RESUMEN
BACKGROUND: Chiral analysis is a crucial way to differentiate selegiline (SG) intake from drug abuse. Oral fluid (OF) has been successfully used as an alternative matrix for blood testing in several pharmacokinetic studies. OBJECTIVE: The aim of this study is to describe the pharmacokinetics of SG and its main metabolites in OF after a single oral administration of SG which is meaningful for results interpretation in forensic analysis. METHODS: Ten milligrams of SG were orally administered to 8 volunteers, and OF samples were collected for up to 96 hours by having participants spit into polypropylene tubes without stimulation. These samples were submitted to liquid-liquid extraction before analysis by liquid chromatography-tandem mass spectrometry operating in positive ion multiple-reaction monitoring mode. RESULTS AND CONCLUSIONS: After oral administration, each analyte could be detected in OF specimens from all volunteers with an initial detection time of 0.50 hours. The Cmax values of SG, R-MA, R-AM and DM-SG were 50.93-992.67 ng/mL, 29.78-653.64 ng/mL, 8.22-150.15 ng/mL, and 4.34-16.25 ng/mL, respectively, at 0.5 hours, 1-11 hours, 1.5-11 hours, and 0.5-6 hours post dose. The times when the compounds were last determined in OF were 5-24 hours for SG, 52-96 hours for R-MA, 31-96 hours for R-AM, and 13-31 hours for DM-SG after oral administration. There is a period of time in OF in which only MA and AM are present without SG and DM-SG after a single dose of SG. The pharmacokinetic data could provide supplementary interpretation for OF tests in forensic science and drug treatment programs.
Asunto(s)
Anfetamina/farmacocinética , Anfetaminas/farmacocinética , Metanfetamina/farmacocinética , Inhibidores de la Monoaminooxidasa/farmacocinética , Saliva/metabolismo , Selegilina/farmacocinética , Administración Oral , Anfetamina/metabolismo , Anfetaminas/metabolismo , Humanos , Extracción Líquido-Líquido , Metanfetamina/metabolismo , Inhibidores de la Monoaminooxidasa/administración & dosificación , Inhibidores de la Monoaminooxidasa/metabolismo , Selegilina/administración & dosificación , Selegilina/metabolismo , Detección de Abuso de SustanciasRESUMEN
BACKGROUND: Selegiline hydrochloride, a hydrophilic anti-Parkinson' moiety, undergoes extensive first-pass metabolism and has low bioavailability. A process to obtain of selegiline (SH) loaded chitosan nanoparticles was attempted to circumvent the above problem, through intranasal delivery. METHODS: SH loaded polymeric nanoparticles were prepared by ionic gelation of chitosan with tripolyphosphate, and stabilized by tween 80/ poloxamer 188. The resulting nanoparticles (NPs) were characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, entrapment efficiency, particle size, zeta potential and surface morphology by scanning electron microscopy. Further, they were schematically evaluated for mucoadhesive strength, in-vitro drug release, release kinetics, pharmacokinetics, catalepsy, akinesia, in-vivo lipid peroxidation, nitrite levels, glutathione, catalase enzyme levels in brain and physicochemical stability parameters. RESULTS: Selegiline nanoparticles (SP18) produced were in size of 63.1 nm, polydispersity index of 0.201, zeta potential of +35.2 mV, mucoadhesion of 65.4% and entrapment efficiency of 74.77%. Selegiline showed biphasic release from nanoparticles, over a period of 36 h, with Fickian diffusion controlled release profile. Maximum concentration of SH in plasma was recognized as 52.71 ng/ml at 2 h for SP18, 20.09 ng/ml at 1 h for marketed formulation, and 21.69 ng/ ml for drug solution. SH loaded NPs showed a reversive effect in catalepsy and akinesia behaviour. This effect was especially pronounced in rats receiving SH loaded CS-NPs. Significant decrease in lipid peroxidation and nitrite concentration; increase in reduced glutathione and catalase enzyme levels were obtained due to antioxidant characteristics of SH, which turned to be useful to treat Parkinson's disease. CONCLUSION: Selegiline loaded chitosan nanoparticles form an effective non-invasive drug delivery system of direct nose to brain targeting in Parkinson's disease.
