Polysomnographic record and successful management of augmentation in restless legs syndrome/Willis-Ekbom disease

BACKGROUND: Dopamine agonists (DAs) represent the first-line treatment in restless legs syndrome (RLS); however, in the long term, a substantial proportion of patients will develop augmentation, which is a severe drug-related exacerbation of symptoms and the main reason for late DA withdrawal. Polysomnographic features and mechanisms underlining augmentation are unknown. No practice guidelines for management of augmentation are available. METHODS: A clinical case series of 24 consecutive outpatients affected by RLS with clinically significant augmentation during treatment with immediate-release DA was performed. All patients underwent a full-night polysomnographic recording during augmentation. A switchover from immediate-release DAs (l-dopa, pramipexole, ropinirole, rotigotine) to the long-acting, extended-release formula of pramipexole was performed. RESULTS: Fifty percent of patients presented more than 15 periodic limb movements per hour of sleep during augmentation, showing longer sleep latency and shorter total sleep time than subjects without periodic limb movements. In all patients, resolution of augmentation was observed within two to four weeks during which immediate-release dopamine agonists could be completely withdrawn. Treatment efficacy of extended-release pramipexole has persisted, thus far, over a mean follow-up interval of 13 months. CONCLUSIONS: Pramipexole extended release could be an easy, safe, and fast pharmacological option to treat augmentation in patients with restless legs syndrome. As such it warrants further prospective and controlled investigations. This observation supports the hypothesis that the duration of action of the drug plays a key role in the mechanism of augmentation.

Monitoring of threo-methylphenidate enantiomers in oral fluid by capillary electrophoresis with head-column field-amplified sample injection

Threo-methylphenidate is a chiral psychostimulant drug widely prescribed to treat attention-deficit hyperactivity disorder in children and adolescents. An enantioselective CE-based assay with head-column field-amplified sample stacking for analysis of threo-methylphenidate enantiomers in liquid/liquid extracts of oral fluid is described. Analytes are electrokinetically injected across a short water plug placed at the capillary inlet and become stacked at the interface between plug and buffer. Enantiomeric separation occurs within a few minutes in a pH 3.0 phosphate/triethanolamine buffer containing 20 mg/mL (2-hydroxypropyl)-β-CD as chiral selector. The assay with six point multilevel internal calibration provides a linear response for each enantiomer in the 10-200 ng/mL concentration range, is simple, inexpensive, and reproducible, and has an LOQ of 5 ng/mL. It was applied to oral fluid patient samples that were collected up to 12 h after intake of an immediate release tablet and two different extended release formulations with racemic methylphenidate. Drug profiles could thereby be assessed in a stereoselective way. Almost no levorotary threo-methylphenidate enantiomer was detected after intake of the two extended release formulations, whereas this enantiomer was detected during the first 2.5 h after intake of the immediate release preparation. The noninvasive collection of oral fluid is an attractive alternative to plasma for the monitoring of methylphenidate exposure in the pediatric community.

Determination of absorption curves, dissolution profiles and establishment of in vitro-in vivo correlation by in silico methods using GastroPlusTM and DDDPlusTM

The use of computer programs to predict drug absorption in humans and to simulate dissolution profiles has become a valuable tool in the pharmaceutical area. The objective of this study was to use in silico methods through software GastroPlusTM and DDDPlusTM to simulate drug absorption curves and dissolution profiles, and to establish in vitro-in vivo correlations (IVIVCs). The work presented herein is divided into five chapters and includes the drugs ketoprofen, pyrimethamine, metronidazole, fluconazole, carvedilol and doxazosin. In Chapter 1, simulated plasma curves for ketoprofen matrix tablets are presented and IVIVC was established. The use of simulated intrinsic dissolution tests for pyrimethamine and metronidazole as a tool for biopharmaceutics classification is detailed in Chapter 2. In Chapter 3, simulation of plasma curves for fluconazole capsules with different dissolution profiles is demonstrated as a tool for biowaiver. IVIVC studies were also conducted for carvedilol immediate-release tablets from dissolution profiles in Chapter 4. Chapter 5 covers the application of simulated dissolution tests for development of doxazosin extended-release formulations. Simulation of plasma curves and IVIVC using the software GastroPlusTM as well as intrinsic dissolution tests and dissolution profiles using the software DDDPlusTM proved to be a tool of wide application in predicting biopharmaceutical characteristics of drugs and formulations, allowing the reduction of time and costs of experimental laboratory work.

