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Dusan Sket - One of the best experts on this subject based on the ideXlab platform.
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Ergoline Derivative lek 8829 induced turning behavior in rats with unilateral striatal ibotenic acid lesions interaction with bromocriptine
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: Lilijana Sprah, Marko Zivin, Dusan SketAbstract:LEK-8829 [9,10-didehydro- N -methyl-(2-propynyl)-6-methyl-8-aminomethylErgoline bimaleinate] is an antagonist of dopamine D 2 receptors and serotonin (5-HT) 2 and 5-HT 1A receptors in intact animals and a D 1 receptor agonist in dopamine-depleted animals. In the present study, we used rats with unilateral striatal lesions with ibotenic acid (IA) to investigate the dopamine receptor activities of LEK-8829 in a model with innervated dopamine receptors. The IA-lesioned rats circled ipsilaterally when challenged with apomorphine, the mixed agonist on D 1 /D 2 receptors. LEK-8829 induced a dose-dependent contralateral turning that was blocked by D 1 receptor antagonist SCH-23390. The treatment with D 1 receptor agonist SKF-82958 induced ipsilateral turning, whereas the treatment with D 2 receptor antagonist haloperidol induced contralateral posture. The combined treatment with SKF-82958 and haloperidol resulted in a weak contralateral turning, indicating the possible receptor mechanism of contralateral turning induced by LEK-8829. Bromocriptine induced a weak ipsilateral turning that was blocked by haloperidol. The ipsilateral turning induced by bromocriptine was significantly potentiated by the coadministration of a low dose but not by a high dose of LEK-8829. The potentiation of turning was blocked either by SCH-23390 or by haloperidol. The potentiation of ipsilateral turning suggests the costimulation of D 2 and D 1 receptors by bromocriptine and LEK-8829, respectively, whereas the lack of potentiation by the highest dose of LEK-8829 may be explained by the opposing activity of LEK-8829 and bromocriptine at D 2 receptors. We propose that the D 2 and 5HT 2 receptor-blocking and D 1 receptor-stimulating profile of LEK-8829 is promising for the treatment of negative symptoms of schizophrenia.
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the d1 receptor mediated effects of the Ergoline Derivative lek 8829 in rats with unilateral 6 hydroxydopamine lesions
British Journal of Pharmacology, 1996Co-Authors: Marko Zivin, Lilijana Sprah, Dusan SketAbstract:1 Previous experiments have suggested a potential atypical antipsychotic activity of the Ergoline Derivative LEK-8829. In vitro experiments showed a high affinity to 5-HT1A, 5-HT2 and D2 receptors (the ratio of pKi values 5-HT2/D2 = 1.11) and a moderate affinity to D1 receptors. In vivo experiments showed antagonism of dopamine and 5-hydroxytryptamine (5-HT) receptor-linked behaviours. 2 In the present study, the rats with unilateral dopaminergic deafferentation of the striatum, induced by the lesion of the median forebrain bundle with 6-hydroxydopamine (6-OHDA), were used to determine the effects of LEK-8829 on turning behaviour and on striatal c-fos mRNA levels. 3 The administration of LEK-8829 induced a long lasting contralateral turning behaviour that was dose-dependent. It was found that the specific D1 receptor antagonist SCH-23390 but not the D2 receptor antagonist haloperidol or 5-HT1A antagonist pindolol, dose-dependently inhibited the turning behaviour induced by LEK–8829. 4 In an attempt to clarify the D1:D2 receptor interactions involved in the action of LEK-8829 in the 6-OHDA model, we used in situ hybridization histochemistry to compare the effect of SCH-23390 pretreatment on striatal c-fos mRNA expression induced either by LEK-8829 or by the typical antipsychotic haloperidol. 5 LEK-8829 induced a bilateral striatal c-fos mRNA expression that was significantly higher in the denervated striatum as compared to the intact striatum and was completely blocked on both sides by pretreatment with SCH-23390. In contrast, haloperidol-induced striatal c-fos mRNA expression was limited to the innervated striatum and was not blocked by SCH-23390. 6 Our data demonstrate an intrinsic activity of LEK-8829 on D1 receptors that is potentiated in the dopamine-depleted striatum. We conclude, therefore, that the putative atypical antipsychotic LEK-8829 may prove useful as an experimental tool for the study of D1:D2 receptor interactions and could have beneficial effects in the treatment of drug-induced psychosis in patients with Parkinson's disease.