Asunto(s)
Antiparkinsonianos/administración & dosificación , Catalepsia/tratamiento farmacológico , Quitosano/administración & dosificación , Nanopartículas/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Selegilina/administración & dosificación , Administración Intranasal , Animales , Antiparkinsonianos/química , Antiparkinsonianos/farmacocinética , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Catalasa/metabolismo , Catalepsia/inducido químicamente , Quitosano/química , Quitosano/farmacocinética , Clorpromazina , Femenino , Glutatión/metabolismo , Masculino , Nanopartículas/química , Nitritos/metabolismo , Ratas Wistar , Selegilina/química , Selegilina/farmacocinética , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
Selegiline, a well-known anti-Parkinson agent, is reported to be associated with poor oral bioavailability and safety. Therefore, we formulated selegiline as chitosan nanoparticles and evaluated its pharmacokinetics and pharmacodynamics after intranasal administration to rats relative to those after oral administration. The optimized formulation exhibited spherical nanoparticles with more than 90% drug loading and steady in vitro and ex vivo drug release. Selegiline concentrations in the brain and plasma were 20- and 12-fold higher, respectively, after intranasal administration than after oral administration. Treatment with intranasal nanoparticles was also associated with better performance in locomotor activity, catalepsy, and stride length tests and significantly increased dopamine, catalase activity, and glutathione content in the brain. Therefore, intranasally administered selegiline nanoparticles holds superior therapeutic value compared to oral administration and can be a promising approach for the treatment of Parkinson's disease.
Asunto(s)
Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Liberación de Fármacos , Nanopartículas/administración & dosificación , Enfermedad de Parkinson/tratamiento farmacológico , Selegilina/farmacología , Selegilina/farmacocinética , Administración Intranasal , Animales , Antiparkinsonianos/química , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacología , Conducta Animal/efectos de los fármacos , Disponibilidad Biológica , Encéfalo/metabolismo , Quitosano/química , Portadores de Fármacos , Masculino , Nanopartículas/química , Enfermedad de Parkinson/metabolismo , Ratas , Ratas Sprague-Dawley , Selegilina/química , Distribución TisularRESUMEN
Selegiline hydrochloride (SL) is chosen as an adjunct for the control of clinical signs of Parkinsonian patients. The aim of the present work is to develop and optimize thermosensitive gels using Pluronic (F-127) for enhancing transport of SL into the brain through the nasal route. SL gels were prepared using a cold method and the Box-Behnken experimental design methodology. Drug (SL), gelling agent (F-127), and emulsifier (Propylene glycol, PG) were selected as independent variables, while the gelation temperature, gel strength, pH, gel content, and gel erosion were considered as dependent variables. For further understanding of the interaction between the various variables, contour plots and surface plots were also applied. Selected formulations, like S10 (contain 25 mg SL, 20 g F-127, and 1 g PG) and S14 (contain 50 mg SL, 18 g F-127 and 1 g PG), had a clear appearance in the sol form, with gelling temperature of the nasal gel ranging between 33 and 34, respectively. The gel strength of the formulations varied from 4.67 and 0.68 mm and the drug content was 100%. The pH of the formulations ranged between 6.71 and 7.11. Detachment force was acceptable (63.69-244.16 N/cm2) to provide prolonged adhesion. In vitro, drug release studies showed that the prepared formulations could release SL for up to 8 h. Permeation flux for the S10 gel was 0.0002 mg/min/cm2. Results demonstrated that the potential use of SL gels can enhance the therapeutic effect of SL through the intranasal administration.
Asunto(s)
Química Farmacéutica/métodos , Mucosa Nasal/efectos de los fármacos , Mucosa Nasal/metabolismo , Selegilina/síntesis química , Selegilina/farmacocinética , Administración Intranasal , Animales , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/síntesis química , Antiparkinsonianos/farmacocinética , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/síntesis química , Preparaciones de Acción Retardada/farmacocinética , Geles , Técnicas de Cultivo de Órganos , Proyectos de Investigación , Selegilina/administración & dosificación , Ovinos , Viscosidad/efectos de los fármacosRESUMEN
Selegiline hydrochloride (SL), is an anti-Parkinson's agent, has low-oral bioavailability due to its high first pass metabolism and scarce oral absorption. In the present study, SL mucoadhesive nasal thermosensitive gel (SNT-gel) was prepared to enhance the bioavailability and subsequently, its concentration in the brain. The SNT-gel was prepared using Poloxamer 407-Chitosan combination and optimised formulation was further evaluated for physicochemical parameters. The comparative pharmacodynamic studies including behavioural studies, biochemical testing and histopathology of the brain was carried out in rats for SNT-gel, SL-nasal solution and SL Marketed Tablets. The optimised SNT-gel formulation (SNT-V) revealed sol-gel transition at 33-34°C. In-vitro diffusion study of SNT-V showed 102.37 ± 2.1% diffusion at 12 h which reduced to 89.64 ± 1.2% in Ex-vivo diffusion. Comparative results of behavioural studies indicated an improved score of photoactometer and reduced motor deficit (catalepsy score) in SNT-gel treatment group as compared with other groups. Similarly, a significant increase in brain dopamine, reduction in monoamine oxidase B level, increase in catalase activity and level of reduced glutathione upon treatment with SNT-gel indicated its effectiveness which was also supported by histopathology results. Therefore, nasal thermosensitive gel holds better potential for brain targeting in Parkinson's disease over the conventional nasal or oral formulations.
