Effect of Pulsed Direct Current on Iontophoretic Delivery of Pramipexole across Human Epidermal Membrane In Vitro.

PURPOSE: Pulsed direct current (PDC) iontophoresis, by allowing skin depolarization, was suggested to provide more efficient ion transport, but the extent of its enhancement effect was unclear. PDC could also offer electric-customized drug delivery. This study examined the effect of PDC iontophoresis on transdermal delivery of pramipexole dihydrochloride (PXCl). METHODS: Iontophoretic delivery of PXCl across human epidermal membrane from pH 7.0 solution was conducted in vitro using continuous direct current (DC) and 6- and 12-cycle PDC iontophoresis (0.5 mA/cm2 and total applied duration of 6 h). Different parameters of PDC iontophoresis were studied, including current density (0.1, 0.2 and 0.5 mA/cm2) and on-off current dosing pattern (1 h/3 h, 0.5 h/3.5 h, and 0.2 h/3.8 h). RESULTS: Both 6- and 12-cycle PDC iontophoresis protocols provided modulation of the permeation profile but delivered smaller amounts of PXCl (396 and 400 µg/cm2, respectively) as compared with continuous DC iontophoresis (482 µg/cm2) at 24 h after 0.5 mA/cm2 and 180 mA/cm2 × min current dose application. Increasing applied current density from 0.1 to 0.5 mA/cm2 increased the PDC iontophoretic flux of PXCl linearly from 5.3 to 14.6 µg/cm2·h (R2 = 0.887). Varying the current level and duration but at the same applied current dose (36 mA/cm2 × min), the total amount of PXCl delivered by PDC iontophoresis at 24 h was independent of the on-off dosing pattern studied (114-128 µg/cm2). CONCLUSIONS: The results indicate that PDC iontophoresis can benefit transdermal delivery of PXCl in terms of controlling its permeation but does not enhance iontophoretic transport compared to continuous DC iontophoresis under the conditions studied.

Effect of pH on Iontophoretic Transport of Pramipexole Dihydrochloride across Human Epidermal Membrane.

PURPOSE: Drugs with higher molecular charges generally show higher flux enhancement when electromigration is the main mechanism in transdermal iontophoresis. This study evaluated the effect of decreasing the formulation pH to increase the positive charges of pramipexole dihydrochloride (PXCl) on its iontophoretic transport across skin. METHODS: In vitro transdermal iontophoresis of PXCl in buffer solution isotonized with either sodium chloride or mannitol were performed in a pH range of 3.0-7.0. Experiments of iontophoresis under symmetric condition with respect to donor and receiver pH and passive transport of the drugs after pretreatment with iontophoresis were conducted to investigate the transport mechanism involved. RESULTS: Iontophoretic permeation of PXCl was pH-dependent in drug solution isotonized with mannitol. The iontophoretic flux of PXCl with valence z = +2 at pH 3.0 was half of that of PXCl with z = +1 at pH 7.0. The results suggest that the decrease in PXCl delivery at higher valence at pH 3 was mainly due to pH-dependent selectivity of PX ion permeation across the skin and not electroosmosis. CONCLUSIONS: Skin permselectivity is a significant factor for iontophoretic transport of PXCl, and reducing formulation pH to increase the positive charges on PX ions did not enhance PXCl delivery.

Structures of the human dopamine D3 receptor-Gi complexes.

The dopamine system, including five dopamine receptors (D1R-D5R), plays essential roles in the central nervous system (CNS), and ligands that activate dopamine receptors have been used to treat many neuropsychiatric disorders. Here, we report two cryo-EM structures of human D3R in complex with an inhibitory G protein and bound to the D3R-selective agonists PD128907 and pramipexole, the latter of which is used to treat patients with Parkinson's disease. The structures reveal agonist binding modes distinct from the antagonist-bound D3R structure and conformational signatures for ligand-induced receptor activation. Mutagenesis and homology modeling illuminate determinants of ligand specificity across dopamine receptors and the mechanisms for Gi protein coupling. Collectively our work reveals the basis of agonist binding and ligand-induced receptor activation and provides structural templates for designing specific ligands to treat CNS diseases targeting the dopaminergic system.

