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Intrest in lisuride


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#1 medievil

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Posted 16 May 2010 - 02:08 PM


Mode of action

Lisuride is a dopamine and serotonin receptor partial agonist. It has a high affinity for the dopamine D2, D3 and D4 receptors, as well as serotonin 5-HT1A[1] and 5-HT2A/C receptors.[2] While lisuride has a similar receptor binding profile to the more well-known and chemically similar ergoloid N,N-diethyl-lysergamide (LSD), it lacks the psychedelic effects of its sister compound.[3]

5HT2A agonism is a interesting target to increase cognition, I also tought that D4 is involved in ADHD/ADD.
While lisuride is only a partional agonist at all receptors i think its pharmacological profile is very interesting.

Lisuride prevents learning and memory impairment and attenuates the increase in extracellular dopamine induced by transient global cerebral ischemia in rats

Maeve A. Caldwella, Jean-Michel Reymannb, Hervé Allainb, Brian E. Leonarda and Danièle Bentué-Ferrerb, *
a Department of Pharmacology, University College Galway, Galway, Ireland
b Laboratoire de Pharmacologie, Faculté de Médecine, Avenue du Pr Léon Bernard, 35043 Rennes, France
Accepted 17 June 1997. Available online 11 February 1998.
Abstract
In this experiment, we tested the efficacy of neuroprotection with lisuride, a dopamine agonist, using the 4-vessel occlusion rat model. Functional improvement was evaluated with two behavior tests exploring learning and memorization capacity in the rat, the Morris water maze and the 14-unit T-maze, 18 days after ischemia. Extracellular dopamine levels during ischemia were determined in search of a possible neuroprotection mechanism. Dopamine and its metabolites, DOPAC and HVA, as well as the serotonin metabolite, 5-HIAA, were assayed with HPLC-EC, in striatal extracellular fluid obtained by in vivo microdialysis in the awake rat. Lisuride was administered at a total dose of 10 ng by continuous intrastriatal infusion or at the dose of 0.5 mg/kg by i.p. infusion, 160 minutes before onset of ischemia for the neurochemical study and at the dose of 0.5 mg/kg via i.p. infusion, 1 hour before occlusion of the carotid arteries, for the behavior tests. Behavioral testing showed significantly better recovery in both sets of behavioral tests, with more pronounced positive results with the 14-unit T-maze, in comparison with the saline-treated animals. Microdialysis confirmed a significant attenuation of the ischemia-induced dopamine surge, whatever the mode of administration, compared with saline-treated animals. These results show that lisuride offers significant neuroprotection from the effect of experimental transient global forebrain cerebral ischemia in the rat; the mechanism would imply, at least in part, reduced levels of extracellular dopamine.


Edited by medievil, 16 May 2010 - 02:17 PM.

  • Agree x 1

#2 medievil

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Posted 16 May 2010 - 03:09 PM

[Therapeutic effect of lisuride maleate on post-stroke depression]
[Article in Japanese]

Hougaku H, Matsumoto M, Hata R, Handa N, Imaizumi M, Sugitani Y, Yoneda S, Etani H, Sueyoshi K, Kusunoki M, et al.

First Department of Medicine, Osaka University Medical School.
Abstract
Twenty post-stroke depressive patients who obtained more than 11 points on Self-Rating Questionnaire for Depression, were treated with 0.075 mg/day lisuride maleate for 12 weeks. The drug effect on depression was evaluated quantitatively by the Hamilton Rating Scale for Depression. The relationships between brain CT or MRI and SRQ-D score were investigated in 24 subjects. More than 80% of post-stroke depressive patients improved after lisuride maleate treatment for 8 or 12 weeks. In particular, depressed mood, hypobulia, sleep disturbance, anxiety, etc. were significantly improved compared to the baseline condition. As for the relationships with CT and/or MRI findings, the group with moderate to severe brain atrophy had a significantly higher grade of depressive state than those without.

80% of the patients recovered, wich is quite remarkable.

It makes sense tough since its pharmacological profile is nearly perfect when it comes to depression, combined 5HT2A, 5HT1A, 5HT2C (strangely agonism of this receptor is antidepressive) D2, D3, D4 agonism.

Dont know how the adaptation period would be tough, since it will not only reduce dopamine but also serotonin when initiating treatment, altough its only a pertional agonist and trivastal also doesnt cause a bad adaptation period unlike pramipexole.