Asunto(s)
Encéfalo , Sistemas de Liberación de Medicamentos/métodos , Enfermedad de Parkinson Secundaria/inducido químicamente , Enfermedad de Parkinson Secundaria/tratamiento farmacológico , Selegilina/administración & dosificación , Adhesividad , Administración Intranasal , Animales , Disponibilidad Biológica , Geles , Humanos , Masculino , Mucosa Nasal , Ratas , Ratas Sprague-Dawley , Rotenona/toxicidad , Selegilina/farmacocinética , Selegilina/uso terapéuticoRESUMEN
In the present study, the potential of transdermal nanoemulsion gel of selegiline hydrochloride for the treatment of Parkinson's disease was investigated. Water-in-oil nanoemulsions were developed by comparing low- and high-energy methods and were subjected to thermodynamic stability tests, in vitro permeation, and characterization studies. In vitro studies indicated that components of nanoemulsion acted as permeation enhancers with highest flux of 3.531 ± 1.94 µg/cm2/h from nanoemulsion SB6 containing 0.5 mg selegiline hydrochloride, 3% distilled water, 21% S mix (Span 85, Tween 80, PEG 400), and 76% isopropyl myristate by weight. SB6 with the least droplet size of 183.4 ± 0.35 nm, polydispersity index of 0.42 ± 0.06 with pH of 5.9 ± 0.32 and viscosity of 22.42 ± 0.14 cps was converted to nanoemulsion gel NEGS4 (viscosity = 22,200 ± 400 cps) by addition of Viscup160® for ease of application and evaluated for permeation, safety, and pharmacokinetic profile in Wistar rats. It provided enhancement ratio 3.69 times greater than conventional gel. NEGS4 showed 6.56 and 5.53 times increase in bioavailability in comparison to tablet and conventional gel, respectively, along with sustained effect. Therefore, the developed water-in-oil nanoemulsion gel promises to be an effective vehicle for transdermal delivery of selegiline hydrochloride.
Asunto(s)
Antiparkinsonianos/administración & dosificación , Selegilina/administración & dosificación , Administración Cutánea , Animales , Antiparkinsonianos/metabolismo , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/uso terapéutico , Emulsiones , Geles , Masculino , Nanoestructuras , Aceites/química , Trastornos Parkinsonianos/tratamiento farmacológico , Vehículos Farmacéuticos , Ratas , Ratas Wistar , Selegilina/metabolismo , Selegilina/farmacocinética , Selegilina/uso terapéutico , Absorción Cutánea , Termodinámica , Viscosidad , Agua/químicaRESUMEN
AIM: To compare the uptake of 11C-deuterodeprenyl (11C-DED) and 11C-methionine (11C-MET) in three human glioma cell lines and study the relationship with glial fibrillary acid protein (GFAP) and monoamine oxidase B (MAO B) expression. 11C-DED is used in positron emission tomography imaging as a marker of astrocytosis in various central nervous system pathologies. It binds irreversibly to MAO B, a glial dimeric enzyme with increased activity in some neurological pathologies. MATERIALS AND METHODS: Binding and internalization studies of 11C-MET and 11C-DED were performed in astrocytoma grade III, glioblastoma grade IV, and radio-resistant glioblastoma grade IV cells. Immunofluorescence was used. RESULTS: 11C-MET specific activity bound to membrane was 9.0%-11.1% and that internalized was 88.9%-91.0%. 11C-DED specific activity bound to membrane was 34.8%-58.0% and that internalized was 38.7%-65.2%. Immunocytochemistry revealed GFAP and MAO B expression. CONCLUSIONS: The expression of MAO B measured by 11C-DED uptake or immunocytochemistry was not significantly different in grade III or IV cells. The GFAP signal was higher for grade IV compared to grade III. 11C-MET uptake was high in all the tumor cells. 11C-DED is a dopamine analogue and the transport across cell membranes is expected to be mediated by DAT receptors present in astrocytes. Reactive astrocytes surround tumor lesions; so the authors suggest that the 11C-DED uptake might be caused by the reactive astrocytosis and not by MAO B expression in tumor cells.
