Comparative study on the metabolism of the ergot alkaloids ergocristine, ergocryptine, ergotamine, and ergovaline in equine and human S9 fractions and equine liver preparations.

1. Ergopeptine alkaloids like ergovaline and ergotamine are suspected to be associated with fescue toxicosis and ergotism in horses. Information on the metabolism of ergot alkaloids is scarce, especially in horses, but needed for toxicological analysis of these drugs in urine/feces of affected horses. The aim of this study was to investigate the metabolism of ergovaline, ergotamine, ergocristine, and ergocryptine in horses and comparison to humans. 2. Supernatants of alkaloid incubations with equine and human liver S9 fractions were analyzed by reversed-phase liquid-chromatography coupled to high-resolution tandem mass spectrometry with full scan and MS2 acquisition. Metabolite structures were postulated based on their MS2 spectra in comparison to those of the parent alkaloids. All compounds were extensively metabolized yielding nor-, N-oxide, hydroxy and dihydro-diole metabolites with largely overlapping patterns in equine and human liver S9 fractions. However, some metabolic steps e.g. the formation of 8'-hydroxy metabolites were unique for human metabolism, while formation of the 13/14-hydroxy and 13,14-dihydro-diol metabolites were unique for equine metabolism. Incubations with equine whole liver preparations yielded less metabolites than the S9 fractions. 3. The acquired data can be used to develop metabolite-based screenings for these alkaloids, which will likely extend their detection windows in urine/feces from affected horses.

Duration of drug action of dopamine D2 agonists in mice with 6-hydroxydopamine-induced lesions.

Although 6-hydroxydopamine-induced (6-OHDA-induced) rats are a well-known Parkinson's disease model, the effects of dopamine D2 agonists in mice with 6-OHDA-induced lesions are not completely understood. We produced mice with 6-OHDA-induced lesions and measured their total locomotion counts following administration of several dopamine D2 agonists (pramipexole, ropinirole, cabergoline, rotigotine, apomorphine, talipexole, and quinelorane). Cabergoline showed the longest duration of drug action, which was in agreement with its long-lived anti-Parkinson effects in rats and humans. In contrast, pramipexole and ropinirole had notably short durations of drug action. We demonstrated that mice with 6-OHDA-induced lesions accompanied with significant lesions in the striatum may be reasonable models to predict the action duration of anti-Parkinson drug candidates in humans.

From ergolines to indoles: improved inhibitors of the human H3 receptor for the treatment of narcolepsy.

Ergolines were recently identified as a novel class of H3 receptor (H3R) inverse agonists. Although their optimization led to drug candidates with encouraging properties for the treatment of narcolepsy, brain penetration remained low. To overcome this issue, ergoline 1 ((6aR,9R,10aR)-4-(2-(dimethylamino)ethyl)-N-phenyl-9-(pyrrolidine-1-carbonyl)-6,6a,8,9,10,10a-hexahydroindolo[4,3-fg]quinoline-7(4H)-carboxamide)) was transformed into a series of indole derivatives with high H3R affinity. These new molecules were profiled by simultaneous determination of their brain receptor occupancy (RO) levels and pharmacodynamic (PD) effects in mice. These efforts culminated in the discovery of 15 m ((R)-1-isopropyl-5-(1-(2-(2-methylpyrrolidin-1-yl)ethyl)-1H-indol-4-yl)pyridin-2(1H)-one), which has an ideal profile showing a strong correlation of PD effects with RO, and no measurable safety liabilities. Its desirably short duration of action was confirmed by electroencephalography (EEG) measurements in rats.

Ergoline-derived inverse agonists of the human h3 receptor for the treatment of narcolepsy.