[Anxiolytic effects of lisuride and its agonistic action to central 5-HT1A receptors]
[Article in Japanese]

Akai T, Takahashi M, Nakada Y, Ohnishi R, Ikoma Y, Yamaguchi M.

Research Department, Nihon Schering K.K., Osaka, Japan.
Abstract
Effects of lisuride, a derivative of ergot alkaloid, on central 5-HT1A receptors were investigated biochemically, behaviorally and electroencephalographically (EEG) in rats and rabbits. Effects of lisuride in water-lick conflict tests were also investigated in rats. Lisuride was found to strongly inhibit the bindings of [3H]8-OH-DPAT to 5-HT1A receptors in the raphe nucleus, hippocampus, cortex, amygdala and hypothalamus of rat brain. Inhibitory effects of lisuride on bindings of [3H]8-OH-DPAT in the hippocampus was almost the same as that of 5-HT (Ki = 0.5 nM) and stronger than those of the 5-HT agonist 5-MeO-DMT (Ki = 2.1 nM) or other ergot derivatives (bromocriptine and pergolide, Ki = 3.0 nM). Lisuride (0.1-0.5 mg/kg, i.p.), like 8-OH-DPAT, dose-dependently induced a 5-HT behavioral syndrome in rats. Lisuride affected locomotor activity in rats, whereas 8-OH-DPAT did not. In hippocampal EEG of rabbits, lisuride (0.01-0.03 mg/kg, i.v.), like 8-OH-DPAT and diazepam, dose-dependently inhibited rhythmical slow activity (RSA) induced by acoustical stimulation (3100 Hz) and also inhibited the RSA increased by administration of anxiogenic FG7142. In water-lick conflict tests, lisuride (0.05-0.1 mg/kg, i.p.), like diazepam, increased the number of shocks. These findings indicated that lisuride acts as a strong agonist on central 5-HT1A receptors and suggested that lisuride might be a potential anxiolytic.

Looks like it could also be a strong anxiolytic, this one looks far more interesting then pramipexole to me atm, cant wait to give it a try.

Edited by medievil, 16 May 2010 - 03:19 PM.


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#3 medievil

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Posted 16 May 2010 - 05:30 PM

lisuride: 4.00 5ht1a, 3.88 Alpha2C, 3.78 Alpha2B, 3.22 Alpha2A, 3.01 5ht2b, 2.99 5ht5a, 2.90 D4, 2.74 5ht2a, 2.65 D2, 2.64 5ht7, 2.61 5ht6, 2.56 Beta1, 2.27 5ht1b, 2.09 Alpha1A, 1.93 Beta2, 1.83 5ht1e, 1.59 D5, 1.42 H2, 1.34 D3, 1.08 Alpha1B; 0.00: 5ht1d, 5ht2c, D1, DAT, NET, Imidazoline1, M1, SERT, CB2, KOR, MOR, M3, M2, M5, M4, CB1, Ca+Channel; ND: Sigma1, H1, Sigma2, DOR, NMDA

http://www.plosone.o...al.pone.0009019

I dont know how to read those affinities tough.

They dont clarify wheter its a agonist or antagonist, just the affinities.

While it seems to bind with the 5HT2B receptors, it acts as antagonist on them.

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.
Hofmann C, Penner U, Dorow R, Pertz HH, Jähnichen S, Horowski R, Latté KP, Palla D, Schurad B.