Kevin B Donnelly - One of the best experts on this subject based on the ideXlab platform.
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cardiac valvular pathology comparative pathology and animal models of acquired cardiac valvular diseases
Toxicologic Pathology, 2008Co-Authors: Kevin B DonnellyAbstract:Recent voluntary withdrawal of the Ergoline-Derivative Alzheimers’ drug Pergolide (Permax) resulting from demonstrated risk of cardiac valve injury illustrates the increased importance of valve injury in pharmaceutical toxicology. Following the 2001 landmark discovery of cardiac valve injury associated with the widely prescribed anti-obesity drug combination fenfluramine-phentermine, and subsequent withdrawal, the need to understand and assess cardiac valve biology and pathology both preclinically and clinically has been accentuated. Unique aspects of the developmental biology, anatomy, and physiology of cardiac valves compared to main cardiac tissue have been discovered, and key elements of the pathophysiology of various valvular injury mechanisms have been described. Although general clinical cardiac valvular disease in humans has been well characterized, animal modeling of valvular injury has proved to be difficult and undersubscribed. Additionally, both the preclinical, pharmaceutical, toxicologic ass...
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cardiac valvular pathology comparative pathology and animal models of acquired cardiac valvular diseases
Toxicologic Pathology, 2008Co-Authors: Kevin B DonnellyAbstract:Recent voluntary withdrawal of the Ergoline-Derivative Alzheimers' drug Pergolide (Permax) resulting from demonstrated risk of cardiac valve injury illustrates the increased importance of valve injury in pharmaceutical toxicology. Following the 2001 landmark discovery of cardiac valve injury associated with the widely prescribed anti-obesity drug combination fenfluramine-phentermine, and subsequent withdrawal, the need to understand and assess cardiac valve biology and pathology both preclinically and clinically has been accentuated. Unique aspects of the developmental biology, anatomy, and physiology of cardiac valves compared to main cardiac tissue have been discovered, and key elements of the pathophysiology of various valvular injury mechanisms have been described. Although general clinical cardiac valvular disease in humans has been well characterized, animal modeling of valvular injury has proved to be difficult and undersubscribed. Additionally, both the preclinical, pharmaceutical, toxicologic assessment of valvular injury and the understanding of species-comparative valvular pathology have been limited. As discoveries and awareness grows, the purpose of this paper is to review the structure and function of cardiac valves, mechanisms, and outcomes of the common acquired human cardiac valve diseases, including those that are drug-related; to summarize comparative laboratory animal valvular pathology; and to review the literature of contemporary animal models of valvular injury.
Jeanlouis Montastruc - One of the best experts on this subject based on the ideXlab platform.
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the long acting dopamine receptor agonist cabErgoline in early parkinson s disease final results of a 5 year double blind levodopa controlled study
CNS Drugs, 2004Co-Authors: F Bracco, Angelo Battaglia, Carlos Chouza, Erik Dupont, Oscar S Gershanik, Jose Felix Marti Masso, Jeanlouis MontastrucAbstract:Objectives: CabErgoline is an Ergoline Derivative with a very long half-life that allows once-daily administration and the potential for more continuous stimulation of dopaminergic receptors than is possible with other dopamine receptor agonists (DAs). The aim of this study was to evaluate whether the possible advantage resulting from a more sustained dopaminergic effect of cabErgoline would translate into delayed onset of motor complications, compared with levodopa, in patients with newly diagnosed Parkinson’s disease.