Ergoline derivative (6aR,9R)-4-(2-(dimethylamino)ethyl)-N-phenyl-9-(pyrrolidine-1-carbonyl)-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-7(4H)-carboxamide (1), a CXCR3 antagonist, also inhibits human histamine H3 receptors (H3R) and represents a structurally novel H3R inverse agonist chemotype. It displays favorable pharmacokinetic and in vitro safety profiles, and served as a lead compound in a program to explore ergoline derivatives as potential drug candidates for the treatment of narcolepsy. A key objective of this work was to enhance the safety and efficacy profiles of 1, while minimizing its duration of action to mitigate the episodes of insomnia documented with previously reported clinical candidates during the night following administration. Modifications to the ergoline core at positions 1, 6 and 8 were systematically investigated, and derivative 23 (1-((4aR,8R,9aR)-8-(hydroxymethyl)-1-(2-((R)-2-methylpyrrolidin-1-yl)ethyl)-4,4a,7,8,9,9a-hexahydroindolo[1,14-fg]quinolin-6(1H)-yl)ethanone) was identified as a promising lead compound. Derivative 23 has a desirable pharmacokinetic profile and demonstrated efficacy by enhancing brain concentrations of tele-methylhistamine, a major histamine metabolite. This validates the potential of the ergoline scaffold to serve as a template for the development of H3R inverse agonists.

Molecular and behavioral pharmacology of two novel orally-active 5HT2 modulators: potential utility as antipsychotic medications.

BACKGROUND: Desired serotonin 5HT2 receptor pharmacology for treatment of psychoses is 5HT2A antagonism and/or 5HT2C agonism. No selective 5HT2A antagonist has been approved for psychosis and the only approved 5HT2C agonist (for obesity) also activates 5HT2A and 5HT2B receptors, which can lead to clinical complications. Studies herein tested the hypothesis that a dual-function 5HT2A antagonist/5HT2C agonist that does not activate 5HT2B receptors would be suitable for development as an antipsychotic drug, without liability for weight gain. METHODS: The novel compounds (+)- and (-)-trans-4-(4'-chlorophenyl)-N,N-dimethyl-2-aminotetralin (p-Cl-PAT) were synthesized, characterized in vitro for affinity and functional activity at human 5HT2 receptors, and administered by intraperitoneal (i.p.) and oral (gavage) routes to mice in behavioral paradigms that assessed antipsychotic efficacy and effects on feeding behavior. RESULTS: (+)- and (-)-p-Cl-PAT activated 5HT2C receptors, with (+)-p-Cl-PAT being 12-times more potent, consistent with its higher affinity across 5HT2 receptors. Neither p-Cl-PAT enantiomer activated 5HT2A or 5HT2B receptors at concentrations up to 300-times greater than their respective affinity (Ki), and (+)-p-Cl-PAT was shown to be a 5HT2A competitive antagonist. When administered i.p. or orally, (+)- and (-)-p-Cl-PAT attenuated the head-twitch response (HTR) in mice elicited by the 5HT2 agonist (-)-2,5-dimethoxy-4-iodoamphetamine (DOI) and reduced intake of a highly palatable food in non-food-deprived mice, with (+)-p-Cl-PAT being more potent across behavioral assays. CONCLUSIONS: The novel in vitro pharmacology of (+)-p-Cl-PAT (5HT2A antagonism/5HT2C agonism without activation of 5HT2B) translated in vivo to an orally-active drug candidate with preclinical efficacy to treat psychoses without liability for weight gain.

ADMET considerations for restless leg syndrome drug treatments.

INTRODUCTION: Restless legs syndrome (RLS) is a common neurological disorder that might impair nocturnal rest causing decreased alertness, depressed mood, reduced job performance, and poor quality of life. In patients affected by severe RLS, a pharmacological treatment is mandatory. AREAS COVERED: The present review is based on a search using PubMed from 1994 to 2012. It is focused on the Absorption, Distribution, Metabolism, Elimination and Toxicology (ADMET) characteristics of the most used medications for RLS. In particular, the ADMET characteristics of dopaminergic agents, anticonvulsants able to improve neuropathic pain, and iron were discussed. EXPERT OPINION: Clinical trials have showed that non-ergolic dopamine agonists are efficacious and safe for patients affected by moderate to severe idiopathic RLS. However, no head-to-head study has compared the long-term effects of the three dopamine agonists approved by the FDA for RLS (ropinirole, pramipexole, and rotigotine). Moreover, further studies should investigate the extended-release formulation of ropinirole and pramipexole in RLS patients affected by all day long distressing symptoms. A standardized treatment for symptomatic forms of RLS is lacking. Randomized, placebo-controlled trials should be performed at least in RLS patients with peripheral neuropathic and chronic kidney disease. Concerning RLS due to iron deficiency, a head-to-head study comparing efficacy, safety and compliance of oral iron versus intravenous one seems to be needed.

