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ERECTILE DYSFUNCTION IN DIABETES MELLITUS PATIENTS: THE ROLE OF
ALPHA-LIPOIC ACID IN THEIR TREATMENT.
Kalinchenko, S.
Russian Research Endocrinology Center, D. Ullanova 11, Moscow 17136,
Russia. (Kalinchenko@list.ru)
ED is one of the forms of sexual dysfunction in men with diabetes
mellitus.. Penile erection is a vascular phenomenon.
Investigations in human and animal models have shown
than both erection and detumescence are haemodynamic
phenomena regulated by the state of relaxation or
contraction of penile smooth muscles. This, in turn,
is controlled by the autonomic nervous system. The
vasodilatory effects of nitric oxide have been evaluated
for decades. It is well established that endothelial
cells as well as neurons release nitric oxide (NO),
which triggers smooth muscle relaxation and penile
erection. The major portion of penile NO is of neuronal
origin and comes from cavernous nerves. Nitric oxide
diffuses into smooth muscle and activates via a guanylate
cyclase, an intracellular signal transduction pathway,
which triggers smooth muscle relaxation. ED in diabetic
patients is due to failure of NO-mediated smooth muscle
relaxation due to autonomic neuropathy and endothelial
cells dysfunction. In diabetic patients these nerve
functions are impaired thus leading in some cases
to a situation, where PDE 5 inhibitors do not work,
mainly due to impaired neuronal NO production. In
some cases the efficacy of PDE 5 inhibitors are reduced
in diabetes due to the decline of nerve function with
time. Having this in mind we have to think about treatment
options, which are able to restore and/or protect
nerve function in patients with diabetes. Diabetic
neuropathy can be assessed via neuropathic deficits
such as decreased temperature sensation, decreased
vibration threashold and by electrophysiological measures
such as nerve conduction velocity. The neurological
impairment in erectile dysfunction can be assessed
at the organ itself (method Kalinchenko-Rozivanov).
How can we manage ED? There are vacuum restriction
devices, intracavernosal injection and PDE5 inhibitors.
It is very important to note that PDE5 inhibitors
are just symptomatic treatment approaches, since they
do not interfere with the primary pathogenetic cause
of ED. Treatment of ED in DM patients should be primarily
based on drugs, which are able to interfere with the
pathogenesis of ED such as endothelial dysfunction,
neuropathy and in some cases low testosterone levels.
We tested alpha-lipoic acid as a pathogenetic first
line treatment option for ED for three reasons: Alpha-lipoic
acid has been shown to improve the NO mediated smooth
muscle relaxation of the corpus cavernosum in diabetic
rats. These results provide the preclinical rationale
to test alpha-lipoic acid in diabetic patients with
ED. Furthermore, alpha-lipoic acid has also been shown
in clinical studies to have beneficial effects on
the risk factors of ED such as neuropathy and endothelial
dysfunction. In diabetic rats the smooth muscle relaxation
is markedly impaired compared to controls. Administration
of alpha-lipoic acid was able to normalize this deficit
after 8 weeks of alpha-lipoic acid treatment. These
results show that alpha-lipoic acid can correct the
impaired neurogenic response of the corpus cavernosum
in diabetic rats. Endothelial dysfunction in diabetic
patients can be assessed by measuring forearm blood
flow in the presence of Acetylcholine. Acetylcholine
triggers the conversion of Argenine to Citrulline,
with the production of NO. NO leads via the conversion
of GTP to cyclic GMP, to smooth muscle relaxation.
Smooth muscle relaxation can be assessed by measuring
the forearm blood flow. In normal subjects acetylcholine
induces a dose dependent NO mediated smooth muscle
relaxation, which can be measured by an increase of
forearm blood flow. The Acetylcholine mediated NO
production can be shut down by the NO inhibitor NMMA.
In diabetic patient the Acetylcholine mediated NO
production is impaired due to endothelial dysfunction.
As a result, there is a decrease of smooth muscle
relaxation and forearm blood flow, when compared to
non diabetic individuals. Administration of alpha-lipoic
acid could increase the Acteylcholine mediated smooth
muscle relaxation and forearm blood flow in diabetic
patients to the levels of non-diabetics. Alpha-lipoic
acid facilitated acetylcholine induced NO production,
because the increase in forearm blood flow was shut
down in the presence of the NO inhibitor NMMA. These
results demonstrate that alpha-lipoic acid can improve
endothelial dysfunction in diabetic patients by facilitating
NO production. We used a similar treatment scheme
for our ED patients, which is recommended for the
treatment of diabetic neuropathy. Patients with moderate
ED were treated for 2 weeks with 1800 mg orally and
then shifted to a 2 month maintenance therapy with
600 mg. Patients with severe ED were treated for 2
weeks with 600 mg infusions and then shifted to a
2 month maintenance therapy. The results will be discussed.
CONCLUSIONS:
ED is a typical complication of DM
ED is highly prevalent, under-diagnosed and under-treated
Neuropathy plays a significant role in pathogenesis
of sexual disorders (erectile and orgasmic dysfunction)
Alpha-lipoic acid (Thioctacid®) appears to be a pathogenetic
treatment option for ED
Alpha-lipoic acid (Thioctacid®) may sustain PDE5 efficacy
in ED treatment
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