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the long acting dopamine receptor agonist cabErgoline in early parkinson s disease final results of a 5 year double blind levodopa controlled study
CNS Drugs, 2004Co-Authors: F Bracco, Angelo Battaglia, Carlos Chouza, Erik Dupont, Oscar S Gershanik, Jose Felix Marti Masso, Jeanlouis MontastrucAbstract:Objectives: CabErgoline is an Ergoline Derivative with a very long half-life that allows once-daily administration and the potential for more continuous stimulation of dopaminergic receptors than is possible with other dopamine receptor agonists (DAs). The aim of this study was to evaluate whether the possible advantage resulting from a more sustained dopaminergic effect of cabErgoline would translate into delayed onset of motor complications, compared with levodopa, in patients with newly diagnosed Parkinson’s disease. Study design and methods: This study was a double-blind, multicentre trial that compared cabErgoline and levodopa as initial therapy for Parkinson’s disease. A total of 419 levodopa-, DA-and selegiline-naive patients with newly diagnosed Parkinson’s disease were randomised to receive either cabErgoline (n = 211) or levodopa (n = 209). Treatment was titrated to an optimal dose over a period of up to 24 weeks and then continued at this dose until the study endpoint (confirmed motor complications) or up to a maximum of 5 years. At years 1–5, the cabErgoline group was receiving cabErgoline at average daily doses ranging from 2.8–2.9mg, with added levodopa at mean daily doses ranging from 322mg at year 1 to 431mg at year 5; over the same period, the levodopa group was receiving daily levodopa doses of 784mg. Thus, patients in the cabErgoline group received >50% levodopa than patients in the levodopa group. Results: Motor complications were significantly delayed (p = 0.0175) and occurred less frequently in cabErgoline-treated patients than in levodopa-treated patients (22.3% vs 33.7%). Cox model proportional hazards regression analysis showed that the relative risk of developing such complications was >50% lower (0.46; p < 0.001) in the cabErgoline group compared with the levodopa group. In particular, development of dyskinesias was markedly delayed in the cabErgoline group and occurred in 9.5% of patients compared with 21.2% in the levodopa group (p < 0.001). Among patients not requiring supplemental levodopa, the frequency of motor complications was three times higher with levodopa (15.5% of 110 patients) than with cabErgoline (5.3% of 76 patients). Among patients who did need supplemental levodopa, motor complications were more frequent in the levodopa arm (54.1% of 98 patients) than in the cabErgoline arm (31.9% of 135 patients). Consistent improvements relative to baseline in average Unified Parkinson’s Disease Rating Scale (UPDRS) daily living activities and motor function sections, and in Clinical Global Impression severity of illness and physician-and patient-rated global improvement scores, were seen in both treatment groups, with maximal effects occurring within 2 years. However, levodopa treatment was associated with a significantly (p < 0.001) greater improvement in motor disability (as measured by the UPDRS motor score) over time, with mean values of 13.8 versus 12.9 in the cabErgoline versus levodopa arm recorded at 1 year, 18.6 versus 17.2 at 3 years and 19.2 versus 16.3 at 5 years, respectively. While the overall frequency of adverse events was similar in the two groups, the cabErgoline-treated group experienced marginally, but not significantly, higher frequencies of nausea, vomiting, dyspepsia and gastritis (37.4% vs 32.2% in the levodopa group) and of dizziness and postural hypotension (31.3% vs 24% in the levodopa group). CabErgoline-treated patients also experienced a significantly higher frequency of peripheral oedema (16.1% vs 3.4%, respectively; p < 0.0001). The cabErgoline and levodopa groups had similar rates of sleepiness (17.5% vs 18.3%, respectively) and hallucinations (4.8% vs 4.4%, respectively); in an elderly population subset, hallucinations were reported in 7.1% and 6.5% of patients taking cabErgoline and levodopa, respectively. Adverse events generally occurred more frequently in female patients (with the exception of dyskinesias, hyperkinesias and hallucinations, which occurred more frequently in men) and in the elderly. Conclusion: This study showed that, compared with levodopa, initial therapy with cabErgoline in patients with Parkinson’s disease is associated with a lower risk of response fluctuations at the cost of a marginally reduced symptomatic improvement and some tolerability disadvantages that are mostly limited to a significantly higher frequency of peripheral oedema.
