Potent Dopamine Agonist Research Articles

Integrating technology into a successful apomorphine delivery program in Thailand: a 10-year journey of achievements with a five-motto concept.

Apomorphine, a potent dopamine agonist, is a therapeutic option for patients with Parkinson's disease and motor fluctuations. However, the adoption of and adherence to this therapy have been limited by the need for complex delivery devices and specialized care as well as resource consumption, posing challenges for new physicians. Thailand is a unique example of a developing nation that has successfully implemented and continued the use of this therapy by employing cooperative technology that has dramatically enhanced apomorphine delivery services. Establishing apomorphine delivery services requires significant resources and step-by-step solutions. We began our services by implementing various strategies in three chronological stages: the initial stage (2013-2015), intermediate stage (2016-2019), and current stage (2020-present), each presenting unique challenges. Together, we also implemented a proposed set of five mottos to strengthen our apomorphine delivery service. Using additive technology, we developed a patient registry platform that combined electronic data acquisition, video and remote monitoring using wearable sensors, and in-house mobile applications to support our service. At the initial stage, we assembled a team to enhance the efficacy and confirm the safety of apomorphine treatment in our hospital. At the intermediate stage, we expanded our apomorphine delivery services beyond just the patients at our hospital. We supported other hospitals in Thailand in setting up their own apomorphine services by educating both physicians and nurses regarding apomorphine therapy. With this educational undertaking, increased apomorphine-related knowledge among medical professionals, and a greater number of hospitals providing apomorphine services, an increasing number of patients were administered apomorphine in subsequent years. Currently, we are providing effective apomorphine delivery to improve patient outcomes and are seamlessly integrating technology into clinical practice. Incorporating integrative technologies in our apomorphine delivery program yielded positive results in data collection and support throughout patient care, in tracking patients' statuses, in the long-term use of this treatment, and in increasing medication adherence rates. This perspective paper describes how technology can help provide supportive healthcare services in resource-constrained environments, such as in Thailand, offering a step-by-step approach to overcoming several limitations. The valuable insights from our 10-year journey in successfully integrating technology into apomorphine delivery services can benefit new physicians seeking to replicate our success.

Levodopa u terapiji Parkinsonove bolesti

January 2023 marks the 100th anniversary of the birth of Arvid Carlsson, a Swedish scientist, one of the three winners of the Nobel Prize in Medicine in 2000 "for proving that Dopamine is a brain neurotransmitter whose deficiency leads to the symptoms of Parkinson's disease". Levodopa therapy is one of the main achievements of neurology in the twentieth century, and Parkinson' s disease was the first disease in which a specific neurochemical deficiency was confirmed in defined regions of the brain, which forms the basis for rational, chemically supported therapy. The paper briefly reviews the most important achievements in the discovery of Dopamine and levodopa, as well as their functions in the development of Parkinson's disease. Dopamine synthesis, understanding of levodopa synthesis method, possibility of measuring Dopamine concentration in putamen and caudate and its loss in Parkinson' s disease, along with histochemical visualization of nigrostriatal pathway and animal lesion model, enabled understanding of the role of nigrostriatal Dopamine system in the development of Parkinson's disease symptoms. Part of the work is devoted to the metabolism of Dopamine in healthy dopaminergic neurons, and then to its functioning in dopaminergic neurons of Parkinson's disease patients. It is known that in Parkinson's disease, Dopamine deficiency occurs due to selective degeneration of nigrostriatal dopaminergic neurons. Their suffering is triggered by a cascade of events that included the action of potential toxins, the influence of susceptibility genes on the body's response to them, oxidative stress caused by mitochondrial dysfunction, dysfunction of the ubiquitous proteasomal system that leads to the accumulation of incorrectly "packaged" proteins, the exhaustion of the endoplasmic reticulum system and the activation of mycoglia that follows inflammatory process. These changes can lead to programmed cell death of dopaminergic neurons with consequent Dopamine deficiency and the development of PD. Special attention is paid to the consequences of neuron loss on the functioning of the remaining dopaminergic neurons and Dopamine receptors, with reference to the therapeutic motor complications that may arise on that occasion. The basic assumptions about the occurrence of therapeutic complications are still related to the pharmacokinetics of levodopa and the model of its delivery to the brain, which results in non-physiological, pulsatile stimulation of Dopamine receptors. Today's possibilities in achieving a more stable concentration of levodopa with existing strategies are presented, with an answer to the question of whether continuous stimulation can be achieved under the conditions of standard, regular patients' levodopa therapy. In the short final part, the position of levodopa in the guidelines and recommendations for treatment is commented. It is expected that L-dopa will remain the "gold standard" for the treatment of PD at least until the development of more potent and safer Dopamine agonists or the development of neuroprotective or neurorestorative therapies.

