The Role of Dopamine Agonists in Pituitary Adenomas.

Dopamine agonist therapy is the primary therapy for prolactin-secreting adenomas and usually results in normoprolactinemia, eugonadism, and tumor reduction. Cabergoline is superior to bromocriptine with regard to efficacy and tolerance. Withdrawal of cabergoline can be attempted in patients with normal prolactin levels on low doses of medication and evidence of radiographic tumor involution. Dopamine agonists have been used off label in patients with acromegaly, Cushing disease, and nonfunctioning adenomas. A trial of cabergoline monotherapy can be effective in patients with biochemically mild acromegaly. Cabergoline combination with somatostatin receptor ligands or pegvisomant improves insulin-like growth factor level 1 in majority of patients.

[Dopaminergic treatment in Parkinson's disease: what has each therapeutic family got to offer?]. / Tratamiento dopaminérgico en la enfermedad de Parkinson: ¿qué puede ofrecer cada familia terapéutica?

Different families of dopaminergic agents have allowed to increase the availability of dopamine within the central nervous system by different mechanisms of action. Each drug family has specific efficacious properties, as well as a different profile of adverse events. The knowledge in detail of these specificities is mandatory to avoid severe systemic or neuropsychiatric complications. Despite these limitations, the development of new drugs within the past 20 years has prolonged survival in Parkinson's disease, increasing the time with preserved daily day functionality compared with the levodopa era, when this drug was the only dopaminergic drug available. The correct combination of dopaminergic drugs with different mechanisms of action allows the management of Parkinson's disease motor symptoms within safety dose ranges, and up to day, this appears as the best algorithm to maintain functionality for longer periods of time.

TITLE: Tratamiento dopaminergico en la enfermedad de Parkinson: que puede ofrecer cada familia terapeutica?Diferentes familias de farmacos dopaminergicos han permitido aumentar el suministro de dopamina en el estriado por diferentes mecanismos. Cada familia de farmacos posee un grado de eficacia determinado, asi como un perfil de efectos secundarios especifico que debe conocerse en detalle para evitar complicaciones sistemicas y neuropsiquiatricas graves. A pesar de estas limitaciones, la disponibilidad de multiples farmacos ha permitido aumentar la supervivencia media en la enfermedad de Parkinson, con un periodo de funcionalidad en el dia a dia significativamente mas largo al que se conseguia cuando la levodopa era practicamente el unico farmaco disponible. La correcta adicion de farmacos dopaminergicos con diferentes mecanismos de accion permite tratar la enfermedad de Parkinson sin tener que llegar a dosis excesivamente altas de ninguno de ellos, lo que parece, en el momento actual, el mejor algoritmo para el control de los sintomas motores durante un periodo lo mas duradero posible.

The effect of dopamine partial agonists on the nicotine dependency in patients with schizophrenia.

OBJECTIVE: We compared the effects of haloperidol and three atypical antipsychotics (risperidone, olanzapine, and aripiprazole) on nicotine dependence in schizophrenic patients. METHODS: One hundred and thirty nine schizophrenic patients, who began using antipsychotic medication, were assessed for severity of nicotine dependence and for cigarette craving at baseline and following 8 weeks of treatment using the Fagerström Tolerance Questionnaire (FTQ) and a Likert-style, seven point, visual-analogue rating scale. RESULTS: Nicotine dependence increased in the haloperidol group, but not in atypical antipsychotics groups. Patients treated with aripiprazole showed a reduction both in nicotine dependence and cigarette craving. CONCLUSIONS: The effects of aripiprazole, a partial agonist of the dopamine D2 receptor, may reduce the severity of nicotine dependence in schizophrenic patients.

Dopamine agonists in the treatment of early Parkinson's disease: a meta-analysis.

Our objective was to perform a meta-analysis of randomized controlled trials of dopamine agonists (DA) as monotherapy as well as adjunctive therapy for the early treatment of Parkinson's disease (PD). A systematic literature search was conducted through April 2007. Both efficacy and safety endpoints were evaluated. DA monotherapy showed superior efficacy but more frequent adverse events compared to placebo. In addition, DA demonstrated inferior efficacy to levodopa, but was associated with fewer motor complications. However, DAs were associated with a greater incidence of nuisance side effects, such as hallucinations, somnolence and dizziness. The use of DA is an effective treatment option for the treatment of early PD and appears especially useful among PD patients with wearing-off phenomenon or dyskinesias on levodopa; however it may result in more adverse events and higher withdrawal rates.