Marko Zivin - One of the best experts on this subject based on the ideXlab platform.
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Ergoline Derivative lek 8829 induced turning behavior in rats with unilateral striatal ibotenic acid lesions interaction with bromocriptine
Journal of Pharmacology and Experimental Therapeutics, 1999Co-Authors: Lilijana Sprah, Marko Zivin, Dusan SketAbstract:LEK-8829 [9,10-didehydro- N -methyl-(2-propynyl)-6-methyl-8-aminomethylErgoline bimaleinate] is an antagonist of dopamine D 2 receptors and serotonin (5-HT) 2 and 5-HT 1A receptors in intact animals and a D 1 receptor agonist in dopamine-depleted animals. In the present study, we used rats with unilateral striatal lesions with ibotenic acid (IA) to investigate the dopamine receptor activities of LEK-8829 in a model with innervated dopamine receptors. The IA-lesioned rats circled ipsilaterally when challenged with apomorphine, the mixed agonist on D 1 /D 2 receptors. LEK-8829 induced a dose-dependent contralateral turning that was blocked by D 1 receptor antagonist SCH-23390. The treatment with D 1 receptor agonist SKF-82958 induced ipsilateral turning, whereas the treatment with D 2 receptor antagonist haloperidol induced contralateral posture. The combined treatment with SKF-82958 and haloperidol resulted in a weak contralateral turning, indicating the possible receptor mechanism of contralateral turning induced by LEK-8829. Bromocriptine induced a weak ipsilateral turning that was blocked by haloperidol. The ipsilateral turning induced by bromocriptine was significantly potentiated by the coadministration of a low dose but not by a high dose of LEK-8829. The potentiation of turning was blocked either by SCH-23390 or by haloperidol. The potentiation of ipsilateral turning suggests the costimulation of D 2 and D 1 receptors by bromocriptine and LEK-8829, respectively, whereas the lack of potentiation by the highest dose of LEK-8829 may be explained by the opposing activity of LEK-8829 and bromocriptine at D 2 receptors. We propose that the D 2 and 5HT 2 receptor-blocking and D 1 receptor-stimulating profile of LEK-8829 is promising for the treatment of negative symptoms of schizophrenia.
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the d1 receptor mediated effects of the Ergoline Derivative lek 8829 in rats with unilateral 6 hydroxydopamine lesions
British Journal of Pharmacology, 1996Co-Authors: Marko Zivin, Lilijana Sprah, Dusan SketAbstract:1 Previous experiments have suggested a potential atypical antipsychotic activity of the Ergoline Derivative LEK-8829. In vitro experiments showed a high affinity to 5-HT1A, 5-HT2 and D2 receptors (the ratio of pKi values 5-HT2/D2 = 1.11) and a moderate affinity to D1 receptors. In vivo experiments showed antagonism of dopamine and 5-hydroxytryptamine (5-HT) receptor-linked behaviours. 2 In the present study, the rats with unilateral dopaminergic deafferentation of the striatum, induced by the lesion of the median forebrain bundle with 6-hydroxydopamine (6-OHDA), were used to determine the effects of LEK-8829 on turning behaviour and on striatal c-fos mRNA levels. 3 The administration of LEK-8829 induced a long lasting contralateral turning behaviour that was dose-dependent. It was found that the specific D1 receptor antagonist SCH-23390 but not the D2 receptor antagonist haloperidol or 5-HT1A antagonist pindolol, dose-dependently inhibited the turning behaviour induced by LEK–8829. 4 In an attempt to clarify the D1:D2 receptor interactions involved in the action of LEK-8829 in the 6-OHDA model, we used in situ hybridization histochemistry to compare the effect of SCH-23390 pretreatment on striatal c-fos mRNA expression induced either by LEK-8829 or by the typical antipsychotic haloperidol. 5 LEK-8829 induced a bilateral striatal c-fos mRNA expression that was significantly higher in the denervated striatum as compared to the intact striatum and was completely blocked on both sides by pretreatment with SCH-23390. In contrast, haloperidol-induced striatal c-fos mRNA expression was limited to the innervated striatum and was not blocked by SCH-23390. 6 Our data demonstrate an intrinsic activity of LEK-8829 on D1 receptors that is potentiated in the dopamine-depleted striatum. We conclude, therefore, that the putative atypical antipsychotic LEK-8829 may prove useful as an experimental tool for the study of D1:D2 receptor interactions and could have beneficial effects in the treatment of drug-induced psychosis in patients with Parkinson's disease.