Asunto(s)
Astrocitos/metabolismo , Astrocitoma/diagnóstico por imagen , Neoplasias Encefálicas/diagnóstico por imagen , Gliosis/metabolismo , Radiofármacos/farmacocinética , Radioisótopos de Carbono/farmacocinética , Línea Celular Tumoral , Deuterio/farmacocinética , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Metionina/farmacocinética , Monoaminooxidasa/metabolismo , Tomografía de Emisión de Positrones/métodos , Selegilina/farmacocinéticaRESUMEN
UNLABELLED: The aim of this study was to radiolabel a novel bis-deuterium substituted l-deprenyl analog (fluorodeprenyl-D2) with (18)F and to evaluate its potential to visualize and quantify monoamine oxidase (MAO) B activity in vivo. METHODS: The precursor compound ( 5A: + 5B: ) and reference standard ( 6: ) were synthesized in multistep syntheses. Recombinant human MAO-B and MAO-A enzyme preparations were used to determine inhibitory concentrations of 50%. Radiolabeling was accomplished by a nucleophilic substitution reaction. Whole-hemisphere autoradiography was performed with (18)F-fluorodeprenyl-D2. A PET study was performed on a cynomolgus monkey. Radiometabolites were measured in monkey plasma using high-performance liquid chromatography. RESULTS: The 50% inhibitory concentration of compound 6 for MAO-B was 227 ± 36.8 nM. Radiolabeling was accomplished with high radiochemical yield, purity, and specific radioactivity. The autoradiography binding density of (18)F-fluorodeprenyl-D2 was consistent with known MAO-B expression in the human brain. In vivo, (18)F-fluorodeprenyl-D2 showed favorable kinetic properties, with relatively fast washout from the brain. Regional time-activity curves were better described by the 2-tissue-compartment model. Administration of a 1 mg/kg dose of l-deprenyl yielded 70% inhibition of MAO-B in all regions. Radiometabolite studies demonstrated 20% unchanged radioligand at 120 min after injection. (18)F-fluorodeprenyl-D2 showed less irreversibility than did previously reported MAO-B radioligands. CONCLUSION: The results suggest that (18)F-fluorodeprenyl-D2 is a suitable PET radioligand for visualization of MAO-B activity in the human brain.
Asunto(s)
Inhibidores de la Monoaminooxidasa/farmacocinética , Monoaminooxidasa , Radiofármacos/farmacocinética , Selegilina/análogos & derivados , Animales , Autorradiografía , Proteínas Sanguíneas/metabolismo , Radioisótopos de Carbono , Radioisótopos de Flúor , Humanos , Marcaje Isotópico , Macaca fascicularis , Masculino , Proteínas Recombinantes , Selegilina/farmacocinéticaRESUMEN
Selegiline hydrochloride (SHCl), a monoamine oxidase B inhibitor, is used as an adjunct in the therapy of Parkinson's disease. This study is concerned with the preparation and evaluation of mucoadhesive buccal tablet for controlled systemic delivery of SHCl. Buccal absorption of selegiline can bypass its first-pass metabolism and improve bioavailability accompanied by greatly reduced metabolite formation, which is potentially of enhanced therapeutic value in patients with Parkinson's disease. Polycarbophil-cysteine (PCP-cys) conjugate, which is a thiolated derivative of the mucoadhesive polymer polycarbophil, was synthesized by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride-mediated amide bond coupling. Tablets of SHCl based on native and thiolated polycarbophil were prepared. The prepared tablets were evaluated for drug content, swelling behavior, mucoadhesive strength, in vitro drug release, ex vivo permeation and in vitro cytotoxicity. PCP-cys tablets showed enhanced mucoadhesion and retarded drug release compared to polycarbophil tablets. Permeation data of SHCl from matrices prepared using the PCP-cys polymer revealed a significantly higher value of apparent permeability in comparison to polycarbophil, which supported the information in literature that thiolation imparts permeation enhancing properties to mucoadhesive polymers. In vitro cytotoxicity studies on PCP-cys using L-929 mouse fibroblast cell line indicated that conjugation with cysteine does not impart any apparent toxicity to polycarbophil. The results from the study indicate that the buccal delivery of SHCl using thiolated polycarbophil tablet could provide a way for improved therapy of Parkinson's disease.
Asunto(s)
Selegilina/administración & dosificación , Resinas Acrílicas/química , Administración Bucal , Animales , Antiparkinsonianos/administración & dosificación , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/toxicidad , Línea Celular , Química Farmacéutica , Cisteína/química , Preparaciones de Acción Retardada , Humanos , Ratones , Inhibidores de la Monoaminooxidasa/administración & dosificación , Inhibidores de la Monoaminooxidasa/farmacocinética , Inhibidores de la Monoaminooxidasa/toxicidad , Absorción por la Mucosa Oral , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Selegilina/farmacocinética , Selegilina/toxicidad , Comprimidos , Resistencia a la TracciónRESUMEN
INTRODUCTION: Parkinson's disease affects a growing number of people. Its major treatment, levodopa therapy, however suffers from response fluctuations in the advanced phase of the disease. Adjunctive therapies have thus gained significant importance. The selective monoamine oxidase B inhibitor, selegiline , is widely used in the treatment of Parkinson's disease. However, selegiline's pharmacokinetics has so far been unfavorable due to its extensive first-pass metabolism to its amphetamine metabolites. A new formulation, an orally disintegrating tablet (ODT), has recently been introduced to overcome these pharmacokinetic problems by avoiding its presystemic metabolism. AREAS COVERED: The authors summarize the pharmacokinetic and clinical efficacy data of selegiline ODT and compare them with the more conventional oral selegiline. This evaluation also presents and compares the drug's safety data. EXPERT OPINION: Selegiline ODT shows a clear pharmacokinetic advantage over the conventional form. It is characterized by improved bioavailability allowing dose reduction and a lower exposure to amphetamine metabolites. This pharmacokinetic improvement, however, is not accompanied with significant clinical advantage, since its efficacy and safety profile are comparable to those of the conventional formulation. This suggests that the metabolites do not participate significantly in the therapeutic or toxic effects of selegiline. On the basis of the available data, the only well-justified advantage of the ODT formulation is its convenient use in parkinsonian patients who have difficulties in swallowing the regular formulation.