Hiperprolactinemia en niños y adolescentes, conceptos e interrogantes actuales / Hyperprolactinemia in children and adolescents, current questions and concepts

La hiperprolactinemia constituye la alteración endocrina más común del eje hipotálamo-hipofisario, aunque su prevalencia en la población infantojuvenil no está aún claramente definida. Además de la Prolactina (PRL) nativa (23Kda), se han descripto numerosas variantes moleculares (PRL glicosilada, fosforilada, sulfatada, deaminada, BIG PRL, BIG BIG PRL, etc.), algunas de ellas con menor o ausente actividad biológica. El recién nacido presenta inmadurez fisiológica del eje prolactínico, alcanzando niveles de hasta 800 ng/mL en las primeras horas de vida. Posteriormente, cualquier proceso que interrumpa la secreción de dopamina, interfiera con su liberación hacia los vasos portales hipofisarios o bloquee los receptores dopaminérgicos de las células lactotróficas, puede causar hiperprolactinemia. La patología tumoral constituye el diagnóstico de mayor relevancia. Los prolactinomas poco frecuentes tienen, por su presentación clínica en niños y adolescentes, algunas características destacables. De acuerdo a nuestra experiencia, el retraso puberal puede observarse en aproximadamente el 50 % de las pacientes de sexo femenino y en más del 25 % de los varones. La mayor prevalencia de macroadenomas en varones coincide con los hallazgos en adultos y no dependería de un mayor retraso en el diagnóstico. En pacientes con hiperprolactinemia asintomática debe evaluarse la presencia de proporciones alteradas de isoformas de PRL. La cromatografía en columna con sephadex G100, la precipitación con suspensión de proteína A o con PEG y la ultracentrifugación constituyen los métodos más frecuentemente empleados para la detección de las distintas isoformas de PRL. En nuestra experiencia la B PRL constituyó el 6,6 - 32,6 % de la PRL total y la BB PRL constituyó el 40 y el 72 % de la misma en este grupo de pacientes. Por su efectividad y tolerancia, los agonistas dopaminérgicos constituyen la terapia inicial de elección en pacientes en edad pediátrica. La bromocriptina y la cabergolina han sido empleadas y con resultados similares a los de los pacientes adultos. La adquisición de nuevos conceptos y la mejor comprensión de la fisiología y la fisiopatología de los estados hiperprolactinémicos en niños y adolescentes, han modificado las alternativas diagnósticas y terapéuticas

Hyperprolactinemia is the most common endocrine alteration of the pituitary-hypothalamic axis, although its prevalence in the pediatric and adolescent population is not clearly defined yet. Apart from native (23Kda) Prolactin (PRL), many molecular variants (glycosylated, phosphorilated, sulphated, deaminated PRL, BIG PRL, BIG BIG PRL, etc) have been described, some of them with less or no biological activity. Newborns have physiological immaturity of the prolactin axis, attaining levels of as much as 800 ng/mL during the first hours after birth. Subsequently, any process that discontinues dopamine secretion, interferes with its secretion to the pituitary portal vessels or blocks dopaminergic receptors of lactotrophic cells, may cause hyperprolactinemia. Tumor disease is the major diagnosis. Prolactinomas, though rare, have some noticeable features, given their clinical presentation in children and adolescents. Based on our experience, pubertal delay occurs in approximately 50 % of females and in over 25 % of males. The larger prevalence of macroadenomas in males is consistent with findings in adults and would not be related to a later diagnosis. In patients with asymptomatic hyperprolactinemia, the presence of altered proportions of PRL isoforms should be evaluated. G100 Sephadex column chromatography, precipitation with a protein A suspension or PEG and ultracentrifugation, are the most common methods for detection of PRL isoforms. In our experience, B PRL accounted for 6.6 - 32.6 % of total PRL and BB PRL accounted for 40 to 72 % of total PRL in this group of patients. Because of their effectiveness and tolerance, dopaminergic agonists are the initial therapy of choice in pediatric age patients. Bromocriptine and cabergoline have been used with similar results to those obtained in adults. The new concepts gained and the better insight into the physiology and pathophysiology of hyperprolactinemic conditions in children and adolescents have brought about a change in diagnostic and therapeutic alternatives

Ergoline and non-ergoline derivatives in the treatment of Parkinson's disease.