Angelo Battaglia - One of the best experts on this subject based on the ideXlab platform.
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the long acting dopamine receptor agonist cabErgoline in early parkinson s disease final results of a 5 year double blind levodopa controlled study
CNS Drugs, 2004Co-Authors: F Bracco, Angelo Battaglia, Carlos Chouza, Erik Dupont, Oscar S Gershanik, Jose Felix Marti Masso, Jeanlouis MontastrucAbstract:Objectives: CabErgoline is an Ergoline Derivative with a very long half-life that allows once-daily administration and the potential for more continuous stimulation of dopaminergic receptors than is possible with other dopamine receptor agonists (DAs). The aim of this study was to evaluate whether the possible advantage resulting from a more sustained dopaminergic effect of cabErgoline would translate into delayed onset of motor complications, compared with levodopa, in patients with newly diagnosed Parkinson’s disease. Study design and methods: This study was a double-blind, multicentre trial that compared cabErgoline and levodopa as initial therapy for Parkinson’s disease. A total of 419 levodopa-, DA-and selegiline-naive patients with newly diagnosed Parkinson’s disease were randomised to receive either cabErgoline (n = 211) or levodopa (n = 209). Treatment was titrated to an optimal dose over a period of up to 24 weeks and then continued at this dose until the study endpoint (confirmed motor complications) or up to a maximum of 5 years. At years 1–5, the cabErgoline group was receiving cabErgoline at average daily doses ranging from 2.8–2.9mg, with added levodopa at mean daily doses ranging from 322mg at year 1 to 431mg at year 5; over the same period, the levodopa group was receiving daily levodopa doses of 784mg. Thus, patients in the cabErgoline group received >50% levodopa than patients in the levodopa group. Results: Motor complications were significantly delayed (p = 0.0175) and occurred less frequently in cabErgoline-treated patients than in levodopa-treated patients (22.3% vs 33.7%). Cox model proportional hazards regression analysis showed that the relative risk of developing such complications was >50% lower (0.46; p < 0.001) in the cabErgoline group compared with the levodopa group. In particular, development of dyskinesias was markedly delayed in the cabErgoline group and occurred in 9.5% of patients compared with 21.2% in the levodopa group (p < 0.001). Among patients not requiring supplemental levodopa, the frequency of motor complications was three times higher with levodopa (15.5% of 110 patients) than with cabErgoline (5.3% of 76 patients). Among patients who did need supplemental levodopa, motor complications were more frequent in the levodopa arm (54.1% of 98 patients) than in the cabErgoline arm (31.9% of 135 patients). Consistent improvements relative to baseline in average Unified Parkinson’s Disease Rating Scale (UPDRS) daily living activities and motor function sections, and in Clinical Global Impression severity of illness and physician-and patient-rated global improvement scores, were seen in both treatment groups, with maximal effects occurring within 2 years. However, levodopa treatment was associated with a significantly (p < 0.001) greater improvement in motor disability (as measured by the UPDRS motor score) over time, with mean values of 13.8 versus 12.9 in the cabErgoline versus levodopa arm recorded at 1 year, 18.6 versus 17.2 at 3 years and 19.2 versus 16.3 at 5 years, respectively. While the overall frequency of adverse events was similar in the two groups, the cabErgoline-treated group experienced marginally, but not significantly, higher frequencies of nausea, vomiting, dyspepsia and gastritis (37.4% vs 32.2% in the levodopa group) and of dizziness and postural hypotension (31.3% vs 24% in the levodopa group). CabErgoline-treated patients also experienced a significantly higher frequency of peripheral oedema (16.1% vs 3.4%, respectively; p < 0.0001). The cabErgoline and levodopa groups had similar rates of sleepiness (17.5% vs 18.3%, respectively) and hallucinations (4.8% vs 4.4%, respectively); in an elderly population subset, hallucinations were reported in 7.1% and 6.5% of patients taking cabErgoline and levodopa, respectively. Adverse events generally occurred more frequently in female patients (with the exception of dyskinesias, hyperkinesias and hallucinations, which occurred more frequently in men) and in the elderly. Conclusion: This study showed that, compared with levodopa, initial therapy with cabErgoline in patients with Parkinson’s disease is associated with a lower risk of response fluctuations at the cost of a marginally reduced symptomatic improvement and some tolerability disadvantages that are mostly limited to a significantly higher frequency of peripheral oedema.
