further studies are necessary to evaluate its clinical efficacy. Nevertheless, extract of TT (protodioscin) is commonly used in patients with low androgen levels in this part of the world.

Dear Ganesan
I believe you that Tribulus acts like an Androgen or has androgenic properties.so it could be beneficial in cases where there is low T,my objections where that it is only used for a short period of time,it cures ED and female sexual problems

All the best for the new year ,hope for no world catastrophes and hope you get good news about your colleague

Digest of recent discussions on ISSM mail (September - December 2004)

Alfuzosin & PDE5 inhibitors

What is sexual satisfaction?

Painful nocturnal erections

Tribulus terrestris!

Last update : 03/05/2005