A Prospective, Open-label, Exploratory Study to Investigate the Safety, Efficacy, and Haemodynamics of Lisuride Subcutaneous Infusion as Add-on to Conventional Treatment in Patients with Pulmonary Arterial Hypertension - Lis-Safe

Start Date07 Aug 2012

Sponsor / Collaborator

Sinoxa Pharma GmbH

NCT00408915

/ CompletedPhase 3

Double-blind, Placebo-controlled, Randomized, Multicentre Phase II/III Study to Evaluate the Efficacy and Safety of Lisuride, Applied Subcutaneously by Means of a Minipump in Patients With Advanced Parkinson's Disease Refractory to Conventional Oral Therapy

The aim of the study is to evaluate the long-term efficacy, local tolerability and safety of Lisuride applied as subcutaneous infusion compared to placebo in patients with advanced Parkinson's disease with motor fluctuations and "OFF" periods refractory to conventional treatment.

Start Date01 Jul 2006

Sponsor / Collaborator

axxonis Pharma AG

EUCTR2004-001589-42-AT

/ Unknown statusNot Applicable

Transdermal lisuride:Phase II/III study (efficacy and tolerance) of transdermal lisuride (patches) in patients with Restless Legs Syndrome (RLS)

Start Date25 Dec 2004

Sponsor / Collaborator-

100 Clinical Results associated with 5-HT1A receptor x D2 receptor x 5-HT2C receptor

100 Translational Medicine associated with 5-HT1A receptor x D2 receptor x 5-HT2C receptor

0 Patents (Medical) associated with 5-HT1A receptor x D2 receptor x 5-HT2C receptor

Literatures (Medical) associated with 5-HT1A receptor x D2 receptor x 5-HT2C receptor

03 Apr 2017·The World Journal of Biological PsychiatryQ3 · MEDICINE

Identification of 5-hydroxytryptamine receptor gene polymorphisms modulating hyperprolactinaemia in antipsychotic drug-treated patients with schizophrenia

Q3 · MEDICINE

Article

Author: Agarkov, Alexey A. ; Bokhan, Nikolay A. ; Osmanova, Diana Z. ; Wilffert, Bob ; Freidin, Maxim B. ; Ivanova, Svetlana A. ; Boiko, Anastasia S. ; Fedorenko, Olga Yu ; Loonen, Anton J.M. ; Semke, Arkadiy V. ; Pozhidaev, Ivan V.

OBJECTIVESHyperprolactinaemia (HPRL) is a classical side effect of antipsychotic drugs primarily attributed to blockade of dopamine D2 subtype receptors in the pituitary gland. Although dopamine is considered the primary factor inhibiting prolactin release, the activity of prolactin-producing lactotrophs is also regulated by the secretagogues thyrotrophin releasing hormone, vasoactive intestinal polypeptide and serotonin (5-hydroxytryptamine; 5-HT).METHODSWe describe the association between HPRL and a set of 29 SNPs from 5-HT receptor genes HTR1A, HTR1B, HTR2A, HTR2C, HTR3A, HTR3B and HTR6 in a population of 446 Caucasians (221 males/225 females) with a clinical diagnosis of schizophrenia (according to ICD-10: F20) who were treated with classical and/or atypical antipsychotic drugs.RESULTSNone of the studied autosomal markers were found to be associated with HPRL. However, a significant association was established between various HTR2C polymorphisms and HPRL.CONCLUSIONSThis study revealed an association between HPRL and X-chromosome haplotypes comprised of the rs569959 and rs17326429 polymorphisms.