Global Medical Safety, Schering AG, Berlin, Germany. christoph.hofmann@schering.de
Abstract
OBJECTIVES: The high incidence of fibrotic cardiac valvulopathies reported in association with the 8beta-ergoline dopamine (DA) agonist, pergolide, and also case reports for cabergoline and bromocriptine have made it necessary to review the theoretical basis and actual findings in the case of another DA agonist, the 8alpha-ergoline lisuride (used since the 1970s for migraine prophylaxis as well as since the 1980s for its prolactin-lowering and anti-Parkinson activity). METHODS: We have reviewed the pharmacology of lisuride in relation to other DA agonists, and we have performed a throughout literature search as well as a search of our own and other adverse drug reaction databases for a possible relationship of lisuride with cardiac valvulopathy or for any reports of fibrosis in other locations. RESULTS: Our review of the pharmacology and the literature strongly suggests that drug-induced cardiac valvulopathies are always related to a stimulatory drug effect on trophic 5-HT(2B) receptors. As lisuride is devoid of such an effect, but on the contrary is an extremely potent 5-HT(2B) antagonist, an association of lisuride therapy with cardiac valvulopathies seems to be highly unlikely. In agreement with this hypothesis, not a single report of a cardiac valvulopathy associated with lisuride therapy has been identified in any database so far.Furthermore, against a background of an estimated 360,000 patient years, we have found only a very small number of cases of any other form of fibrosis (1x retroperitoneal, 2x pleural, 2x pulmonary, 1x interstitial pulmonary changes), in part combined with other risk factors and confounding variables. This closely matches 4 reports available from WHO (1x retroperitoneal, 3x pleural fibrosis). In addition, only 5 other possibly related conditions (3x pleural effusion, 1x pleuritis, 1x pericarditis) were identified in the lisuride adverse drug reaction database of Schering, Berlin. CONCLUSIONS: No link has been found between lisuride use and fibrotic cardiac valvulopathy, in agreement with the 5-HT(2B) receptor antagonist effect of this drug. The very low incidence of spontaneous reports of any other fibrosis could be even compatible with an association by chance in the population exposed to lisuride. Although close monitoring for this kind of side effects is still to be recommended in the therapy with lisuride, our data do not support the concept of a class effect suggesting that all ergot-derived drugs and especially DA receptor agonists with some chemical similarity to the ergot structure will cause or facilitate cardiac valvulopathies as observed with pergolide.


Also the findings that it interacts with several adrenergic receptors and 5HT6 and 5HT7 is interesting.

EDIT:

It is also useful to present the npKi data of Fig. S2 in numerical format. In the listing below, the npKi values for each drug are arranged in decreasing order. A value of 0.00 means that the Ki value was measured as >10,000 nm. “ND” indicates that the data is not available. The 5-HT2A and 5-HT2C receptors are also highlighted in bold font for easier location. npKi values below about 2.0 should be imperceptible, while values above about 2.0 should be perceptible, and the higher the npKi value, the more perceptible a receptor should be.

So basicly, this is what counts:
lisuride: 4.00 5ht1a, 3.88 Alpha2C, 3.78 Alpha2B, 3.22 Alpha2A, 3.01 5ht2b, 2.99 5ht5a, 2.90 D4, 2.74 5ht2a, 2.65 D2, 2.64 5ht7, 2.61 5ht6, 2.56 Beta1, 2.27 5ht1b, 2.09 Alpha1A


Since this one is a very potent 5HT2B agonist it can be usefull for preventing cardiovascular damage by other ergot derivatives too.

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#4 medievil

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Posted 18 May 2010 - 06:02 PM

Also appears to be a potent neuroprotectant.

Exp Neurol. 2003 Nov;184(1):530-5.
The dopamine receptor agonist lisuride attenuates iron-mediated dopaminergic neurodegeneration.
Double KL, Halliday GM, Henderson J, Griffiths FM, Heinemann T, Riederer P, Gerlach M.

Prince of Wales Medical Research Institute, 2031, Sydney, Australia. K.Double@unsw.edu.au
Abstract
Many dopamine agonists used in the treatment of Parkinson's disease are suggested to be potentially neuroprotective. On the basis of its structure, the dopamine agonist lisuride may share this characteristic. In the current study discrete asymptomatic lesions were produced by the injection of iron-laden neuromelanin into the rat substantia nigra and the animals treated with lisuride to determine the protective potential of this substance. Two treatment regimes were utilised. In the neuroprotective protocol, animals were treated with 0.1 mg.kg(-1) lisuride twice daily 3 days prior to, and 7 days following, the iron lesion. In the neurorescue protocol, the animals received 0.1 mg.kg(-1) lisuride twice daily for 1 week beginning on the fourth day post surgery. Eight weeks post surgery, tyrosine hydroxylase-positive neurons surrounding the injection site (33% of total nigral volume) were counted. Dopamine neuron number in iron-lesioned animals was reduced to 50% of that in vehicle-injected animals. The absence of motoric disturbances or a striatal dopamine deficit in these animals suggests a subclinical dopaminergic lesion. Dopamine neuron number in the quantified area in sham-injected animals receiving lisuride or iron-lesioned animals receiving lisuride in both the neuroprotection and neurorescue groups were not significantly reduced. These results suggest that lisuride can protect neurons against iron-induced cell death and might thus be neuroprotective in Parkinson's disease.