There are a large variety of dopamine agonists available. Especially de novo patients are treated with dopamine agonists to avoid dyskinesia. Dopamine agonists can be subdivided into ergoline and non-ergoline derivatives. This distinction raises the question whether there are differences in the effects to treat symptoms, not only in the side effects between the individual dopamine agonists but also between these two groups. Pergolide is now considered a second line drug because of its particularly high tendency towards valvular heart disease. Some authors claim that all ergoline-derivatives may cause this problem, while own results do not necessarily support this view. We recommend performing echocardiography on those patients being treated with an ergot-derivative. New data support the view that all dopaminergic drugs may cause somnolence and that there is no preference for non-ergots. It may be that the number of gamblers is slightly higher among patients treated with pramipexole than in others. Dopamine agonists with a high affinity to D3 receptors have a good anti-anhedonic potency. In cell culture all dopamine agonists studied so far show neuroprotective properties in cell culture. The introduction of a slow-release formulation for ropinirole and the rotigotine and lisuride patches have opened new ways of continuous dopamine receptor stimulation. Taken together, dopamine agonists show individual properties and there are differences between ergot and non-ergot derivatives.

G-protein coupled receptors: SAR analyses of neurotransmitters and antagonists.

BACKGROUND: From the deductive point of view, neurotransmitter receptors can be divided into categories such as cholinergic (muscarinic, nicotinic), adrenergic (alpha- and beta-), dopaminergic, serotoninergic (5-HT1 approximately 5-HT5), and histaminergic (H1 and H2). Selective agonists and antagonists of each receptor subtype can have specific useful therapeutic applications. For understanding the molecular mechanisms of action, an inductive method of analysis is useful. OBJECTIVE: The aim of the present study is to examine the structure-activity relationships of agents acting on G-protein coupled receptors. METHOD: Representative sets of G-PCR agonists and antagonists were identified from the literature and Medline [P.M. Walsh (2003) Physicians' Desk Reference; M.J. O'Neil (2001) The Merck Index]. The molecular weight (MW), calculated logarithm of octanol/water partition coefficient (C log P) and molar refraction (CMR), dipole moment (DM), E(lumo) (the energy of the lowest unoccupied molecular orbital, a measure of the electron affinity of a molecule and its reactivity as an electrophile), E(homo) (the energy of the highest occupied molecular orbital, related to the ionization potential of a molecule, and its reactivity as a nucleophile), and the total number of hydrogen bonds (H(b)) (donors and receptors), were chosen as molecular descriptors for SAR analyses. RESULTS: The data suggest that not only do neurotransmitters share common structural features but their receptors belong to the same ensemble of G-protein coupled receptor with seven to eight transmembrane domains with their resultant dipoles in an antiparallel configuration. Moreover, the analysis indicates that the receptor exists in a dynamic equilibrium between the closed state and the open state. The energy needed to open the closed state is provided by the hydrolysis of GTP. A composite 3-D parameter frame setting of all the neurotransmitter agonists and antagonists are presented using MW, Hb and mu as independent variables. CONCLUSION: It appears that all neurotransmitters examined in this study operate by a similar mechanism with the G-protein coupled receptors.

Practice parameters for the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder.

Dopaminergic agents, particularly dopamine agonists, have been used with increasing frequency in the treatment of restless legs syndrome and periodic limb movement disorder. These evidence-based practice parameters are complementary to the Practice Parameters for the Treatment of Restless Legs Syndrome and Periodic Limb Movement Disorder, published in 1999. These practice parameters were developed by the Standards of Practice Committee and reviewed and approved by the Board of Directors of the American Academy of Sleep Medicine. Recommendations are based on the accompanying comprehensive review of the medical literature regarding the dopaminergic treatment of restless legs syndrome (RLS) and periodic limb movement disorder (PLMD), which was developed by a task force commissioned by the American Academy of Sleep Medicine. The following recommendations serve as a guide to the appropriate use of dopaminergic agents in the treatment of RLS and PLMD. Levodopa with decarboxylase inhibitor, and the dopaminergic agonists pergolide, pramipexole, and ropinirole are effective in the treatment of RLS and PLMD. Other dopamine agonists (talipexole, cabergoline, piribidel, and alpha-dihydroergocryptine) and the dopaminergic agents amantadine and selegiline may be effective in the treatment of RLS and PLMD, but the level of effectiveness of these medications is not currently established. Lastly, no specific recommendations can be made regarding dopaminergic treatment of children or pregnant women with RLS or PLMD.

Punding in Parkinson's disease: its relation to the dopamine dysregulation syndrome.