Comparison of pramipexole versus ropinirole in the treatment of Parkinson's disease.

Parkinson's disease is a progressive neurodegenerative disease characterized by motor and non-motor symptoms. Levodopa is the most effective drug in the symptomatic treatment of the disease. Dopamine receptor agonists provide sustained dopamin-ergic stimulation and have been found to delay the initiation of levodopa treatment and reduce the frequency of various motor complications due to the long-term use of levodopa. The primary aim of this study was to compare the efficacy of potent nonergoline dopamine agonists pramipexole and ropinirole in both "dopamine agonist monotherapy group" and "levodopa add-on therapy group" in Parkinson's disease. The secondary aims were to evaluate the effects of these agents on depression and the safety of pramipexole and ropinirole. A total of 44 patients aged between 36 and 80 years who were presented to the neurology clinic at Ministry of Health Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkey and were diagnosed with idiopathic Parkinson's disease, were included into this randomized parallel-group clinical study. Dopamine agonist monotherapy and levodopa add-on therapy patients were randomized into two groups to receive either pramipexole or ropinirole. The maximum daily dosages of pramipexole and ropinirole were 4.5 mg and 24 mg respectively. Patients were followed for 6 months and changes on Unified Parkinson's Disease Rating Scale, Clinical Global Impression-severity of illness, Clinical Global Impression-improvement, Beck Depression Inven-tory scores, and additionally in advanced stages, changes in levodopa dosages were evaluated. Drug associated side effects were noted and compared. In dopamine agonist monotherapy group all of the subsections and total scores of Unified Parkinson's Disease Rating Scale and Clinical Global Impression-severity of illness of the pramipexole subgroup showed significant improvement particularly at the end of the sixth month. In the pramipexole subgroup of levodopa add-on therapy group, there were significant improvements on Clinical Global Impression-severity of illness and Beck Depression Inventory scores, but we found significant improvement on Clinical Global Impression-severity of illness score at the end of the sixth month in ropinirole subgroup too. The efficacy of pramipexole and ropinirole as antiparkinsonian drugs for monotherapy and levodopa add-on therapy in Parkinson's disease and their effects on motor complications when used with levodopa treatment for add-on therapy have been demonstrated in several previous studies. This study supports the effectiveness and safety of pramipexole and ropinirole in the monotherapy and levodopa add-on therapy in the treatment of Parkinson's disease.

Necrotic Ulcers Secondary to Apomorphine Infusion.

Background:Apomorphine is a potent dopamine agonist used in the treatment of advanced and fluctuating Parkinson’s Disease. However the need for its subcutaneous infusion can lead to skin reactions.Phenomenology Shown:We illustrate necrotic ulcers at infusion sites as a rare event during continuous subcutaneous apomorphine infusion.Educational value:This case demonstrates the rare adverse event of necrotic ulcers in a patient with long term apomorphine infusion.

THE UTILIZATION AREAS OF CABERGOLINE IN VETERINARY GYNECOLOGY

Cabergoline is a potent dopamine agonist and a synthetic ergot derivative, and it acts by inhibiting prolactin secretion from the pituitary gland. It reduces the amount of plasma prolactin and inhibits progesterone secretion at the same time. Because of these effects, it has found a widespread area of use in the treatment of hyperprolactinemic disorders both in the human medicine and veterinary medicine.