Asunto(s)
Enfermedad de Parkinson/tratamiento farmacológico , Selegilina/farmacocinética , Selegilina/uso terapéutico , Administración Oral , Anfetamina/farmacocinética , Anfetamina/uso terapéutico , Disponibilidad Biológica , Evaluación de Medicamentos , Humanos , Levodopa/farmacocinética , Levodopa/uso terapéutico , Inhibidores de la Monoaminooxidasa/farmacocinética , Inhibidores de la Monoaminooxidasa/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , ComprimidosRESUMEN
The aim in this project was to synthesize and to study fluorine-18 labeled analogues of l-deprenyl which bind selectively to the enzyme monoamine oxidase B (MAO-B). Three fluorinated l-deprenyl analogues have been generated in multistep organic syntheses. The most promising fluorine-18 compound N-[(2S)-1-[(18)F]fluoro-3-phenylpropan-2-yl]-N-methylprop-2-yn-1-amine (4c) was synthesized by a one-step fluorine-18 nucleophilic substitution reaction. Autoradiography on human brain tissue sections demonstrated specific binding for compound 4c to brain regions known to have a high content of MAO-B. In addition, the corresponding nonradioactive fluorine-19 compound (13) inhibited recombinant human MAO-B with an IC(50) of 170.5 ± 29 nM but did not inhibit recombinant human MAO-A (IC(50) > 2000 nM), demonstrating its specificity. Biodistribution of 4c in mice showed high initial brain uptake leveling at 5.2 ± 0.04%ID/g after 2 min post injection. In conclusion, compound 4c is a specific inhibitor of MAO-B with high initial brain uptake in mice and is, therefore, a candidate for further investigation in PET.
Asunto(s)
Proteínas Sanguíneas/metabolismo , Monoaminooxidasa/metabolismo , Radiofármacos/síntesis química , Selegilina/análogos & derivados , Selegilina/síntesis química , Animales , Autorradiografía , Barrera Hematoencefálica/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/enzimología , Femenino , Radioisótopos de Flúor , Humanos , Técnicas In Vitro , Isoenzimas/metabolismo , Masculino , Ratones , Tomografía de Emisión de Positrones , Unión Proteica , Radiofármacos/química , Radiofármacos/farmacocinética , Selegilina/química , Selegilina/farmacocinética , Estereoisomerismo , Relación Estructura-Actividad , Distribución TisularRESUMEN
PURPOSE: Astrocytosis is an important feature of the neuropathology of Alzheimer's disease (AD), yet there is currently no way of detecting this phenomenon in vivo. METHODS: In this study we examine the retention of the positron emission tomography (PET) tracer (11)C-L-deuteriodeprenyl (DED), thought to bind activated astrocytes, in 9 patients with moderate to severe AD compared with 11 healthy controls. As a measure of amyloid load, (11)C-labelled Pittsburgh Compound B (PIB) retention was determined. RESULTS: Results show a significantly higher (11)C-L-DED retention in the frontal (35.1% increase, p = 0.001), parietal (35.2%, p = 0.001), temporal (30.9%, p = 0.0001) and medial temporal lobes (22.3%, p = 0.001) in AD compared to healthy controls after blood flow correction. DED retention in the sensorimotor and occipital cortices, and in white matter and subcortical structures, did not differ between groups. There was a moderate but statistically significant (r = 0.492, p = 0.01) correlation between DED and PIB retention values. CONCLUSION: Our conclusion is that DED may serve as an in vivo marker for astrocytosis in AD, providing a window into intermediate processes between amyloidosis and neuronal loss and a means of monitoring immunotherapy.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Compuestos de Anilina/farmacocinética , Encéfalo/metabolismo , Gliosis/metabolismo , Tomografía de Emisión de Positrones/métodos , Selegilina/farmacocinética , Tiazoles/farmacocinética , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Radioisótopos de Carbono , Deuterio , Femenino , Gliosis/complicaciones , Gliosis/diagnóstico por imagen , Humanos , Radiofármacos/metabolismo , Radiofármacos/farmacocinética , Distribución TisularRESUMEN
The present work was carried out to design a practical, controlled-release transdermal system for selegiline using thermosensitive hydrogels. The copolymers of alginate and Pluronic F127 (PF127) were used to design thermogels by either physical blending (A+P) or chemical grafting (AP). The thermogels were characterized in terms of the sol-gel temperature, scanning electron microscopy (SEM), degradation ratio, and skin permeation behavior. The chemical grafting of alginate to PF127 could delay the sol-gel temperature from 24.1 to 30.4°C, which is near the temperature of the skin surface. The gelling temperature of the physical mixture of alginate and PF127 (A+P) did not significantly differ. The porosity of the A+P structure was greater compared to that of the AP structure. AP thermogels were regularly degraded, with 60% of the gel matrix remaining after a 48-h incubation. PF127 and A+P hydrogels showed almost no degradation. The results of skin permeation across porcine skin and nude mouse skin suggested that the thermogels could produce sustained selegiline release, with AP showing the most-sustained permeation. AP hydrogels exhibited linear permeation properties for the transdermal delivery of selegiline. Inter-subject variations in skin permeation were reduced by incorporation of the thermogel. Such a thermosensitive hydrogel can be advantageous as a topical therapeutic formulation for selegiline.