Punding is a term that was coined originally to describe complex prolonged, purposeless, and stereotyped behaviour in chronic amphetamine users. A structured interview of 50 patients with higher dopamine replacement therapy requirements (>800 levodopa equivalent units/day) from 123 unselected patients with Parkinson's disease (PD) from a PD clinic identified 17 (14%) patients with punding. Punding was acknowledged as disruptive and unproductive by the patients themselves, but forcible attempts by family to interrupt the behaviour led to irritability and dysphoria. Punding was associated with very high doses of dopamine replacement therapy often related to a pattern of chronic inappropriate overuse of dopaminergic medication. We believe that this is an underreported, socially disabling phenomenon that is commonly associated with the syndrome of dopamine dysregulation and is phenomenologically distinct from both obsessive-compulsive disorder and mania.

Role of dopamine receptor agonists in the treatment of restless legs syndrome.

The restless legs syndrome (RLS) is defined by four essential criteria obligatory for clinical diagnosis which were established, and recently revised, by the International RLS Study Group. These are (i) the urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs, which are (ii) worse during rest/inactivity, (iii) partially or totally relieved by movement and (iv) worse at night/in the evening. Treatment with levodopa leads to symptom relief, but augmentation (occurrence of symptoms before levodopa administration in the evening) may occur, limiting the long-term use of this drug. This article gives an overview of the treatment in general and the role of dopamine receptor agonists in the therapy of RLS and periodic limb movements (PLMs). Dopamine receptor agonists are widely used as an effective treatment for RLS and PLMs, presumably because of their longer half-lives, lower likelihood of augmentation and good tolerability compared with levodopa. It was shown that, for example, pergolide, ropinirole, pramipexole and cabergoline alleviated RLS symptoms in 70-90% of patients. A new non-oral (transdermal) formulation of one dopamine receptor agonist, rotigotine, has recently been developed and shown to be efficacious in RLS. Further research should focus on long-term observations and comparisons of different dopamine receptor agonists in RLS.

Dopaminergic modulation of behavioral states in mesopontine tegmentum: a reverse microdialysis study in freely moving cats.

STUDY OBJECTIVES: We investigated the role of dopamine (DA) in behavioral state control and, in particular, paradoxical (or rapid eye movement) sleep (PS) generation in mesopontine structures. DESIGN: Reverse microdialysis and polygraphic recordings in freely moving cats were used to assess the effects on sleep-wake states of applied DA and monoaminergic agonists and antagonists. SETTINGS: NA. PATIENTS OR PARTICIPANTS: NA. INTERVENTION: NA. MEASUREMENTS AND RESULTS: Quantitative and qualitative analysis of behavioral states and electroencephalogram showed that DA had no significant effect when applied to any part of the mesopontine tegmentum, except the peri-locus coeruleus alpha, a region located just ventromedial to the locus coeruleus, pars alpha, and critically implicated in PS generation. In this structure, DA caused a selective and dose-dependent inhibition of PS and induced PS without atonia. These effects were not mimicked by SKF-81297, a selective D1-like agonist, or selective D2-like agonists such as quinelorane, quinpirole, and 7-OH-DPAT. Instead, D2-like agonists induced a significant decrease in wakefulness and increases in both slow-wave sleep and PS. The effects of DA were mimicked, however, by application of clonidine, a selective alpha2 adrenoceptor agonist, and blocked by co-application of RX821002, a selective antagonist of alpha2 adrenoceptors. CONCLUSIONS: Our results indicate that DA inhibits PS in the peri-locus coeruleus alpha via excitation of alpha2 adrenoceptors, but application of D2-like agonists to the same region markedly decreases wakefulness and increases both slow-wave sleep and PS. This effect may be responsible for the excessive daytime sleepiness and sleep attacks induced by antiparkinsonian dopaminergic agents.

[Dopamine receptor agonists in treatment of outpatient patients with Parkinson's disease]. / Opyt ispol'zovaniia agonistov dofaminovykh retseptorov v ambulatornom lechenii bolezni Parkinsona.

The paper summarized an experience of pronoran (piribedil) treatment of 516 patients with Parkinson's disease (primary parkinsonism) conducted in the district outpatient clinics of 7 Moscow administrative areas. In 84 cases, the medication was used as a monotherapy and in 432--in combination with levodopa-contained drug madopar. An improvement of patient's state, with reducing of bradikinesia, tremor and rigidity, was achieved in 73.0 +/- 20.4% of the patients. Combined therapy allowed decreasing of madopar dosage in 58.5 +/- 16.7% of the patients. Pronoran (piribedil) is well tolerated. The authors recommend it for the treatment of outpatients with Parkinson's disease.