Indwelling catheters and medical implants with FXIIIa inhibitors:a novel approach to the treatment of catheter and medical device-related infections

Central venous catheters (CVCs) are being utilized with increasing frequency in intensive care and general medical wards. In spite of the extensive experience gained in their application, CVCs are related to the long-term risks of catheter sheath formation, infection, and thrombosis (of the catheter or vessel itself) during catheterization. Such CVC-related-complications are associated with increased morbidity, mortality, duration of hospitalization, and medical care cost [1]. The present study incorporates a novel group of Factor XIIIa (FXIIIa, plasma transglutaminase) inhibitors into a lubricious silicone elastomer in order to generate an optimized drug delivery system whereby a secondary sustained drug release profile occurs following an initial burst release for catheters and other medical devices. We propose that the incorporation of FXIIIa inhibitors into catheters, stents, and other medical implant devices would reduce the incidence of catheter sheath formation, thrombotic occlusion, and associated staphylococcal infection. This technique could be used as a local delivery system for extended release with an immediate onset of action for other poorly aqueous soluble compounds. © 2012 Elsevier B.V. All rights reserved.

Design and evaluation of compound metformin/glipizide elementary osmotic pump tablets

A simple elementary osmotic pump (EOP) system that could deliver metformin hydrochloride (MT) and glipizide (GZ) simultaneously for extended periods of time was developed in order to reduce the problems associated with multidrug therapy of type 2 non-insulin-dependent diabetes mellitus. In general, both highly and poorly water-soluble drugs are not good candidates for elementary osmotic delivery. However, MT is a highly soluble drug with a high dose (500 mg) while GZ is a water-insoluble drug with a low dose (5 mg) so it is a great challenge to pharmacists to provide satisfactory extended release of MT and GZ. In this paper sodium carbonate was used to modulate the solubility of GZ within the core and MT was not only one of the active ingredients but also the osmotic agent. The optimal EOP was found to deliver both drugs at a rate of approximately zero order for up to 10 h in pH 6.8, independent of environment media. In-vivo evaluation was performed relative to the equivalent dose of conventional MT tablet and GZ tablet by a cross-study in six Beagle dogs. The EOP had a good sustained effect in comparison with the conventional product. The prototype design of the system could be applied to other combinations of drugs used for cardiovascular diseases, diabetes, etc.

Descripción de resultados de la reconstrucción de placa plantar en inestabilidad de la segunda articulación metatarsofalángica

Objetivo: Describir los desenlaces funcionales, complicaciones postoperatorias, dolor y satisfacción de un grupo de pacientes con diagnóstico de inestabilidad de segunda articulación metatarsofalángica y lesión de la placa plantar, que fueron intervenidos quirúrgicamente para su reconstrucción en el Hospital Universitario de cuarto nivel Fundación Santa Fé de Bogotá, en el periodo comprendido entre Enero de 2010 hasta Diciembre de 2015. Métodos: Estudio descriptivo de corte transversal que evalúa desenlaces funcionales, dolor y satisfacción para un grupo consecutivo de pacientes con diagnóstico de inestabilidad de la segunda articulación metatarsofalángica que fueron intervenidos quirúrgicamente mediante reconstrucción de la placa plantar entre Enero de 2010 a Diciembre de 2015 en el Hospital Universitario Fundación Santa fe de Bogotá. Resultados: El procedimiento se realizó a 39 pacientes (40 MTF), encontrando mejoría en dolor, función y satisfacción. El dolor postoperatorio paso de severo a leve en el 80% de los pacientes, 67.5% de los pacientes presentaron prueba de aprehensión positiva, 85% alineamiento adecuado, el reporte de escala de AOFAS postoperatoria fue de 87, y los resultados fueron satisfactorios en un 94.5%. La principal complicación con la cirugía fue la extensión residual del dedo operado (22.5%). Conclusiones: La reconstrucción de la placa plantar en casos de inestabilidad metatarsofalángica ha demostrado tener resultados satisfactorios, en el presente estudio encontramos mejoría respecto a dolor, función y satisfacción posterior a la realización del procedimiento. Sin embargo puede presentar complicaciones como extensión residual del dedo o elevación, rigidez y recidiva.