Asunto(s)
Alginatos/química , Portadores de Fármacos/química , Inhibidores de la Monoaminooxidasa/administración & dosificación , Poloxámero/química , Selegilina/administración & dosificación , Piel/metabolismo , Administración Cutánea , Animales , Cromatografía Líquida de Alta Presión , Portadores de Fármacos/síntesis química , Composición de Medicamentos , Femenino , Liofilización , Ácido Glucurónico/química , Ácidos Hexurónicos/química , Hidrogeles , Técnicas In Vitro , Ratones , Ratones Desnudos , Microscopía Electrónica de Rastreo , Inhibidores de la Monoaminooxidasa/química , Inhibidores de la Monoaminooxidasa/farmacocinética , Transición de Fase , Selegilina/química , Selegilina/farmacocinética , Absorción Cutánea , Temperatura Cutánea , Propiedades de Superficie , Porcinos , Temperatura de TransiciónRESUMEN
There are few diagnostic tools for chronic musculoskeletal pain as structural imaging methods seldom reveal pathological alterations. This is especially true for Whiplash Associated Disorder, for which physical signs of persistent injuries to the neck have yet to be established. Here, we sought to visualize inflammatory processes in the neck region by means Positron Emission Tomography using the tracer (11)C-D-deprenyl, a potential marker for inflammation. Twenty-two patients with enduring pain after a rear impact car accident (Whiplash Associated Disorder grade II) and 14 healthy controls were investigated. Patients displayed significantly elevated tracer uptake in the neck, particularly in regions around the spineous process of the second cervical vertebra. This suggests that whiplash patients have signs of local persistent peripheral tissue inflammation, which may potentially serve as a diagnostic biomarker. The present investigation demonstrates that painful processes in the periphery can be objectively visualized and quantified with PET and that (11)C-D-deprenyl is a promising tracer for these purposes.
Asunto(s)
Inflamación/diagnóstico por imagen , Sistema Musculoesquelético/diagnóstico por imagen , Sistema Musculoesquelético/patología , Selegilina/farmacocinética , Lesiones por Latigazo Cervical/diagnóstico por imagen , Lesiones por Latigazo Cervical/patología , Adulto , Radioisótopos de Carbono , Estudios de Casos y Controles , Vértebras Cervicales/diagnóstico por imagen , Enfermedad Crónica , Femenino , Humanos , Inflamación/patología , Masculino , Cintigrafía , Reproducibilidad de los Resultados , Factores de TiempoRESUMEN
Parkinson's disease is a complicated disease state that affects patients' quality of life. The first monoamine oxidase (MAO-B) inhibitor for PD, selegiline (Eldepryl), was approved by the Food and Drug Administration (FDA) in 1996, and rasagiline (Azilect) received FDA approval in 2006. At first, pharmacists may assume that rasagiline is just another me-too drug. There are three areas in which the two medications differ from each other: MAO type A inhibitors are found in high concentrations in the intestines, and MAO type B inhibitors are found mostly in the brain. If MAO-A inhibition occurs, the body cannot protect itself from exogenous amines such as tyramine. The absorbed tyramine can cause hypertensive crisis, also known as the cheese reaction. Selegiline's capsule product labeling includes a bolded warning that it "should not be used at daily doses exceeding 10 mg per day because of the risks associated with non-selective inhibition of MAO." It also says, "the selectivity of selegiline for MAO B may not be absolute, even at the recommended daily dose." The fact that rasagiline has the same effect has been challenged by two main-stream studies. Selegiline is a propargyl amphetamine derivative that undergoes extensive first-pass metabolism to L-methamphetamine and L-amphetamine. Rasagiline's major metabolite is amioindan, which has no amphetaminelike properties. Selegiline has been reviewed looking for neuroprotection, but studies have been unable to come to a definite positive neuroprotection conclusion. Proponents of rasagiline's neuroprotective effects also point to clinical studies in humans that demonstrate delayed and reduced need for future use of levodopa. In summary, selegiline and rasagiline look more and more like distant cousins instead of twins.