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the long acting dopamine receptor agonist cabErgoline in early parkinson s disease final results of a 5 year double blind levodopa controlled study
CNS Drugs, 2004Co-Authors: F Bracco, Angelo Battaglia, Carlos Chouza, Erik Dupont, Oscar S Gershanik, Jose Felix Marti Masso, Jeanlouis MontastrucAbstract:Objectives: CabErgoline is an Ergoline Derivative with a very long half-life that allows once-daily administration and the potential for more continuous stimulation of dopaminergic receptors than is possible with other dopamine receptor agonists (DAs). The aim of this study was to evaluate whether the possible advantage resulting from a more sustained dopaminergic effect of cabErgoline would translate into delayed onset of motor complications, compared with levodopa, in patients with newly diagnosed Parkinson’s disease.
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NicErgoline in Dementia
CNS Drugs, 2000Co-Authors: Bengt Winblad, Nicola Carfagna, Eric H. F. Wong, Bianca M Rossini, Luisa Bonura, Angelo BattagliaAbstract:NicErgoline is a semisynthetic Ergoline Derivative indicated for the treatment of cognitive impairment in various forms of dementia. It is currently available for use in Italy and some other European countries, in Latin America and the Near and Far East. In animal studies nicErgoline exhibits a broad spectrum of actions on cellular and molecular mechanisms involved in the pathophysiology of dementia. NicErgoline appears to enhance cholinergic and catecholaminergic neurotransmitter function and improve related cognitive deficits; stimulate phosphoinositide turnover; modulate protein kinase C (PKC) translocation and PKC-mediated α-secretase processing of amyloid precursor protein; increase regional cerebral blood flow, and glucose uptake and utilisation; activate protein synthesis; protect neurons from death induced by oxidative stress or apoptosis; and interact with endogenous nerve growth factor-mediated processes providing trophic support to cholinergic neurons. Whether these actions are interrelated or represent multiple, unrelated effects is still unknown, but all may be relevant to the therapeutical use of the drug. Recent double-blind, placebo-controlled, randomised clinical studies of up to 12 months’ duration indicated a measurable effect of nicErgoline on cognitive performance in patients with dementing illnesses. Medium and long term treatment resulted in significantly greater cognitive improvement or less decline than placebo as measured by Mini-Mental State Examination (MMSE) or Alzheimer’s Disease Assessment Scale — Cognitive Subscale (ADAS-cog) scores. While deterioration represents the natural course of the disease, nicErgoline-treated patients improved or maintained their previous clinical status. The objective improvement of the cognitive symptoms was paralleled by a stabilised or improved clinical global condition as evaluated by clinicians, caregivers and patients. NicErgoline was well tolerated in all clinical studies. The type, frequency and severity of adverse events were generally comparable with those observed in the placebo control groups. No clinically or statistically significant changes in vital signs and laboratory evaluations were reported, except for an asymptomatic increase of serum uric acid levels. Overall, data strongly support the hypothesis that nicErgoline might interfere with fundamental molecular mechanisms underlying cognitive processes in vivo. The clinical results also indicate that nicErgoline is a well tolerated and effective treatment that improves cognitive and global functions in patients with mild to moderate dementia.