Laboratory and Field Evaluation of Biodegradable Polyesters for Sustained Release of Isometamidium and Ethidium

An overview is presented of the results obtained with biodegradable sustained release devices (SRDs) containing a mixture of polymers and either isometamidium (ISMM) or ethidium. Under controlled laboratory conditions (monthly challenge with tsetse flies infected with Trypanosoma congolense) the protection period in SRD treated cattle could be extended by a factor 2.8 (for ethidium) up to 4.2 (for ISMM) as compared to animals treated intramuscularly with the same drugs. Using a competitive drug ELISA ISMM concentrations were detected up to 330 days after the implantation of the SRDs, whereas after i.m. injection the drug was no longer present three to four months post treatment. Two field trials carried out in Mali under heavy tsetse challenge showed that the cumulative infection rate was significantly lower in the ISMM-SRD implanted cattle than in those which received ISMM intramuscularly. Using ethidium SRD, however, contradictory results were obtained in field trials in Zambia and in Mali. The potential advantages and inconvenients of the use of SRDs are discussed and suggestions are made in order to further improve the currently available devices.

Intraocular implants for extended drug delivery: therapeutic applications.

An overview of ocular implants with therapeutic application potentials is provided. Various types of implants can be used as slow release devices delivering locally the needed drug for an extended period of time. Thus, multiple periocular or intraocular injections of the drug can be circumvented and secondary complications minimized. The various compositions of polymers fulfilling specific delivery goals are described. Several of these implants are undergoing clinical trials while a few are already commercialized. Despite the paramount progress in design, safety and efficacy, the place of these implants in our clinical therapeutic arsenal remains limited. Miniaturization of the implants allowing for their direct injection without the need for a complicated surgery is a necessary development avenue. Particulate systems which can be engineered to target specifically certain cells or tissues are another promising alternative. For ocular diseases affecting the choroid and outer retina, transscleral or intrasscleral implants are gaining momentum.

High-amylose carboxymethyl starch matrices for oral sustained drug-release : in vitro and in vivo evaluation