Asunto(s)
Indanos/efectos adversos , Indanos/farmacología , Inhibidores de la Monoaminooxidasa/efectos adversos , Inhibidores de la Monoaminooxidasa/farmacología , Selegilina/efectos adversos , Selegilina/farmacología , Humanos , Inactivación Metabólica/fisiología , Indanos/farmacocinética , Inhibidores de la Monoaminooxidasa/farmacocinética , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Selegilina/farmacocinéticaRESUMEN
Monoamine oxidase (MAO) inhibitors were the first antidepressants introduced, but their use has dwindled because of their reported side effects, their food and drug interactions, and the introduction of other classes of agents. However, interest in MAO inhibitors is reviving. Here, we discuss their use, risks, and benefits in clinical medicine.
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Antidepresivos/efectos adversos , Presión Sanguínea/efectos de los fármacos , Hipertensión/inducido químicamente , Inhibidores de la Monoaminooxidasa/efectos adversos , Selegilina/uso terapéutico , Administración Cutánea , Antidepresivos/uso terapéutico , Queso , Trastorno Depresivo Mayor/tratamiento farmacológico , Conducta Alimentaria , Interacciones Alimento-Droga , Humanos , Hipertensión/prevención & control , Inhibidores de la Monoaminooxidasa/uso terapéutico , Miocardio , Factores de Riesgo , Selegilina/efectos adversos , Selegilina/farmacocinética , TiraminaRESUMEN
Deprenyl has been discovered by Knoll and co-workers. The R-enantiomer of deprenyl (selegiline) is a selective and irreversible inhibitor of the B-isoform of monoamine oxidase (MAO-B) enzyme. Due to its dopamine potentiating and possible neuroprotective properties it has an established role in the treatment of parkinsonian patients. By inhibiting MAO-B enzyme, R-deprenyl decreases the formation of hydrogen peroxide, alleviating the oxidative stress also reduced by increased expression of antioxidant enzymes (superoxide dismutases and catalase) reported during chronic treatment. It was shown to prevent the detrimental effects of neurotoxins like MPTP and DSP-4. R-Deprenyl elicits neuroprotective and neuronal rescue activities in concentrations too low to inhibit MAO-B. It is extensively metabolized and some of the metabolites possess pharmacological activities, thus their contribution to neuroprotective properties was also suggested. The recently identified deprenyl-N-oxide is extensively studied in our laboratory. Effects other than neuroprotection, like influencing cell adhesion and proliferation cannot be neglected.
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Inhibidores de la Monoaminooxidasa/farmacología , Selegilina/farmacología , Animales , Humanos , Inhibidores de la Monoaminooxidasa/farmacocinética , Fármacos Neuroprotectores/farmacocinética , Fármacos Neuroprotectores/farmacología , Selegilina/farmacocinética , EstereoisomerismoRESUMEN
BACKGROUND: The selective MAO-B inhibitor selegiline has been evaluated in clinical trials as a potential medication for the treatment of cocaine dependence. This study evaluated the safety of and pharmacologic interactions between 7 days of transdermal selegiline dosed with patches (Selegiline Transdermal System, STS) that deliver 6 mg/24 hours and 2.5 mg/kg of cocaine administered over 4 hours. METHODS: Twelve nondependent cocaine-experienced subjects received deuterium-labeled cocaine-d5 intravenously (IV) 0.5 mg/kg over 10 minutes followed by 2 mg/kg over 4 hours before and after one week of transdermal selegiline 6 mg/24 hours. Plasma and urine were collected for analysis of selegiline, cocaine, catecholamine and metabolite concentrations. Pharmacodynamic measures were obtained. RESULTS: Selegiline did not change cocaine pharmacokinetic parameters. Selegiline administration increased phenylethylamine (PEA) urinary excretion and decreased urinary MHPG-sulfate concentration after cocaine when compared to cocaine alone. No serious adverse effects occurred with the combination of selegiline and cocaine, and cocaine-induced physiological effects were unchanged after selegiline. Only 1 peak subjective cocaine effects rating changed, and only a few subjective ratings decreased across time after selegiline. CONCLUSION: No pharmacological interaction occurred between selegiline and a substantial dose of intravenous cocaine, suggesting the combination will be safe in pharmacotherapy trials. Selegiline produced few changes in subjective response to the cocaine challenge perhaps because of some psychoactive neurotransmitters changing in opposite directions.