Simultaneous quantification of berberine and lysergol by HPLC-UV: evidence that lysergol enhances the oral bioavailability of berberine in rats.

A sensitive and simple HPLC method was developed for the simultaneous quantification of berberine and lysergol in rat plasma. The chromatographic separation was achieved on a C(18) column using isocratic elution with methanol-acetonitrile-0.1% ortho-phosphoric acid (25:20:55, v/v/v), pH adjusted to 6.5 with triethylamine and detected at a UV wavelength of 230 nm. The extraction of the berberine and lysergol from the rat plasma with methylene chloride resulted in their high recoveries (82.62 and 90.17%). HPLC calibration curves for both berberine and lysergol based on the extracts from the rat plasma were linear over a broad concentration range of 50-1000 ng/mL. The limit of quantification was 50 ng/mL. Intra- and inter-day precisions were <15% and accuracy was 87.12-92.55% for berberine and 87.01-92.26% for lysergol. Stability studies showed that berberine and lysergol were stable in rat plasma for short- and long-term period for sample preparation and analysis. The described method was successfully applied to study the pharmacokinetics of berberine as well as lysergol following oral administration in Sprague-Dawley rats. The results of the study inferred that lysergol improved the oral bioavailability of berberine.

Permeability of ergot alkaloids across the blood-brain barrier in vitro and influence on the barrier integrity.

SCOPE: Ergot alkaloids are secondary metabolites of Claviceps spp. and they have been in the focus of research for many years. Experiments focusing on ergotamine as a former migraine drug referring to the ability to reach the brain revealed controversial results. The question to which extent ergot alkaloids are able to cross the blood-brain barrier is still not answered. METHODS AND RESULTS: In order to answer this question we have studied the ability of ergot alkaloids to penetrate the blood-brain barrier in a well established in vitro model system using primary porcine brain endothelial cells. It could clearly be demonstrated that ergot alkaloids are able to cross the blood-brain barrier in high quantities in only a few hours. We could further identify an active transport for ergometrine as a substrate for the BCRP/ABCG2 transporter. Investigations concerning barrier integrity properties have identified ergocristinine as a potent substance to accumulate in these cells ultimately leading to a weakened barrier function. CONCLUSION: For the first time we could show that the so far as biologically inactive described 8-(S) isomers of ergot alkaloids seem to have an influence on barrier integrity underlining the necessity for a risk assessment of ergot alkaloids in food and feed.

Small molecule CXCR3 antagonist NIBR2130 has only a limited impact on type 1 diabetes in a virus-induced mouse model.

CXCL10 is one of the key chemokines involved in trafficking of autoaggressive T cells to the islets of Langerhans during the autoimmune destruction of beta cells in type 1 diabetes (T1D). Blockade of CXCL10 or genetic deletion of its receptor CXCR3 results in a reduction of T1D in animal models. As an alternative to the use of neutralizing monoclonal antibodies to CXCL10 or CXCR3 we evaluated the small molecule CXCR3 antagonist NIBR2130 in a virus-induced mouse model for T1D. We found that the overall frequency of T1D was not reduced in mice administered with NIBR2130. An initial slight delay of diabetes onset was not stable over time, because the mice turned diabetic upon removal of the antagonist. Accordingly, no significant differences were found in the islet infiltration rate and the frequency and activity of islet antigen-specific T cells between protected mice administered with NIBR2130 and control mice. Our data indicate that in contrast to direct inhibition of CXCL10, blockade of CXCR3 with the small molecule antagonist NIBR2130 has no impact on trafficking and/or activation of autoaggressive T cells and is not sufficient to prevent T1D.

Comparative efficacy of bromocriptine, cabergoline and thyroxine in inducing oestrus in bitches.