Les amidons non modifiées et modifiés représentent un groupe d’excipients biodégradables et abondants particulièrement intéressant. Ils ont été largement utilisés en tant qu’excipients à des fins diverses dans des formulations de comprimés, tels que liants et/ou agents de délitement. Le carboxyméthylamidon sodique à haute teneur en amylose atomisé (SD HASCA) a été récemment proposé comme un excipient hydrophile à libération prolongée innovant dans les formes posologiques orales solides. Le carboxyméthylamidon sodique à haute teneur en amylose amorphe (HASCA) a d'abord été produit par l'éthérification de l'amidon de maïs à haute teneur en amylose avec le chloroacétate. HASCA a été par la suite séché par atomisation pour obtenir le SD HASCA. Ce nouvel excipient a montré des propriétés présentant certains avantages dans la production de formes galéniques à libération prolongée. Les comprimés matriciels produits à partir de SD HASCA sont peu coûteux, simples à formuler et faciles à produire par compression directe. Le principal objectif de cette recherche était de poursuivre le développement et l'optimisation des comprimés matriciels utilisant SD HASCA comme excipient pour des formulations orales à libération prolongée. A cet effet, des tests de dissolution simulant les conditions physiologiques du tractus gastro-intestinal les plus pertinentes, en tenant compte de la nature du polymère à l’étude, ont été utilisés pour évaluer les caractéristiques à libération prolongée et démontrer la performance des formulations SD HASCA. Une étude clinique exploratoire a également été réalisée pour évaluer les propriétés de libération prolongée de cette nouvelle forme galénique dans le tractus gastro-intestinal. Le premier article présenté dans cette thèse a évalué les propriétés de libération prolongée et l'intégrité physique de formulations contenant un mélange comprimé de principe actif, de chlorure de sodium et de SD HASCA, dans des milieux de dissolution biologiquement pertinentes. L'influence de différentes valeurs de pH acide et de temps de séjour dans le milieu acide a été étudiée. Le profil de libération prolongée du principe actif à partir d'une formulation de SD HASCA optimisée n'a pas été significativement affecté ni par la valeur de pH acide ni par le temps de séjour dans le milieu acide. Ces résultats suggèrent une influence limitée de la variabilité intra et interindividuelle du pH gastrique sur la cinétique de libération à partir de matrices de SD HASCA. De plus, la formulation optimisée a gardé son intégrité pendant toute la durée des tests de dissolution. L’étude in vivo exploratoire a démontré une absorption prolongée du principe actif après administration orale des comprimés matriciels de SD HASCA et a montré que les comprimés ne se sont pas désintégrés en passant par l'estomac et qu’ils ont résisté à l’hydrolyse par les α-amylases dans l'intestin. Le deuxième article présente le développement de comprimés SD HASCA pour une administration orale une fois par jour et deux fois par jour contenant du chlorhydrate de tramadol (100 mg et 200 mg). Ces formulations à libération prolongée ont présenté des valeurs de dureté élevées sans nécessiter l'ajout de liants, ce qui facilite la production et la manipulation des comprimés au niveau industriel. La force de compression appliquée pour produire les comprimés n'a pas d'incidence significative sur les profils de libération du principe actif. Le temps de libération totale à partir de comprimés SD HASCA a augmenté de manière significative avec le poids du comprimé et peut, de ce fait, être utilisé pour moduler le temps de libération à partir de ces formulations. Lorsque les comprimés ont été exposés à un gradient de pH et à un milieu à 40% d'éthanol, un gel très rigide s’est formé progressivement sur leur surface amenant à la libération prolongée du principe actif. Ces propriétés ont indiqué que SD HASCA est un excipient robuste pour la production de formes galéniques orales à libération prolongée, pouvant réduire la probabilité d’une libération massive de principe actif et, en conséquence, des effets secondaires, même dans le cas de co-administration avec une forte dose d'alcool. Le troisième article a étudié l'effet de α-amylase sur la libération de principe actif à partir de comprimés SD HASCA contenant de l’acétaminophène et du chlorhydrate de tramadol qui ont été développés dans les premières étapes de cette recherche (Acetaminophen SR et Tramadol SR). La modélisation mathématique a montré qu'une augmentation de la concentration d’α-amylase a entraîné une augmentation de l'érosion de polymère par rapport à la diffusion de principe actif comme étant le principal mécanisme contrôlant la libération de principe actif, pour les deux formulations et les deux temps de résidence en milieu acide. Cependant, même si le mécanisme de libération peut être affecté, des concentrations d’α-amylase allant de 0 UI/L à 20000 UI/L n'ont pas eu d'incidence significative sur les profils de libération prolongée à partir de comprimés SD HASCA, indépendamment de la durée de séjour en milieu acide, le principe actif utilisé, la teneur en polymère et la différente composition de chaque formulation. Le travail présenté dans cette thèse démontre clairement l'utilité de SD HASCA en tant qu'un excipient à libération prolongée efficace.