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Cocaína/farmacología , Inhibidores de Captación de Dopamina/farmacología , Inhibidores de la Monoaminooxidasa/farmacología , Selegilina/farmacología , Administración Cutánea , Adulto , Afecto/efectos de los fármacos , Anfetamina/metabolismo , Anfetaminas/metabolismo , Análisis de Varianza , Cocaína/administración & dosificación , Cocaína/análogos & derivados , Cocaína/metabolismo , Cocaína/farmacocinética , Cocaína/toxicidad , Inhibidores de Captación de Dopamina/farmacocinética , Inhibidores de Captación de Dopamina/toxicidad , Interacciones Farmacológicas/fisiología , Femenino , Ácido Homovanílico/sangre , Ácido Homovanílico/metabolismo , Humanos , Infusiones Intravenosas , Masculino , Metanfetamina/metabolismo , Metoxihidroxifenilglicol/análogos & derivados , Metoxihidroxifenilglicol/metabolismo , Metoxihidroxifenilglicol/orina , Monitoreo Fisiológico , Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/administración & dosificación , Inhibidores de la Monoaminooxidasa/farmacocinética , Fenetilaminas/metabolismo , Fenetilaminas/orina , Prolactina/sangre , Prolactina/metabolismo , Selegilina/administración & dosificación , Selegilina/farmacocinética , Estadísticas no Paramétricas , Síndrome de Abstinencia a Sustancias/psicología , Adulto JovenRESUMEN
In the present work, we attempted to design a transdermal system for delivering selegiline using a hydrogel-based drug reservoir and a rate-controlling membrane (Solupor polyethylene membranes). The appearances of these preparations were evaluated by scanning electron microscopy (SEM), and the in vitro skin permeation of selegiline across porcine skin was examined. Both the R- and S-forms of selegiline were examined in this study to elucidate the stereoselectivity of skin to selegiline. Solupor membranes and hydrogels exhibited a cross-linking structure with micropores. R-Selegiline revealed a flux of 1.13 microg/cm(2)/h across porcine skin. Solupor membranes were rate limiting for skin permeation of selegiline. Around a 2-fold reduction in the drug flux was determined after Solupor membrane incorporation. There were no significant differences in drug flux across the four Solupor membranes tested. The flux of R-selegiline from cellulose hydrogels approximated that from the aqueous solution (control). Both the membrane and hydrogel greatly reduced the inter-subject variations in skin permeation. According to the results of skin permeation and the partition coefficient between the skin and water (logP(skin/water)), the S-enantiomer may be preferable for permeation into the skin. However, the R- and S-forms demonstrated equal absorption of the drug fluxed in the presence of the membrane and/or the hydrogel. The results of this study encouraged us to further investigate hydrogel-membrane delivery systems for transdermal selegiline administration.
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Sistemas de Liberación de Medicamentos/métodos , Membranas Artificiales , Inhibidores de la Monoaminooxidasa/farmacocinética , Selegilina/farmacocinética , Absorción Cutánea , Administración Cutánea , Animales , Hidrogeles/química , Técnicas In Vitro , Permeabilidad , Polietileno/química , Estereoisomerismo , PorcinosRESUMEN
Stimulants are banned by the World Anti-Doping Agency (WADA) if used "in competition". Being the analysis of stimulants presently carried out on urine samples only, it might be useful, for a better interpretation of analytical data, to discriminate between an early intake of the substance and an administration specifically aimed to improve the sport performance. The purpose of the study was to investigate the differences, in terms of excretion/disappearance of drugs, between urine and oral fluid, a sample that can reflect plasmatic concentrations. Oral fluid and urine samples were collected following oral administration of the following stimulants: modafinil (100 mg), selegiline (10 mg), crotetamide/cropropamide (50 mg each), pentetrazol (100 mg), ephedrine (12 mg), sibutramine (10 mg), mate de coca (a dose containing about 3mg of cocaine); analysis of drugs/metabolites was carried out by gas chromatography/mass spectrometry (GC/MS) in both body fluids. Our results show that both the absolute concentrations and their variation as a function of time, in urine and in oral fluid, are generally markedly different, being the drugs eliminated from urine much more slowly than from oral fluid. Our results also suggest that the analysis of oral fluid could be used to successfully complement the data obtained from urine for "in competition" anti-doping tests; in all those cases in which the metabolite(s) concentration of a substance in urine is very low and the parent compound is not detected, it is indeed impossible, relying on urinary data only, to discriminate between recent administrations of small doses and remote administrations of higher doses.