Forty bitches in anoestrus for more than six months from the last heat, with a serum progesterone level less than 1 ng/ml were subjected to oestrus induction trials using anti-prolactin drugs and levothyroxine, once daily orally for 20 consecutive days. The mean serum progesterone level among them was found to be 0.57 +/- 0.03 ng/ml. Out of 10 animals treated in each group, five (50%) in Group I (bromocriptine @ 50 microg/kg body weight), nine (90%) in Group II (cabergoline @ 5 microg/kg body weight), eight (80%) in Group III (thyroxine @10 microg/kg body weight) and seven (70%) in Group IV (thyroxine @ 5 microg/kg body weight) responded by evincing proestrual bleeding. The mean (+/-SEM) time taken from initiation of treatment to onset of proestrual bleeding in Groups I, II, III and IV was 28 +/- 3.39, 13.44 +/- 3.12 (P < 0.05), 24.50 +/- 3.18 and 33 +/- 2.21 days respectively. The mean (+/-SEM) duration of proestrus and oestrus in the treatment groups was 9.80 +/- 0.86, 10.11 +/- 0.68, 11.25 +/- 0.88 and 10.71 +/- 0.68 days and 7.60 +/- 0.24, 8 +/- 0.29, 8.5 +/- 0.63 and 7.85 +/- 0.46 days respectively. The conception rate in relation to the number of animals responding to oestrus induction in the treatment groups was 80%, 78%, 63% and 57%, respectively. The mean (+/-SEM) gestation length calculated from the last breeding date and litter size in the treatment groups varied from 60.50 +/- 1.55 to 64.00 +/- 0.82 days and 5.14 +/- 0.34 to 6.40 +/- 0.40 respectively.

Intranasal cabergoline: pharmacokinetic and pharmacodynamic studies.

Aims of this investigation were to prepare and characterize cabergoline intranasal microemulsion formulations, determine brain drug delivery through biodistribution using technetium-99m (99mTc) as a tracer, and assess its performance pharmacodynamically in weight control. Cabergoline microemulsions of different compositions were prepared by water titration method and characterized for globule size and zeta potential. Microemulsion with maximum drug solubilization and stability was considered optimal and taken for further studies with or without addition of mucoadhesive agent. Pharmacokinetics of optimized 99mTc-labeled cabergoline formulations and 99mTc-labeled drug solution were studied by estimating radioactivity in brain and blood of albino rats post intranasal, intravenous, and oral administrations. To confirm localization of drug in brain following intranasal, intravenous, and oral administrations, gamma scintigraphy imaging was also performed. To assess weight control performance of formulations, body weight, white adipose tissue mass, serum lipids, leptin, and prolactin were determined before and after 40 days of intranasal administrations of these formulations to Wistar rats. Microemulsions were found to be stable both physically and chemically when stored at various stress conditions. Brain/blood uptake ratios, drug targeting efficiency, and direct drug transport were found to be highest for drug mucoadhesive microemulsion followed by drug microemulsion and drug solution post-intranasal administration compared to intravenous drug microemulsion. Significant (p<0.05) reduction in assessed pharmacodynamic parameters was observed after intranasal administration of mucoadhesive microemulsion against control group. The results of the studies conclusively demonstrate that intranasal microemulsion formulations developed in this investigation are stable and can deliver cabergoline selectively and in higher amounts to the brain compared to both drug administrations as a solution intranasally or microemulsion intravenously. The results also demonstrate reduction in weight, adipose tissue mass, serum lipids, and serum prolactin after intranasal administration of drug microemulsion. Hence, long-term studies in at least two more animal models followed by extensive clinical evaluation can safely result into a product for clinical use.

Resonancia magnética en la respuesta al tratamiento del síndrome de hiperestimulación ovárica: comparación de modelos farmacocinéticos / Magnetic resonance for evaluating the response to treatment for ovarian hyperstimulation syndrome: comparison of pharmokinetic models