Interaction of graphene with antipsychotic drugs: Is there any charge transfer process?

Antipsychotics represent an effective therapy for schizophrenia (a chronic mental disorder). Their benefits are related to the interaction of the drugs with dopamine D2 receptor (D2R). Antipsychotics are classified as agonists or antagonists. One of the working hypotheses is that there is a charge transfer process between the drugs and the receptors, which is different for agonists and antagonists. To have more insight into the nature of the interaction of these molecules and the differences between agonists and antagonists, we analyze the interaction of graphene with three molecules: dopamine, pramipexole (an agonist of dopamine), and risperidone (an antagonist of dopamine). The idea is to use graphene as a simple model to analyze the charge transfer process of these three drugs. Optimized structures, atomic charges, and Density of States results indicate that global charges of dopamine and pramipexole are similar, while for risperidone, it is more than double. Pramipexole is an agonist, and the charge transfer process is similar to that of dopamine. Risperidone is an antagonist, and the charge transfer process is different from dopamine. The charge transfer is more significant with risperidone than with dopamine, and this could be related to the mechanism of action. This is in agreement with the working hypotheses that establish that it is possible to distinguish between agonists and antagonists since they have different capacity to transfer charge.

From Riluzole to Dexpramipexole via Substituted-Benzothiazole Derivatives for Amyotrophic Lateral Sclerosis Disease Treatment: Case Studies.

The 1,3-benzothiazole (BTZ) ring may offer a valid option for scaffold-hopping from indole derivatives. Several BTZs have clinically relevant roles, mainly as CNS medicines and diagnostic agents, with riluzole being one of the most famous examples. Riluzole is currently the only approved drug to treat amyotrophic lateral sclerosis (ALS) but its efficacy is marginal. Several clinical studies have demonstrated only limited improvements in survival, without benefits to motor function in patients with ALS. Despite significant clinical trial efforts to understand the genetic, epigenetic, and molecular pathways linked to ALS pathophysiology, therapeutic translation has remained disappointingly slow, probably due to the complexity and the heterogeneity of this disease. Many other drugs to tackle ALS have been tested for 20 years without any success. Dexpramipexole is a BTZ structural analog of riluzole and was a great hope for the treatment of ALS. In this review, as an interesting case study in the development of a new medicine to treat ALS, we present the strategy of the development of dexpramipexole, which was one of the most promising drugs against ALS.

Self-inflating floating nanofiber membranes for controlled drug delivery.

Floating gastro-retentive delivery systems can prolong the gastric residence providing sustained drug release. In this study, we report on self-inflating effervescence-based electrospun nanofiber membranes embedding polyethylene oxide/sodium bicarbonate cast films. In this system, sodium bicarbonate results in an effervescence effect by creating carbon dioxide gas upon contacting an acidic gastric fluid, with the resulting gas bubbles being entrapped within the swollen network of nanofibers. Eudragit RL and RS polymers are utilized as a host material to manipulate release kinetics of incorporated drugs. Pramipexole, a common medication for chronic Parkinson's disease (PD), is used as a model drug. Uniform and bead-free nanofibers with diameters of ~300 nm were obtained. Although floating nanofibers initially exhibited high water contact angles (WCA), water droplets were quickly absorbed into the surface and the WCA decreased to ~0° within 60 s. Floating lag time, total floating time, swelling properties and drug release profiles were investigated both in a simulated gastric fluid (pH 1.2 buffer solution) and in a simulated intestinal fluid (pH 6.8 buffer solution) at 37 °C. All floating nanofiber formulations began to float instantly with nearly zero floating lag time and did not sink into the solution even after 24 h. By comparison, the same formulations without sodium bicarbonate cast films could not maintain continuous floating beyond 15 min. The floating nanofiber pouches presented lower initial release of between 20 and 57 %, compared to that of non-floating nanofiber pouches (40-82% within 2 h). Clearly, floating nanofibers reduced the initial burst release and provided sustained drug release. This demonstrates the potential to result in 'once-a-day' oral introduction of drugs that normally must be taken frequently. Effervescence-based floating nanofibers present a novel and promising prototype delivery system for the drug delivery in the upper gastro-intestinal (GI) tract.