Effect of cabergoline alginate nanocomposite on the transgenic Drosophila melanogaster model of Parkinson’s disease

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra of the midbrain. Dopamine agonists help the patients with PD by reversing the dopamine depletion and related motor deficits. In the present work, cabergoline, a potent ergot dopamine agonist, was given in the form of cabergoline alginate nanocomposite (CANC) to the PD model flies to study its effects on climbing ability, activity pattern, life span, lipid peroxidation, glutathione (GSH) content, glutathione-S-transferase (GST) activity, dopamine content, protein carbonyl content, mean gray-scale values, and caspase-3 and caspase-9 activities. Cabergoline alginate nanocomposite was synthesized by adding the cabergoline solution in the warm aqueous solution of sodium alginate; The synthesized CANC was characterized using fourier transform (FTIR) infrared spectroscopy, transmission electron microscopy (TEM), and UV–Visible spectroscopic techniques. The synthesized CANC having the final doses of 1, 2, and 3 μM was supplemented with diet and the flies were allowed to feed on it for 24 days. Cabergoline alginate nanocomposite significantly increases climbing ability, reduces lipid peroxidation, GST activity, protein carbonyl content, caspase 3/9 activity, mean gray-scale values, and increases the GSH as well as dopamine content in a dose-dependent manner. The results of this study suggest that CANC is potent in delaying and reducing the symptoms of PD.

Response to Cabergoline treatment in Invasive Prolactinoma with hemorrhage- A case report

Patients with invasive prolactinoma present with constellation of symptoms including headache, blurred vision, lethargy, menstrual irregularity and sexual dysfunction. Cabergoline, a potent dopamine agonist, is a known medication prescribed for the treatment of prolactinoma. Here, we report a case of invasive macroprolactinoma with hemorrhage in a 18 years female with dramatic response to cabergoline treatment clinically, biochemically, and radiologically.Jour of Diab and Endo Assoc of Nepal 2017; 1(1): 18-20

Effects of chronic exposure to octamethylcyclotetrasiloxane and decamethylcyclopentasiloxane in the aging female Fischer 344 rat

Octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5) are used as intermediates or monomers in the synthesis of silicon-based polymers for industrial or consumer applications. D4 and D5 may remain as residual monomer in these polymers at less than 1000ppm and may therefore be present as a minor impurity in consumer products. For D5, in addition to the manufacture of polymers, its uses include intentional addition to consumer products, personal care products and some dry- cleaning solvents. Two-year rodent chronic bioassays were conducted with both substances and borderline increases in the incidence of uterine tumors were observed, specifically, benign uterine adenoma with D4 and adenocarcinoma with D5. The effects profile and induction of uterine tumors share some similarity with that seen with chronic exposure to dopamine agonists. The current study investigated the potential for D4 and D5 to elicit dopamine agonist-like effects on estrous cyclicity. Separate groups of reproductively senescent female Fischer 344 rats (F344) were exposed via vapor inhalation to D4 (700ppm, 9.3mg/L) or D5 (160ppm, 2.1mg/L) or to a diet containing 0.0045, 0.045, or 4.5ppm pergolide mesylate (PM), a potent dopamine agonist used here as a reference substance, from 11 through 24 months of age. The primary focus was to characterize the effects of D4 and D5 exposure on estrous cyclicity relative to that observed with PM. As a monitoring effort, circulating endogenous estradiol, progesterone, prolactin and corticosterone levels were evaluated monthly. A blood sample from each rat was obtained via tail vein in the afternoon after the daily inhalation exposure period once every 4 weeks. Histomorphologic examination of the major organs including the reproductive tract was conducted on all animals at study termination.This study has shown that chronic exposure to D4 and D5 can affect cyclicity in the reproductively senescent F344 rat. For each substance the effect on cyclicity involved reduction in the incidence of pseudopregnancy with a shift toward cycles more typical of younger animals. D4 and D5 induced an increase in estrous cycle repetition whereas D4 also increased the incidence of extended estrus. These shifts resulted in animals entering proestrus/estrus significantly more times over the duration of the study than seen in the control group. Similar effects were observed with the reference substance, PM. However, distinct differences in the timing and magnitude of the effects on the estrous cycle and impact on prolactin, progesterone, estradiol, and corticosterone suggest that D4 and D5 are not classical dopamine agonists even though a similar increased incidence of proestrus/estrus was also observed with PM. These results may prove important with respect to understanding D4- and D5-induced uterine tumor response in the F344 rat, given the relationship between increased incidence of uterine endometrium stimulation by endogenous estrogen as a consequence of extended or more frequent proestrus/estrus, uterine tumor risk, and questions of relevance to humans. Recent publications have summarized the existing data on D4 and D5, with emphasis on exploring the biological relevance of the uterine tumors (Klaunig et al., 2016a,b; Franzen et al., 2017; Dekant and Klaunig, 2016; Dekant et al., 2017). The authors concluded that although the mode of action has not yet been fully established, the data, including the findings from this study, indicate that the D4- and D5-induced uterine tumors observed in the rodent chronic bioassays have no relevance for human risk characterization based not only on the distinct species differences in regulation of the reproductive systems, but also the high exposure levels and duration required for expression in rats.