01 Nov 2014·The International Journal of Neuropsychopharmacology

Editorial

Article

Author: Albert, Paul R

This issue of the Journal focuses on roles of the serotonin system and its receptors in mental illness and treatment responses. The brain serotonin system is implicated in a wide diversity of mood and emotional phenotypes, which raises the question of how a small group of neurons can influence so many processes (Jacobs and Azmitia, 1992). The answer lies in the extensive projections of serotonin neurons throughout the corticolimbic system and the variety of receptor and signaling mechanisms that mediate 5-HT actions at these target areas (Hoyer et al., 2002). The Ohmura (Ohmura et al., 2014) study provides evidence that optogenetic activation in mice of serotonin neurons to increase acutely 5-HT release leads to an immediate increase in anxiety-like behaviour in the elevated plus maze. Interestingly 5-HT release in the ventral hippocampus but not in the striatum, was associated with spatial anxiety. Most interestingly, activation of neurons located in the median but not dorsal raphe increased anxiety, consistent with strong projections of median raphe neurons to prefrontal cortex, amygdala and hippocampus (Bang et al., 2012). While an increase in 5-HT may elicit acute anxiety, acute treatment with SSRI can reverse depression-like phenotype in the forced swim test (FST) (Lucki et al., 2001). Tang et al., compared 4 different mice strains for their immobility time and response to SSRI in the FST and tail suspension test and found a correlation of antidepressant response with levels of 5-HT transporter (5-HTT) protein in ventral hippocampus. These results are consistent with the depressive phenotype and resistance to SSRI treatment that is associated with the 5-HTT s/s genotype in humans and primates that leads to lower levels of 5-HTT expression. How can we reconcile the differing effects of increased 5-HT activity on anxiety vs. anti-depressant response? This could be due to activity changes in dorsal vs. median raphe and differential activity of these projections in different brain targets such as hippocampus or prefrontal cortex. In addition, the actions of 5-HT depend on the repertoire of receptors expressed on target neurons such as pyramidal vs. interneurons (Albert et al., 2014; Varga et al., 2009). In human subjects, atypical antipsychotics such as quetiapine antagonize 5-HT2A receptors in addition to dopamine-D2 receptors, and have fewer extrapyramidal side effects but are associated with weight gain. Rasmussen et al., found a strong association between the level of cortical 5-HT2A binding potential in antipsychotic naive first episode schizophrenic patients and the extent of weight gain (average of 5 kg) produced by chronic 6-month quetiapine treatment. This result suggests a key role for 5-HT2A receptors in this adverse effect of quetiapine that may apply to other atypical antipsychotics that target 5-HT2A receptors. 5-HT2C receptors have been implicated in reducing cocaine reinstatement. Pockros-Burgess et al., show that pharmacological activation of 5-HT2C receptors in the central amygdala reduced cocaine reinstatement; while injection in the basolateral amygdala, an area implicated in fear memory, 5-HT2C agonist increased anxiety-like behavior in the elevated plus maze without affecting cocaine reinstatement. These studies show that activation of the same 5-HT receptor within different sub-regions within the same target (amygdala) can have very different behavioral outcomes. This suggests that differential regulation of 5-HT receptors in different brain areas may contribute to different behavioral phenotypes. In this light, Szewczyk et al., have examined the effects of four different chronic stress paradigms of depression-like behavior including olfactory bulbectomy, chronic mild stress, prenatal stress, and stress during pregnancy, on the levels of 5-HT1A receptors and its known transcriptional regulators (NUDR/Deaf1 and Freud-1) in prefrontal cortex and hippocampus. 5-HT1A receptors were generally down-regulated by stress, but the effect depended on the types of stress and the gender. In some cases, 5-HT1A regulation was compensated for by alterations in transcription factors, in some case it appeared to be driven by an increase in transcription factors, while in the hippocampus 5-HT1A down-regulation appeared to be post-transcriptional at the protein level. These studies illustrate the region and stress dependency of 5-HT receptor regulation that we are only beginning to understand. In summary, the studies demonstrate and exploit the remarkable brain region specificity of 5-HT projections and cell specificity of 5-HT receptors to modulate different behavioral outcomes. By specifically targeting 5-HT projections or specific 5-HT receptor subtypes or their long-term expression, it may be possible to design better more selective strategies to treat mental illness.

01 May 2012·Current Pharmaceutical BiotechnologyQ4 · MEDICINE

Serotonin Receptors as Targets for Drugs Useful to Treat Psychosis and Cognitive Impairment in Schizophrenia

Q4 · MEDICINE

Review

Author: M. Horiguchi ; B. W. Massey ; Herbert Y Meltzer

The concept that the efficacy of all antipsychotic drugs (APDs) can be explained by their action on dopamine (DA) D2 receptors is most challenged by drugs such as clozapine which target serotonin (5-HT)2A receptors as an essential component of their efficacy and tolerability. The 5-HT2A receptor, along with 5-HT1A, 5-HT 2C, 5-HT 6 or 5-HT 7 receptors, all of which are components of the mechanism of action of clozapine, represent important targets for treating multiple aspects of schizophrenia, especially psychosis and cognitive impairment. The class of atypical antipsychotic drugs (APDs), of which clozapine is the prototype, share in common more effective 5-HT 2A receptor inverse agonism and weaker interference with D2 receptor stimulation, either through D2 receptor blockade or partial D2 receptor agonism. This has led to development of a selective 5-HT2A antagonist, ACP-103 (pimavanserin), which has been found to be effective as monotherapy in L-DOPA psychosis and has promise as an add-on agent for sub-effective doses of atypical APDs. We review here the extensive preclinical evidence to support the importance of 5-HT2A receptor inverse agonism to the action of clozapine and related atypical APDs, and evidence supporting the potential of selective 5-HT2A, 5-HT 6 , and 5-HT 7, antagonists, 5-HT1A partial agonists and 5-HT2C agonists for development of drugs which ameliorate psychosis or cognitive impairment.

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