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| Some general information
on lisuride |
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No valvulopathies observed with lisuride as
a result of 5-HT2B antagonistic effects
Lisuride, in contrast to all other marketed
ergot-derived drugs (such as pergolide, cabergoline,
ergotamine etc.), is an 8-α-ergoline
(iso-ergoline), a structure not found in natural
ergot. It had been synthetized by M. Semonsky
(1) in former CSSR as a very potent peripheral
serotonin (5-HT) antagonist for migraine prophylaxis
(Lysenyl®, Cuvalit® at a dose of 3 x 0.025
mg p.o./day; in Germany marketing approval
in 1977). Lisuride was discovered to be also
a potent dopamine agonist (2) for the treatment
of hyperprolactinemia and pituitary tumours
(marketed as Dopergin® tablets (0.2 mg) since
1983) and Parkinson’s disease (Dopergin® 0.2
mg, 0.5 mg and 1.0 mg tablets since 1986 in
various European and other countries). For
this reason there exists a large database for
lisuride, which also has become a standard
(with more than 2000 publications) for new
research, due to its outstanding affinity (10-8 – 10-10 molar)
for some monoamine receptors (DA receptors
as agonist or partial agonist, 5-HT1A receptors
as agonist, 5-HT2A,
5-HT2B and
5-HT2C receptors
as antagonist (3)).
The potent pure 5-HT2B antagonist
action of lisuride explains why lisuride was
shown to be effective in migraine prophylaxis,
and why it is also devoid of any stimulatory
action on trophic 5-HT2B receptors
e.g. of the heart (in contrast to pergolide,
cabergoline, nor-fenfluramine and 5-HT itself
(as released from carcinoid tumours). In agreement
with this, not a single case of cardiac valvulopathy
has ever been reported (4) for lisuride (WHO
and CSM database, Lisuride database covering
at least 350 000 patients’ years of lisuride
use etc.). Whilst class label warnings had
been issued by various European drug regulatory
agencies (including the German BfArM) for all
DA agonists regarding induction of hypersexuality
and pathological gambling, no warning regarding
cardiac valvulopathy has been given for lisuride
(again in contrast to pergolide and cabergoline
which had been found to carry an increased
risk (5,6)). In his editorial in the same issue
of the New Engl. J. Med., B.L. Roth states
that “lisuride… which is not a 5-HT2B serotonin-receptor
agonist was not associated with valve disease.
The findings concerning lisuride further implicate
5-HT2B serotonin-receptor
activation as a key step in the progression
of drug-induced valvulopathy…” (7).
Thus it can be concluded that also in its new application forms (‘New Medical
Entities’: lisuride patch and lisuride minipump), in addition to providing continuous
dopaminergic stimulation (CDS) lisuride can also be considered as a drug with
an excellent safety profile.
Addendum as of May 20th 2007:
In the meantime, the valvulopathy data have caused Lilly to withdraw pergolide, once the market leader, from the US market whilst Pfizer has recommended restricted use of high-dosed cabergoline in Parkinson´s disease. This is a very sad development for many patients who rely on this drug especially when longacting dopaminergic stimulation (e.g. overnight) is needed, and it is to be hoped that this will not jeopardize a valuable product in the therapy of Parkinson´s disease (once
developed by Carlo Esba/Farmitalia, taken over by Pharmacia, Upjohn and eventually by Pfizer). Unfortunately valvulopathies are not just observed with a new diagnostic tool where experts still can disagree with each other (echo cardiography) but Schade et al.´s prospective study yielded also clinical events relevant for the patients. Again, it is obvious that the availability of different drugs and application forms offers best therapies to patients, and Axxonis Pharma hopes to be able to add a few more options.
Poster:
KP Latté, B. Schurad, R. Horowski: "Lisuride,
a dopamine agonist, is a potent serotonin 5-HT2B
receptor antagonist and is not connected to
valvular heart disease"
| 1. |
Zikán, V., Semonský, M.
(1960)
Mutterkornalkaloide XVI.
Einige N-(D-6-Methyl-isoergolenyl-8),
N-(D-6-Methylergolenyl-8-)-und N-
(D-6-methylergolin/I/-yl-8)N’-
substituierte Harnstoffe
Coll. Czech. Chem. Commun. 25: 1922-1928 |
| 2. |
Calne,
D., Horowski, R., McDonald, R.J., Wuttke,
W., eds. (1983)
Lisuride and other Dopamine Agonists
Raven Press, New York |
| 3. |
Millan,
M.J., Maiofiss, L., Cussac, D., Audinot,
V., Boutin, J.A., Newman-Tancredi,
A. (2002)
Differential Actions of Antiparkinson
Agents at Multiple Classes of Monoaminergic
Receptor. I.
A Multivariate Analysis of the Binding
Profiles of 14 Drugs at 21 Native and
Cloned Human Receptor Subtypes
JPET 303: 791-804 |
| 4. |
Hofmann,
C., Penner, U., Dorow, R., Pertz, H.H.,
Jähnichen, S., Horowski, R.,
Latté, K.P., Palla, D., Schurad,
B. (2006)
Lisuride, a Dopamine receptor Agonist
with 5-HT2B Receptor Antagonist Properties:
Absence of Cardiac Valvulopathy Adverse
Drug Reaction Reports Supports the Concept
of a Crucial Role for
5-HT2B Receptor Agonism in Cardiac Valvular
Fibrosis
Clin Neuropharmacol 29: 80-86 |
| 5. |
Schade, R., Andersohn, F., Suissa, S.,
Haverkamp, W., Garbe, E. (2007)
Dopamine Agonists and the Risk of Cardiac-Valve
Regurgitation
N Engl J Med 356: 19-28 |
| 6. |
Zanettini,
R., Antonini, A., Gatto, G., Gentile,
R., Tesei, S. , Pezzoli, G.
(2007)
Valvular Heart Disease and the Use of
Dopamine Agonists for Parkinson’s
Disease
N Engl J Med 356: 39-46 |
| 7. |
Roth,
B.L.(2007)
Drugs and Valvular Heart Disease
N Engl J Med 356: 6-9 |
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