Objetivo Valorar el efecto del tratamiento con cabergolina en el síndrome de hiperestimulación ovárica (SHO) mediante la aplicación de modelos mono y bicompartimentales en resonancia magnética (RM). Material y métodosSe estudiaron 20 mujeres donantes de óvulos con riesgo de desarrollar SHO, divididas en 2 grupos (placebo y tratamiento). Se realizaron 2 estudios de RM de perfusión, antes y tras el inicio del tratamiento. Se comparó el modelo monocompartimental, con parámetros de permeabilidad vascular (Ktrans), ratio de extracción (kep) y fracción de espacio extravascular extracelular (ve), y el bicompartimental, que añade la fracción de espacio intravascular (vp). El análisis de las diferencias entre grupos (placebo frente a tratamiento) para los 2 estudios de RM y para cada modelo farmacocinético se realizó con una prueba t para muestras independientes. El coeficiente de correlación intraclase (CCI) analizó la variabilidad de las medidas. ResultadosEn el grupo placebo se observó un incremento significativo de Ktrans para ambos modelos (p=0,021 para un compartimiento, y p<0,001 para 2 compartimientos). En las pacientes tratadas no hubo diferencias en ningún parámetro para ninguno de los modelos. Por diferencias entre grupos, para 2 compartimentos Ktrans aumentó un 168,6±151,9% para placebo y un 43,3±54,5% para tratamiento (p=0,04). Para un único compartimiento no hubo diferencias significativas. En el análisis de variabilidad se obtuvo un CCI >0,95 para todos los parámetros, excepto vp (CCI=0,89). ConclusionesLa permeabilidad capilar calculada empleando modelos farmacocinéticos bicompartimentales tras la administración de un contraste en RM es un biomarcador del efecto del tratamiento en pacientes con SHO (AU)

ObjectiveTo evaluate the response to treatment with cabergoline for ovarian hyperstimulation syndrome (OHS) using mono- and bi-compartmental MRI models. Material and methodsWe studied 20 ovum donors with a high risk of developing OHS, divided in two groups (placebo vs. treatment). MRI perfusion studies were performed before and after the beginning of treatment. We compared the monocompartmental model, with the parameters vascular permeability (Ktrans), extraction ratio (kep), and extravascular extracellular space fraction (ve), against the bicompartmental model, with the same parameters as in the monocompartmental model and the additional parameter vascular space fraction (vp). The differences between groups (placebo vs. treatment) on the two MRI studies and for each pharmacokinetic model were analyzed using t-tests for independent samples. The intraclass correlation coefficient (ICC) was used to assess the variability of the measurements. ResultsIn the placebo group, a significant increase in Ktrans was observed with both models (p=0.021 for one compartment; and p<0.001 for two compartments). In the treatment group, no statistically significant differences were found for any parameter in either model. Regarding differences between groups, in the bicompartmental model Ktrans increased 168.6%±151.9% in the placebo group versus 43.3%±54.5% in the treatment group, p=0.04). In the monocompartmental model, no differences were found between groups. In the variability analysis, the ICC was higher than 0.95 for all parameters except vp (ICC=0.89). ConclusionsCapillary permeability calculated with bicompartmental pharmacokinetic models after MRI contrast administration is a biomarker of the treatment effect in OHS patients (AU)

[Magnetic resonance for evaluating the response to treatment for ovarian hyperstimulation syndrome: comparison of pharmokinetic models.]. / Resonancia magnética en la respuesta al tratamiento del síndrome de hiperestimulación ovárica: comparación de modelos farmacocinéticos.

OBJECTIVE: To evaluate the response to treatment with cabergoline for ovarian hyperstimulation syndrome (OHS) using mono- and bi-compartmental MRI models. MATERIAL AND METHODS: We studied 20 ovum donors with a high risk of developing OHS, divided in two groups (placebo vs. treatment). MRI perfusion studies were performed before and after the beginning of treatment. We compared the monocompartmental model, with the parameters vascular permeability (K(trans)), extraction ratio (k(ep)), and extravascular extracellular space fraction (v(e)), against the bicompartmental model, with the same parameters as in the monocompartmental model and the additional parameter vascular space fraction (v(p)). The differences between groups (placebo vs. treatment) on the two MRI studies and for each pharmacokinetic model were analyzed using t-tests for independent samples. The intraclass correlation coefficient (ICC) was used to assess the variability of the measurements. RESULTS: In the placebo group, a significant increase in K(trans) was observed with both models (p=0.021 for one compartment; and p<0.001 for two compartments). In the treatment group, no statistically significant differences were found for any parameter in either model. Regarding differences between groups, in the bicompartmental model K(trans) increased 168.6%+/-151.9% in the placebo group versus 43.3%+/-54.5% in the treatment group, p=0.04). In the monocompartmental model, no differences were found between groups. In the variability analysis, the ICC was higher than 0.95 for all parameters except v(p) (ICC=0.89). CONCLUSIONS: Capillary permeability calculated with bicompartmental pharmacokinetic models after MRI contrast administration is a biomarker of the treatment effect in OHS patients.