Advancing synthetic therapies for the treatment of restless legs syndrome.

Introduction: Restless Legs Syndrome/Willis-Ekbom disease (RLS/WED) is a common sensory-motor neurological disorder that impairs nocturnal rest causing decreased alertness, depressed mood, reduced job performance and poor quality of life. In patients affected by moderate to severe RLS/WED, a pharmacological treatment is mandatory. Areas covered: The present review is based on an extensive Internet and PubMed search from 1996 to 2019. It is focused on drugs currently used and under development (phase III and beyond) for the treatment of RLS/WED. Expert opinion: The drugs currently available for the treatment of the disease do not always allow for obtaining the optimal control of symptoms, in particular in the long-term treatment. Although initially effective, long-term dopaminergic treatment tends to wane over time and augmentation can occur. Updated international guidelines now recommend α2δ calcium channel ligand medications as the initial drug of choice. Oxycodone-naloxone demonstrated a significant and sustained treatment effect for patients with severe RLS/WED insufficiently controlled with previous treatments. Head-to-head trials of different drugs, as well as more studies on nondopaminergic agents and combination therapy, are greatly needed. Monoamine oxidase B inhibitors could be good candidates for the initial treatment of RLS/WED, sparing stronger dopaminergic agents for later stages of the disease.

The role of pramipexole functionalized MWCNTs to the fabrication of Pd nanoparticles modified GCE for electrochemical detection of dopamine.

BACKGROUND: Interest in functionalized carbon nanotubes for many applications arises from a variety on the kind of modification atoms or molecules that are attached to it. Dopamine, the feel-good hormone, release by neurons and playing an important role in body systems. Abnormal dopamine levels cause nerve disorders such as Parkinson's disease and schizophrenia. OBJECTIVES: The aim of this study was the design and fabrication of electrochemical sensor based on MWCNTs and Pd nanoparticles for detection and determination of dopamine in biological samples. METHODS: For this purpose, we report the synthesis of pramipexole-functionalized MWCNTs (pp-MWCNTs) for efficient capture of palladium nanoparticles and fabrication of Pd/pp-MWCNTs nanocomposite. Morphological and structural characteristics of the nanocomposites were characterized using various techniques including field emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), energy dispersive X-ray spectroscopy (EDX), and Fourier transform infrared spectroscopy (FT-IR). RESULTS: This newly synthesized nanocomposite may have numerous applications in nanotechnology and sensing. We show that the synthesized nanocomposite reported here will be applicable for modifications of bare glassy carbon electrode (Pd/pp-MWCNTs/GCE) to sense of dopamine electrochemically. Two linear calibrations for dopamine are obtained over ranges of 0.01 to 10 µM and 10 to 200 µM with a detection limit of 1.4 nM. The Pd/pp-MWCNTs/GCE shows high stability and sensitivity, and an acceptable decrease of over-potential for the electrooxidation of dopamine that decreases interference in the analysis. The proposed Pd/pp-MWCNTs nanocomposite can be used as a voltammetric detector for dopamine monitoring in routine real sample analysis. CONCLUSIONS: The proposed sensor showed high sensitivity and selectivity in sensing dopamine in biological samples. Graphical abstract Preparation of Pd/pp-MWCNTs/GCE for detection of dopamine.

Near-infrared light-responsive, pramipexole-loaded biodegradable PLGA microspheres for therapeutic use in Parkinson's disease.