Apomorphine - pharmacological properties and clinical trials in Parkinson's disease

Apomorphine is often considered an archetypal dopamine agonist used in the treatment of Parkinson's disease (PD). However, it can be clearly differentiated from most other commonly used dopamine agonists on the basis of its pharmacology and on its unique clinical profile. Like levodopa and dopamine, apomorphine acts as a potent, direct and broad spectrum dopamine agonist activating all dopamine receptor subtypes. It also has affinity for serotonin receptors, and α-adrenergic receptors. Apomorphine is usually titrated to a dose that provides an equivalent antiparkinsonian response to that provided by levodopa, and its subcutaneous delivery allows a rapid onset of action, usually within 7–10 min. The mode of apomorphine delivery impacts on its clinical profile so as to provide two very different approaches to therapy in PD. When administered as an acute subcutaneous injection, it induces reliable and rapid relief from OFF periods underscoring its utility as a rescue medication. When given as a subcutaneous infusion, it significantly improves overall daily OFF time and there is also evidence to suggest that, in those patients who replace most or all of their oral drugs with apomorphine infusion, dyskinesia may also improve. In this paper, we review the rich pharmacology of apomorphine and review its efficacy in PD based on data from clinical trials.

Cabergoline Treatment in Invasive Giant Prolactinoma

Patients with invasive giant prolactinoma suffer from a constellation of symptoms including headache, blurred vision, lethargy, and sexual dysfunction. Cabergoline, a potent dopamine agonist, is a known medication prescribed for the treatment of invasive giant prolactinoma. Here, we report a case of invasive giant prolactinoma in a 52-year-old Saudi male with dramatic response to cabergoline treatment clinically, biochemically, and radiologically.

1-substituted apomorphines as potent dopamine agonists

A novel set of 1-substituted apomorphines as dopaminergic agonists were synthesized according to our new strategy employing the acid-catalyzed rearrangement of diversely functionalized 5β-substituted-6-demethoxythebaines. The activities of new compounds for dopamine receptors subtypes were evaluated using HEK293 based stable cell lines expressing D1, D2L or D3 receptor subtypes. All studied compounds had affinities in nanomolar range for D2L and D3 receptors and the change of the nature of substituent in position 1 had only moderate effect. D1 receptors were sensitive to the introduction of the 4-OH-benzyl function resulting in an increased affinity. The small hydrophilic group (hydroxymethyl) highly reduced the agonist affinity and potency thereby increasing subtype selectivity. This strategy for selective modulation of affinities and potencies of 1-substituted apomorphines gives essential hints for future design of subtype selective dopaminergic ligands.

Dopamine‐transporter levels drive striatal responses to apomorphine in Parkinson's disease