Cabergoline: Pharmacology, ocular hypotensive studies in multiple species, and aqueous humor dynamic modulation in the Cynomolgus monkey eyes.

The aims of the current studies were to determine the in vitro and in vivo ocular and non-ocular pharmacological properties of cabergoline using well documented receptor binding, cell-based functional assays, and in vivo models. Cabergoline bound to native and/or human cloned serotonin-2A/B/C (5HT(2A/B/C)), 5HT(1A), 5HT(7), alpha(2B), and dopamine-2/3 (D(2/3)) receptor subtypes with nanomolar affinity. Cabergoline was an agonist at human recombinant 5HT(2), 5HT(1A) and D(2/3) receptors but an antagonist at 5HT(7) and alpha(2) receptors. In primary human ciliary muscle (h-CM) and trabecular meshwork (h-TM) cells, cabergoline stimulated phosphoinositide (PI) hydrolysis (EC(50)=19+/-7 nM in TM; 76 nM in h-CM) and intracellular Ca(2+) ([Ca(2+)](i)) mobilization (EC(50)=570+/-83 nM in h-TM; EC(50)=900+/-320 nM in h-CM). Cabergoline-induced [Ca(2+)](i) mobilization in h-TM and h-CM cells was potently antagonized by a 5HT(2A)-selective antagonist (M-100907, K(i)=0.29-0.53 nM). Cabergoline also stimulated [Ca(2+)](i) mobilization more potently via human cloned 5HT(2A) (EC(50)=63.4+/-10.3 nM) than via 5HT(2B) and 5HT(2C) receptors. In h-CM cells, cabergoline (1 microM) stimulated production of pro-matrix metalloproteinases-1 and -3 and synergized with forskolin to enhance cAMP production. Cabergoline (1 microM) perfused through anterior segments of porcine eyes caused a significant (27%) increase in outflow facility. Topically administered cabergoline (300-500 microg) in Dutch-belted rabbit eyes yielded 4.5 microMM and 1.97 microM levels in the aqueous humor 30 min and 90 min post-dose but failed to modulate intraocular pressure (IOP). However, cabergoline was an efficacious IOP-lowering agent in normotensive Brown Norway rats (25% IOP decrease with 6 microg at 4h post-dose) and in conscious ocular hypertensive cynomolgus monkeys (peak reduction of 30.6+/-3.6% with 50 microg at 3h post-dose; 30.4+/-4.5% with 500 microg at 7h post-dose). In ketamine-sedated monkeys, IOP was significantly lowered at 2.5h after the second topical ocular dose (300 microg) of cabergoline by 23% (p<0.02) and 35% (p<0.004) in normotensive and ocular hypertensive eyes, respectively. In normotensive eyes, cabergoline increased uveoscleral outflow (0.69+/-0.7 microL/min-1.61+/-0.97 microL/min, n=13; p<0.01). However, only seven of the eleven ocular hypertensive monkeys showed significantly increased uveoscleral outflow. These data indicate that cabergoline's most prominent agonist activity involves activation of 5HT(2), 5HT(1A), and D(2/3) receptors. Since 5HT(1A) agonists, 5HT(7) antagonists, and alpha(2) antagonists do not lower IOP in conscious ocular hypertensive monkeys, the 5HT(2) and dopaminergic agonist activities of cabergoline probably mediated the IOP reduction observed with this compound in this species.

Ergoline derivatives as highly potent and selective antagonists at the somatostatin sst 1 receptor.

Non-peptidic compounds containing the octahydro-indolo[4,3-fg]quinoline (ergoline) structural element have been optimized into derivatives with high affinity (pK(d) r sst(1)>9) and selectivity (>1000-fold for h sst(1) over h sst(2)-h sst(5)) for the somatostatin sst(1) receptor. In functional assays, these ergolines act as antagonists at human recombinant sst(1) receptors. Pharmacokinetic studies in rodents reveal good oral bioavailability and brain penetration for some of these compounds.

Effect of dopamine agonists on prolactinomas and normal pituitary assessed by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI).