Parkinson's disease (PD) is associated with symptoms such as tremor and bradykinesia which, together with a rigorous dosing regimen, can place an untenable burden on patients. These issues underscore the need for triggerable, modulated drug delivery systems. Currently, pramipexole (PRX) is the most widely used non-ergot dopamine agonist for the treatment of PD. In this study, near-infrared light-responsive PRX and hollow gold nanospheres (HGNS)-loaded biodegradable poly (D, L-lactide-co-glycolide) (PLGA) microspheres (PRX/HGNS MS) were fabricated using solid-in-oil-in-water (S/O/W) and water-in-oil-in-water (W/O/W) emulsion-solvent evaporation techniques to achieve modulated drug release. The PRX/HGNS MS were uniform, with an average diameter of approximately 24 µm, favorable PRX and HGNS encapsulation efficiencies (51.71 ±â€¯0.54% and 65.15 ±â€¯2.30%, respectively) and rapid, controllable drug release both in vitro and in vivo. Cytotoxicity tests revealed no significant differences between HGNS and PRX/HGNS MS when compared with a negative control. Pharmacodynamics and immunohistochemistry studies revealed a more rapid recovery of striatum in the group treated with PRX/HGNS MS produced using the S/O/W method. The results clearly demonstrate that light-responsive PRX/HGNS MS produced using the S/O/W method have the potential to address PD patients' mobility problems in a smart, controllable and remotely triggerable manner.

Design of selective molecularly imprinted sorbent for the optimized solid-phase extraction of S-pramipexole from the model multicomponent sample of human urine.

The objective of this article was to design the selective molecularly imprinted sorbent dedicated to the solid-phase extraction of S-pramipexole from the complex matrix such as human urine. For that purpose, S-2,6-diamino-4,5,6,7-tetrahydrobenzothiazole was used as the template acting as the structural analog of S-pramipexole and five various monomers were employed in the presence of ethylene glycol dimethacrylate to produce molecularly imprinted polymers. The binding capabilities of resulted polymers revealed that the highest imprinting effect was noted for polymer prepared from the itaconic acid. The comprehensive analysis of morphology and the characterization of binding sites showed not only negligible differences in the extension of surfaces of imprinted and nonimprinted polymers but also higher heterogeneity of binding sites in the imprinted material. Comprehensive optimization of the molecularly imprinted solid-phase extraction allowed to select the most appropriate solvents for loading, washing, and elution steps. Subsequent optimization of mass of sorbent and volumes of solvents allowed to achieve satisfactory total recoveries of S-pramipexole from the model multicomponent real sample of human urine that equals to 91.8 ± 3.2% for imprinted sorbent with comparison to only 37.1 ± 1.1% for Oasis MCX.

Novel contribution to the simultaneous monitoring of pramipexole dihydrochloride monohydrate and levodopa as co-administered drugs in human plasma utilizing UPLC-MS/MS.

An efficient, selective, sensitive, and rapid ultra-performance liquid chromatography tandem mass spectrometry method was established and validated for the quantification of pramipexole dihydrochloride monohydrate and levodopa simultaneously in human plasma with the aid of diphenhydramine as an internal standard. A simple protein precipitation technique with HPLC grade acetonitrile was efficiently utilized for the cleanup of plasma. The analysis was performed using a Hypersil gold 50 mm × 2.1 mm (1.9 µm) column and a mobile phase of 0.2% formic acid and methanol (90: 10 v/v). The triple-quadrupole mass spectrometer equipped with an electrospray source operated in the positive mode was set up in the selective reaction monitoring mode (SRM) to detect the ion transitions m/z 212.15 →153.01, m/z 198.10→ 135.16, and m/z 255.75 → 166.16 for pramipexole dihydrochloride monohydrate, levodopa, and diphenhydramine, respectively. The method was thoroughly validated according to FDA guidelines and proved to be linear, accurate, and precise over the range 100-4000 pg/mL for pramipexole dihydrochloride monohydrate and 60-4000 ng/mL for levodopa. The proposed method was effectively applied for monitoring both drugs in plasma samples of healthy volunteers.