Lisuride

Abstract: Levodopa-induced dyskinesias (LID) in Parkinson's disease (PD) may be classified into three main categories: "On" dyskinesias, diphasic dyskinesias (DD), and "off" periods. The study of 168 parkinsonian patients showed that about half (n = 84) showed one pattern of LID only. A combination of two was present in 68, and 16 had the three presentation patterns. A fairly good correlation between type of dyskinesia and presentation pattern was established. Chorea, myoclonus, and dystonic movements occurred during the "on" period. Dystonic postures, particularly affecting the feet, were mainly present in the "off" period, but a few patients had a diphasic presentation. Repetitive stereotyped movements of the lower limbs always corresponded to DD. Acute pharmacological tests using dopamine agonists (subcutaneous apomorphine 3-8 mg; intravenous lisuride 0.1-0.15 mg) and dopamine antagonists (intravenous sulpiride 200-400 mg and intravenous chlorpromazine 25 mg) were performed in 40 patients. Dopamine agonists enhanced "on" dyskinesias and markedly reduced or abolished "off" period dystonia and DD. Dopamine antagonists reduced all types of LID but usually aggravated parkinsonism. These clinical and pharmacological results indicate that LID in PD are a heterogeneous phenomenon difficult to explain on the basis of a single pathophysiological mechanism.

Abstract: Extracellular single-cell recording and microiontophoretic techniques were used to characterize the presynaptic dopamine (DA) receptors (autoreceptors) on A10 DA neurons in the rat ventral tegmental area. Thus, the ability of various agonists to inhibit the activity of A10 DA neurons was compared. DA and the DA agonists N-n-propylnorapomorphine (NPA), apomorphine, lisuride, pergolide, LY141865 and bromocriptine all suppressed the activity of A10DA neurons. NPA was the most potent exogenous agonist, exerting effects that were similar to an equimolar concentration of DA (0.01 M). When ejected at equimolar concentrations (0.01 M) and equivalent ejection currents, the rank order of potency for these agonists was DA = NPA greater than LY141865 greater than pergolide = lisuride = apomorphine greater than norepinephrine greater than bromocriptine. The alpha-2 adrenoceptor agonist clonidine, the beta adrenoceptor agonist isoproterenol, the D-1 specific DA agonist SKF 38393 and the hallucinogenic ergot lysergic acid diethylamide exerted only weak effects or were inactive. The D-2 specific DA antagonist sulpiride completely blocked the rate-suppressant effects of DA and DA agonists but not those of gamma-aminobutyric acid. The purported D-1 specific DA antagonist SCH 23390 failed to block the effects of either DA or the D-2 specific DA agonist LY141865. These results indicate that DA agonists suppress the activity of the majority of A10 DA neurons by acting directly on somatodendritic DA autoreceptors which exhibit the pharmacological characteristics of D-2 receptors.

Abstract: On first picking up this book the response is likely to be similar to that of the child who was given a present of a book on penguins. When asked how she liked her present she replied "It was very nice but it told me more about penguins than I wanted to know". Who, one must ask, wants a book of 550 pages devoted to lisuride and other dopamine agonists? This book was compiled from the proceedings of a symposium held in West Berlin in December 1981. It suffers therefore from the disadvantages common to such compilations being at times repetitive with essentially similar work being presented by different groups of scientists; and in being somewhat patchy in its scope. There is also the inevitable criticism that much of the work presented in this way has already been superseded. Nevertheless there are some excellent things to be found in this volume. The main sections of the book are devoted to the endocrine pharmacology of dopamine agonists and the neurological pharmacology of these compounds. In the preliminary sections some aspects of receptor pharmacology are reported. The dopamine receptor is proving to be a highly variable and complex structure which responds slightly differently to each of the new dopaminergic ergot compounds. The chapter on oestrogens and dopamine receptor sensitivity provides a fascinating example of hormonal affects on brain neuronal mechanisms. The unusual pharmacokinetics of ergot compounds is explained and in particular their extensive metabolism during their initial passage through the liver. The section devoted to the neuroendocrine effects of dopaminergic agonists provides a comprehensive review of the subject. The place of these compounds in the treatment of prolactinomas, acromegaly, suppression of lactation, infertility and premenstrual tension is considered in detail by many of the leading workers in this field. It is no exaggeration to say that the management of patients with these conditions has been revolutionised by the introduction of compounds such as bromocriptine and lisuride and these chapters will provide an important source of references in the clinical management of patients with these conditions. The use of dopamine agonists other than levodopa in the treatment of Parkinsonism remains highly contentious. The wide variations in dose and response may relate partly to the complex pharmacokinetics already mentioned. Similarly their value appears to be their longer duration of action than levodopa so that in patients with marked fluctuations in response the addition of a dopamine agonist may be beneficial. It is clear, however, from reading these chapters that the aim must be to find more specific and better tolerated dopamine agonists which avoid the disadvantages of levodopa treatment and might therefore replace levodopa for primary treatment for Parkinson's disease. This book can only be recommended as a reference work. It will be used by pharmacologists needing a review of these compounds and their mode of action; and by clinicians looking for guidance in the treatment of their patients with Parkinson's disease and a wide variety of neuroendocrine disorders.

Abstract: Although certain antiparkinson agents interact with serotonin (5-HT) receptors, little information is available concerning functional actions. Herein, we characterized efficacies of apomorphine, bromocriptine, cabergoline, lisuride, piribedil, pergolide, roxindole, and terguride at human (h)5-HT(1A), h5-HT(1B), and h5-HT(1D) receptors [guanosine 5'-O-(3-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) binding], and at h5-HT(2A), h5-HT(2B), and h5-HT(2C) receptors (depletion of membrane-bound [(3)H]phosphatydilinositol). All drugs stimulated h5-HT(1A) receptors with efficacies (compared with 5-HT, 100%) ranging from modest (apomorphine, 35%) to high (cabergoline, 93%). At h5-HT(1B) receptors, efficacies varied from mild (terguride, 37%) to marked (cabergoline, 102%) and potencies were modest (pEC(50) values of 5.8-7.6): h5-HT(1D) sites were activated with a similar range of efficacies and greater potency (7.1-8.5). Piribedil and apomorphine were inactive at h5-HT(1B) and h5-HT(1D) receptors. At h5-HT(2A) receptors, terguride, lisuride, bromocriptine, cabergoline, and pergolide displayed potent (7.6-8.8) agonist properties (49-103%), whereas apomorphine and roxindole were antagonists and piribedil was inactive. Only pergolide (113%/8.2) and cabergoline (123%/8.6) displayed pronounced agonist properties at h5-HT(2B) receptors. At 5-HT(2C) receptors, lisuride, bromocriptine, pergolide, and cabergoline were efficacious (75-96%) agonists, apomorphine and terguride were antagonists, and piribedil was inactive. MDL100,907 and SB242,084, selective antagonists at 5-HT(2A) and 5-HT(2C) receptors, respectively, abolished these actions of pergolide, cabergoline, and bromocriptine. In conclusion, antiparkinson agents display markedly different patterns of agonist and antagonist properties at multiple 5-HT receptor subtypes. Although all show modest (agonist) activity at 5-HT(1A) sites, their contrasting actions at 5-HT(2A) and 5-HT(2C) sites may be of particular significance to their functional profiles in vivo.