CONTEXT: Dopamine agonists (DA) may act on prolactinoma size and secretion through additional effects on adenoma vascularity that can be visualized using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). OBJECTIVE: We hypothesized that DAs may exert their effect through a change in tumour functional vascularity leading to a reduction of prolactin (PRL) levels and tumour size. SUBJECTS AND METHODS: To investigate this, 23 subjects were studied comprising five with macroprolactinomas, 11 with microprolactinomas, seven with non-lesion hyperprolactinemia and 15 normal volunteers (including five females on oral contraceptive pills). Patients with macroprolactinomas were treated with cabergoline 4 mg weekly and microprolactinomas were treated with quinagolide 75 microg daily for the duration of study. DCE-MRI was performed immediately pre-treatment and at 3-4 days, 1 and 3-4 months after treatment. Normal volunteers took three 75 microg quinagolide doses and were scanned pre-treatment and at 3 days. Data were analysed using the Brix model, producing a measure of vascular permeability and leakage space. RESULTS: PRL levels were significantly reduced in all patients and volunteers. Vascular parameters decreased significantly for four of five macroprolactinomas and all microprolactinomas which were maintained during the treatment period (p < 0.01). No changes were seen in normal volunteers or non-lesion hyperprolactinemia. One of five macroprolactinomas showed no change in either permeability or tumour size. CONCLUSION: Functional prolactinoma vascularity differs from non-lesion hyperprolactinemic pituitary and normal pituitary, and is responsive to DA therapy. The reduction in vascular parameters precedes shrinkage in macroprolactinomas, and if not seen within days of treatment may indicate DA resistance requiring early surgery.

A review of the receptor-binding and pharmacokinetic properties of dopamine agonists.

BACKGROUND: Dopamine agonists (DAs), which can be categorized as ergot derived and non-ergot derived, are used in the treatment of Parkinson's disease. OBJECTIVES: This review describes the pharmacologic and pharmacokinetic properties of selected DAs and relates these characteristics to clinical outcomes, with an emphasis on adverse events. METHODS: Relevant articles were identified through a search of MEDLINE (to May 2006) using the terms dopamine agonists (or each individual drug name) and pbarmacokinetics, metabolism, drug-drug interaction, interactions, CYP450, fibrosis, valvular heart disease, tremor, clinical trials, reviews, and meta-analyses. Abstracts from recent sessions of the International Congress of Parkinson's Disease and Movement Disorders were also examined. Clinical studies with <20 patients overall or <10 patients per treatment group in the final analysis were excluded. All DAs that were graded at least possibly useful with respect to at least 3 of 4 items connected to the treatment/prevention of motor symptoms/complications in the most recent evidence-based medical review update were included. This resulted in a focus on the ergot-derived DAs bromocriptine, cabergoline, and pergolide, and the non-ergot-derived DAs pramipexole and ropinirole. RESULTS: Bromocriptine, cabergoline, pergolide, and ropinirole, but not pramipexole, have the potential for drug-drug interactions mediated by the cytochrome P450 (CYP) enzyme system. The occurrence of dyskinesia may be linked to stimulation of the dopamine D(1) receptor, for which cabergoline and pergolide have a similar and relatively high affinity; bromocriptine, pramipexole, and ropinirole have been associated with a lower risk of dyskinesias. The valvular heart disease (VHD) and pulmonary and retroperitoneal fibrosis seen with long-term use appear to represent a class effect of the ergot-derived DAs that may be related to stimulation of serotonin 5-HT(2B) (and possibly 5-HT(2A)) receptors. The incidence of valvular regurgitation was 31% to 47% with ergot-derived DAs, 10% with non-ergot-derived DAs, and 13% with controls. CONCLUSIONS: As reflected in the results of the clinical trials included in this review, dyskinesia associated with DA therapy may be linked to stimulation of the D(1) receptor. Fibrosis (including VHD) seemed to be a class effect of the ergot-derived DAs. Each of the DAs except pramipexole has the potential to interact with other drugs via the CYP enzyme system.

Fatty acids differentially affect serotonin receptor and transporter binding in the rat brain.