Imo this one easily blows prami away and does alot more, it's a very powerfull antidepressant/anxiolytic because of its potent 5HT1A agonism. Its anxiolytic as a whole and been shown to potently enhance other antidepressants. Prami was anxiogenic for a few ppl, this shouldnt be an issue with this one, i also beleive it would be a highly effective nootropic because of its high affinity for the D4 receptors.

Anyone up to give this one a try? Dont have enough money to order it atm but want to give it a try in the future.

Edited by medievil, 18 May 2010 - 06:03 PM.


#5 medievil

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Posted 25 May 2010 - 10:49 PM

Yet another bump:p but just came across this:

http://www.freepaten...m/4045562.html:

'Lisuride and the physiologically acceptable salts thereof are psychic energizers without simultaneously exhibiting the disadvantages (stimulating effect and development of dependency) of the phenylethylamine derivatives. There is a significant therapeutic effect in so-called neurasthenic symptomatology, mainly in the following symptoms: loss of interest, loss of drive and activity, loss of energy and functional capacity, loss of concentration and learning ability. They possess surprisingly high compatibility even at the large doses of this invention and there is no development of dependency, even after long-term administration at these large dosages.

The spectrum of psychic energizer activity, discovered with the aid of the quantitative Pharmaco-EEG, (T. M. Itil; Diseases of the Nervous System 8 (1972) 8) is novel and has not been found for another drug. The objective results are laid down in parameters of the EEG's analyzed by computer and the spectrum of effectiveness is characterized by a decrease of the delta and theta waves, and increase in the alpha and slow beta waves, as well as a decrease of the superimposed fast waves (up to 100/second). These phenomena affecting the physiology of the brain point to certain stimulating and simultaneously inhibiting effects exerted by lisuride. Accordingly, lisuride has a clinical spectrum of activity which can be called "Energizer Anxiolytic" (T. M. Itil et al., Int. J. Clin. Pharmacol. Ther. & Toxicol. 10[ 1974] 143).'

EXAMPLE A

Effect of high dosages of lisuride on geriatric patients with psychosomatic complaints and mental disturbances.

In an open pilot trial without any control drugs, the effect of lisuride has been studied in a group of 8 male and 6 female patients. The age range was 45-75 years. The diagnosis was based on rating scales and performance tests. Lisuride was given in a dosage of 500 μg daily for a period of 8 weeks. The results are based on the clinical rating scales and the performance tests. Lisuride acted as psychostimulant and neotropic agent in 6 out of the 8 male and in 5 out of the 6 female patients. The improved symptoms were memory and concentration, improvement in neuroticism, psychosomatic complaints and improvement in motoric and mental performance. There was no change in the laboratory control test from pre- to post-treatment and despite some nausea at the beginning of the treatment no remarkable side effects were observed.

The preceding examples can be repeated with similar success by substituting the generically and specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.


Edited by medievil, 25 May 2010 - 10:52 PM.


#6 xdopamine

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Posted 26 May 2010 - 11:40 AM

Wow, this sounds awesome! Do you any source? I might ask my doctor about it since I am suffering from RLS.

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#7 medievil

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Posted 26 May 2010 - 12:57 PM

Wow, this sounds awesome! Do you any source? I might ask my doctor about it since I am suffering from RLS.

Pharmacy escrow has it:
http://www.pharmacye...s-DOPERGIN.aspx

The patent describes:

This invention is based upon the discovery that patients as described above who respond poorly to lisuride therapy at conventional dosages, i.e., at a daily dosage of 1-300 μg., surprisingly respond in a satisfactory manner to such therapy at a daily dosage in excess thereof, viz., from 300 to 1,000 μg., preferably from 300 to 600 μg.

Lisuride was given in a dosage of 500 μg daily for a period of 8 weeks.


So 0.5mg seems to be the opimal ammount to take daily, its pretty expensive in that dose tough. Unless anyone else find a cheaper reliable source to order it from.

EDIT: I see you live in germany, if you can get it insured by a prescription that would be great.

Edited by medievil, 26 May 2010 - 01:04 PM.





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