Dopaminergic therapy in Parkinson's disease (PD) can improve some cognitive functions while worsening others. These opposite effects might reflect different levels of residual dopamine in distinct parts of the striatum, although the underlying mechanisms remain poorly understood. We used functional magnetic resonance imaging (fMRI) to address how apomorphine, a potent dopamine agonist, influences brain activity associated with working memory in PD patients with variable levels of nigrostriatal degeneration, as assessed via dopamine-transporter (DAT) scan. Twelve PD patients underwent two fMRI sessions (Off-, On-apomorphine) and one DAT-scan session. Twelve sex-, age-, and education-matched healthy controls underwent one fMRI session. The core fMRI analyses explored: (1) the main effect of group; (2) the main effect of treatment; and (3) linear and nonlinear interactions between treatment and DAT levels. Relative to controls, PD-Off patients showed greater activations within posterior attentional regions (e.g., precuneus). PD-On versus PD-Off patients displayed reduced left superior frontal gyrus activation and enhanced striatal activation during working-memory task. The relation between DAT levels and striatal responses to apomorphine followed an inverted-U-shaped model (i.e., the apomorphine effect on striatal activity in PD patients with intermediate DAT levels was opposite to that observed in PD patients with higher and lower DAT levels). Previous research in PD demonstrated that the nigrostriatal degeneration (tracked via DAT scan) is associated with inverted-U-shaped rearrangements of postsynaptic D2-receptors sensitivity. Hence, it can be hypothesized that individual differences in DAT levels drove striatal responses to apomorphine via D2-receptor-mediated mechanisms.

The Pharmacokinetics and Pharmacological Effect of (S)-5-OH-DPAT Following Controlled Delivery with Transdermal Iontophoresis

The pharmacokinetic (PK) and pharmacodynamic (PD) properties of the active (S)-enantiomer of the potent dopamine (DA) agonist 5-hydroxy-2-(N,N,-di-n-propylamino)tetralin (5-OH-DPAT) were investigated in a novel anesthetized animal model. First, the relationship between current density, in vivo transport, and plasma profile was characterized. Second, the effect of the anesthetic mixture, transdermal iontophoresis, and blood sampling on the striatal DA release (PD end point) was investigated. Third, the PK-PD relationship following transdermal iontophoresis was investigated during a controlled reversible pharmacological response. Given that striatal DA levels are unaltered during experimental procedures, this rat model can be used to investigate the PK-PD relationship. The in vivo flux was linearly correlated with the current density, indicating that drug delivery can be titrated by the current density. Following transdermal iontophoresis and intravenous infusion, a strong reversible effect was observed. Compartmental modeling showed that the relationship between plasma concentration and biomarker response is best characterized by an effect compartment, rather than an indirect response model. In addition, covariate analysis suggested that the delivery rate can affect the PD efficiency. Finally, PK-PD analysis revealed that steady delivery rates are translated into continuous dopaminergic stimulation. This can be of benefit for reducing side effects in the symptomatic treatment of Parkinson's disease with 5-OH-DPAT.

The hydroxy-hexanydronaphthoxazines: a new group of very potent and selective dopamine agonists.

Replacement of the pyrrole ring system in the dopaminergic oxaergolines (e.g. RU 29717) by a phenolic OH group leads to the hydroxy-hexahydronaphthoxazines, a new group of potent dopamine agonists which exhibit increased selectivity due to their lower affinity for adrenergic and 5-HT receptors.

Facile synthesis of octahydrobenzo[h]isoquinolines: Novel and highly potent D1 dopamine agonists

The octahydrobenzo[h]isoquinoline scaffold is of interest as a conformationally-restricted phenethylamine that may be useful for constructing biologically active products. Surprisingly, however, no tractable synthesis of this ring system has been reported. We now describe a facile method for obtaining this framework, and illustrate that our approach is easily amenable to substitutions at the 5-position. Importantly, we demonstrate that the 7,8-dihydroxy-5-phenyl-substituted ligand is an extremely potent, high-affinity, full D1 dopamine receptor-selective agonist.