The aim of this study was to examine the influence of different fat diets on serotonin receptor and transporter binding. Male Sprague-Dawley rats were fed a diet of either high saturated fat, omega-6 polyunsaturated fatty acid, omega-3 polyunsaturated fatty acid or low fat (control) for eight weeks. Using Beta-Imager quantification techniques, [(3)H]ketanserin, [(3)H]mesulergine and [(3)H]paroxetine binding to serotonin (5-HT)(2A), 5-HT(2C) receptors and 5-HT transporters (5-HTT) was measured throughout the brain in all four groups. All three high fatty acid diets influenced serotonin receptor binding, however the most pronounced effects were that compared with the low fat control group, i) 5-HT(2A) receptor binding was increased in the caudate putamen, but reduced in the mammillary nucleus in high saturated fat and high omega-6 polyunsaturated fatty acid diet groups; ii) 5-HT(2C) receptor binding was reduced in the mamillary nucleus of saturated fat group and reduced in prefrontal cortex of the omega-6 polyunsaturated fatty acid and omega-3 polyunsaturated fatty acid groups; and iii) 5-HTT binding was reduced in the hippocampus in the omega-6 polyunsaturated fatty acid group. Overall, the omega-6 polyunsaturated fatty acid diet exerted the most influence on serotonin receptor and transporter binding. These results may be of importance in relation to neuropsychiatric diseases such as schizophrenia, where associations between altered fatty acid levels and the serotonergic system have been made.

Effect of clarithromycin on the pharmacokinetics of cabergoline in healthy controls and in patients with Parkinson's disease.

Cabergoline is used in the treatment of Parkinson's disease (PD). Clarithromycin is a potent inhibitor of CYP3A4 and P-glycoprotein and is often co-administered with cabergoline in usual clinical practice. We studied the effect of clarithromycin co-administration on the blood concentration of cabergoline in healthy male volunteers and in PD patients. Study 1: Ten healthy male volunteers were enrolled and were randomized to take a single oral dose of cabergoline (1 mg/day) for 6 days or a single oral dose of cabergoline plus clarithromycin (400 mg/day) for 6 days. Study 2: Seven PD patients receiving stable cabergoline doses were enrolled. They were evaluated for the plasma cabergoline concentration before and after the addition of clarithromycin 400 mg/day for 6 days, and again 1 month after discontinuation of clarithromycin. The dose and duration of clarithromycin were decided according to usual clinical practice. In healthy male volunteers, mean Cmax and AUC(0-10 h) of cabergoline increased to a similar degree during co-administration of clarithromycin. Mean plasma cabergoline concentration over 10 h post-dosing increased 2.6-fold with clarithromycin co-administration. In PD patients, plasma cabergoline concentration increased 1.7-fold during clarithromycin co-administration. Co-administration with clarithromycin may increase the blood concentration of cabergoline in healthy volunteers and in PD patients.

Evaluation of the transdermal permeation behavior of Proterguride from drug in adhesive matrix patches through hairless mouse skin.

The transdermal in vitro permeation behavior of the highly potent dopamine agonist Proterguride was investigated using hairless mouse skin as a model membrane. Drug in adhesive matrix formulations based on different types of pressure-sensitive adhesives (Eudragit E 100 and Gelva7883 as acrylates, Oppanol B 15 SFN as polyisobutylene, and BioPSA 7-4202 as silicone) with a drug load of 3% by weight were manufactured. All patches were examined for drug crystallization by polarized microscopy immediately after the manufacturing process and after storage for 30 days in sealed aluminium laminate bags at ambient temperature and at 40 degrees C, respectively. Furthermore, the influence of the drug load in acrylate-based formulations onto the steady-state flux of Proterguride was examined. The Eudragit E 100 system delivered a significantly higher steady-state flux than the systems based on Oppanol B 15 SFN and also a somewhat higher steady-state flux than the Gelva-based patch. An addition of 10% by weight of the crystallization inhibitor povidone 25 did not significantly influence the steady-state flux of Proterguride from acrylate matrices. The lipophilic silicone and polyisobutylene adhesives facilitated drug crystallization within the short storage periods at both conditions, probably due to the absence of povidone 25, which was incompatible with these polymers. Varying the drug load in acrylate-based formulations led to a linear increase of the steady-state flux until the steady-state flux of Proterguride leveled off and the patches tended to drug crystallization. It was found that Gelva-based patches show good physical stability, good skin adhesion, and moderate flux values and, thus, can be evaluated as a basis for a suitable formulation for the transdermal administration of Proterguride.