Nonlinear analysis of partial dopamine agonist effects on cAMP in C6 glioma cells.

Most drugs have some efficacy so that improved methods to determine the relative intrinsic efficacy of partial agonists should be of benefit to preclinical and clinical investigators. We examined the effects of partial D(1) or partial D(2) dopamine agonists using a partial agonist interaction model. The dependent variable was the modulation of the dopamine-receptor-mediated cAMP response in C6 glioma cells selectively and stably expressing either D(1) or D(2) recombinant dopamine receptors. The dissociation constant (K(B)) and relative intrinsic efficacy (E(r)) for each partial agonist were calculated using a partial agonist interaction null model in which the effects of fixed concentrations of each partial agonist on the dopamine dose-response curve were evaluated. This model is an extension of the competitive antagonist null model to drugs with efficacy and assumes only that the log-dose--response curve is monotonic. Generally, the partial agonist interaction model fit the data, as well as fits of the independent logistic curves. Furthermore, the partial agonist K(B) values could be shared across partial agonist concentrations without worsening the model fit (by increasing the residual variance). K(B) values were also similar to drug affinities reported in the literature. The model was validated in three ways. First, we assumed a common tissue stimulus parameter (beta) and calculated the E(r) values. This provided a qualitative check on the interaction model results. Second, we calculated new relative efficacy values, E(r)(beta), using the beta estimate. Third, we calculated relative efficacy using relative maxima times midpoint shift ratios (J. Theor. Biol. 198 (1999) 347.). All three methods indicated that the present model yielded reasonable estimates of affinity and relative efficacy for the set of compounds studied. Our results provide a quick and convenient method of quantification of partial agonist efficacy. Special applications and limitations of the model are discussed. In addition, the present results are the first report of the relative intrinsic efficacy values for this set of D(2) ligands.

Behavioral responsitivity to dopamine receptor agonists after extensive striatal dopamine lesions during development.

Dopamine (DA) receptor responsitivity was investigated in adult rats that received intrastriatal (i.s.) injections of 6-OHDA (20 micrograms per striatum) on day of birth or postnatal Day 1 (Day 0/Day 1). Neonatally lesioned rats exhibited self-biting behavior and increases in stereotypic gnawing following treatment with the mixed D1/D2 receptor agonist apomorphine (0.32-3.2 mg/kg) or the D1-like receptor agonist SKF38393 (10 mg/kg). Increases in locomotor activity, rearing, and paw treading were also observed in the lesioned rats after SKF38393 (1-10 mg/kg) treatment. The incidences of the prototypical D1 receptor-mediated behaviors, grooming and abnormal perioral movements (i.e., oral dyskinesias) were not increased in the lesioned rats. However, the low dose (0.32 mg/kg) of apomorphien as well as all doses of the D2-like receptor agonist quinpirole (0.32-3.2 mg/kg) induced grooming in the lesioned rats, which was not observed in nonlesioned control rats. Autoradiographs of [3H]mazindol binding to high affinity DA uptake sites revealed an extensive loss of DA terminals in the striata of the neonatally lesioned rats. These data suggest that near-total (> or = 95%) DA depletions on Day 0/Day 1 result in long-term alterations in the functional sensitivity of DA receptors, as well as possible changes in the interactions between D1 and D2 receptors. Comparisons of these results with those seen following lesions of the early-developing DA system ("patch-selective" lesions) and lesions made at other time points will be discussed.

Discriminating D1 and D2 agonists with a hydrophobic similarity index.

Currently, methods for calculating molecular similarity indices have been developed for comparing steric, charge density, and molecular electrostatic potential (MEP) properties. Much of the existing technology may, however, be applied to the quantitative comparison of molecular hydrophobicities. In this article we present an empirical hydrophobic similarity index. We utilize atomic hydrophobic parameters derived from a quantum mechanical semiempirical wavefunction. Hydrophobicity at points on a grid is computed with a recently introduced "molecular lipophilicity potential." The overlap of pairs of molecules is calculated with the metric introduced by Carbó. This approach is applied to a case in which steric and electrostatic criteria have already been shown to be inadequate in rationalizing selectivity, namely, requirements for recognition at the dopamine D1 and D2 receptors. We demonstrate that, for a set of dopamine agonists, D1 ligands show higher similarity in this property that D2 analogs. This indicator of similarity is more successful at accounting for D1 selectivity than previous methods.