Effect of subcutaneous apomorphine on tremor in idiopathic Parkinson's disease

Among the cardinal symptoms of Parkinson's disease (PD) rest tremor is the least responsive to dopaminergic treatment, raising the assumption that it may not be directly related to the loss of dopaminergic neurons. Apomorphine is a potent short-acting dopamine agonist that rapidly ameliorates symptoms of PD. The aim of this study was to evaluate the extent to which apomorphine can suppress tremor in patients with idiopathic PD compared to other symptoms. The study group included 18 patients with Parkinson's disease. Increasing doses of 1 mg, 2 mg, and 4 mg of subcutaneous apomorphine were used. Treatment response was assessed with the motor section of the unified Parkinson's disease rating scale (UPDRS). Tremor, rigidity and bradykinesia were scored using specific items of the UPDRS. UPDRS motor score improved from 31.5 ± 9 at baseline to 20.0 ± 6.4 after treatment. The scores for tremor, bradykinesia and rigidity improved after administration of apomorphine. The improvement in each of these scores for each individual patient was not significantly different, i.e., the magnitude of improvement was similar for all symptoms. These results indicate that subcutaneous apomorphine appears to be as effective in the treatment of tremor in Parkinson's disease as compared to the other symptoms.

Extremely Potent Orally Active Benzo[g]quinoline Analogue of the Dopaminergic Prodrug: 6-(N,N-Di-n-propyl)amino-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one

Enone prodrugs of dopaminergic catecholamines represent a new type of prodrug in the research area of dopamine agonists. Here, we demonstrate the first benzo[g]quinoline-derived enone that induces potent dopamine agonist effects similar to aminotetralin-derived enones. Significant effects of (−)-4 were observed in microdialysis studies after administration of 1 nmol kg-1 sc and 3 nmol kg-1 po. With a potency comparable to that of the most potent apomorphines, (−)-4 could potentially compete with l-DOPA and apomorphine in the treatment of Parkinson's disease.

Transdermal iontophoresis of the dopamine agonist 5-OH-DPAT in human skin in vitro

The feasibility of transdermal iontophoretic delivery of a potent dopamine agonist 5-OH-DPAT was studied in vitro in side by side diffusion cells across human stratum corneum (HSC) and dermatomed human skin (DHS) according to the following protocol: 6 h of passive diffusion, 9 h of iontophoresis and 5 h of passive diffusion. The influences of the following parameters on the flux were studied: donor solution pH, NaCl concentration, drug donor concentration, current density and skin type. A current density of 0.5 mA cm −2 was used, except for one series of experiments to study the current density effect. Probably due to the influence of the skin perm-selectivity and the competition with H +, increase in pH from 3 to 5 resulted in a significant increase in flux. Further increase in pH to 6 did not further increase the flux. The iontophoretic transport was found to increase linearly with concentration and current density, providing a convenient way to manage dose titration for Parkinson's disease therapy. Increase in concentration of NaCl dramatically reduced the flux of 5-OH-DPAT as a result of ion competition to the transport. When DHS was used, the iontophoretic transport was less. Also, with DHS the response in flux profile, by switching the current on and off, was shallower than that with HSC. With the optimum condition, a delivery of 104 μg of 5-OH-DPAT per cm 2 patch per hour is feasible, indicating that the therapeutic level could be achieved with a smaller patch size than required in case of rotigotine. Thus, based on this in vitro study, transdermal iontophoretic delivery of 5-OH-DPAT is very promising.

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 Gelva®7883 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°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.

Transdermal iontophoretic delivery of apomorphine in patients improved by surfactant formulation pretreatment

The objective of the present study is to evaluate the efficacy and the safety of transdermal iontophoretic delivery of R-apomorphine, a potent dopamine agonist, in combination with surfactant pretreatment in patients with advanced Parkinson's disease. Iontophoresis patches were applied in 16 patients for 3.5 h, with 0.5 h of passive delivery followed by 3 h of current application at a current density of 250 μA/cm 2. Eight of these patients were treated with a surfactant formulation prior to iontophoresis. The pharmacokinetics, pharmacodynamic effects, systemic and local side effects of R-apomorphine were assessed. The plasma concentration vs. time profiles upon iontophoresis of R-apomorphine were described successfully by a novel pharmacokinetic model. The model suggests that only 1.9% of the dose that has been released from the patch accumulated in the skin. The patients treated with the surfactant formulations showed a statistically significant increase of bioavailability (from 10.6±0.8% to 13.2±1.4%) and of the steady state input rate (from 75.3±6.6 to 98.3±12.1 nmol/cm 2 h) compared to the control patients (iontophoresis without absorption enhancers). In five out of eight patients in the study group and in three out of eight patients in the control group, clinical improvement was observed.