Apatite-Polymer Composite Particles for Controlled Delivery of BMP-2: In Vitro Release and Cellular Response

Bone morphogenetic protein-2 (BMP-2) has the ability to induce osteoblast differentiation of undifferentiated cells, resulting in the healing of skeletal defects when delivered with a suitable carrier. We have applied a versatile delivery platform comprising a novel composite of two biomaterials with proven track records – apatite and poly(lactic-co-glycolic acid) (PLGA) – to the delivery of BMP-2. Sustained release of this growth factor was tuned with variables that affect polymer degradation and/or apatite dissolution, such as polymer molecular weight, polymer composition, apatite loading, and apatite particle size. The effect of released BMP-2 on C3H10T1/2 murine pluripotent mesenchymal cells was assessed by tracking the expression of osteoblastic makers, alkaline phosphatase (ALP) and osteocalcin. Release media collected over 100 days induced elevated ALP activity in C3H10T1/2 cells. The expression of osteocalcin was also upregulated significantly. These results demonstrated the potential of apatite-PLGA composite particles for releasing protein in bioactive form over extended periods of time.

Fabrication of Controlled Release Devices Using Supercritical Antisolvent Method

In this study, the supercritical antisolvent with enhanced mass transfer method (SASEM) is used to fabricate micro and nanoparticles of biocompatible and biodegradable polymer PLGA (poly DL lactide co glycolic acid). This process may be extended to the encapsulation of drugs in these micro and nanoparticles for controlled release purposes. Conventional supercritical antisolvent (SAS) process involves spraying a solution (organic solvent + dissolved polymer) into supercritical fluid (CO[subscript 2]), which acts as an antisolvent. The high rate of mass transfer between organic solvent and supercritical CO[subscript 2] results in supersaturation of the polymer in the spray droplet and precipitation of the polymer as micro or nanoparticles occurs. In the SASEM method, ultrasonic vibration is used to atomize the solution entering the high pressure with supercritical CO[subscript 2]. At the same time, the ultrasonic vibration generated turbulence in the high pressure vessel, leading to better mass transfer between the organic solvent and the supercritical CO₂. In this study, two organic solvents, acetone and dichloromethane (DCM) were used in the SASEM process. Phase Doppler Particle Analyzer (PDPA) was used to study the ultrasonic atomization of liquid using the ultrasonic probe for the SASEM process. Scanning Electron Microscopy (SEM) was used to study the size and morphology of the polymer particles collected at the end of the process.

Synaptic vesicle glycoprotein 2A modulates vesicular release and calcium channel function at peripheral sympathetic synapses

Synaptic vesicle glycoprotein (SV)2A is a transmembrane protein found in secretory vesicles and is critical for Ca2+-dependent exocytosis in central neurons, although its mechanism of action remains uncertain. Previous studies have proposed, variously, a role of SV2 in the maintenance and formation of the readily releasable pool (RRP) or in the regulation of Ca2+ responsiveness of primed vesicles. Such previous studies have typically used genetic approaches to ablate SV2 levels; here, we used a strategy involving small interference RNA (siRNA) injection to knockdown solely presynaptic SV2A levels in rat superior cervical ganglion (SCG) neuron synapses. Moreover, we investigated the effects of SV2A knockdown on voltage-dependent Ca2+ channel (VDCC) function in SCG neurons. Thus, we extended the studies of SV2A mechanisms by investigating the effects on vesicular transmitter release and VDCC function in peripheral sympathetic neurons. We first demonstrated an siRNA-mediated SV2A knockdown. We showed that this SV2A knockdown markedly affected presynaptic function, causing an attenuated RRP size, increased paired-pulse depression and delayed RRP recovery after stimulus-dependent depletion. We further demonstrated that the SV2A–siRNA-mediated effects on vesicular release were accompanied by a reduction in VDCC current density in isolated SCG neurons. Together, our data showed that SV2A is required for correct transmitter release at sympathetic neurons. Mechanistically, we demonstrated that presynaptic SV2A: (i) acted to direct normal synaptic transmission by maintaining RRP size, (ii) had a facilitatory role in recovery from synaptic depression, and that (iii) SV2A deficits were associated with aberrant Ca2+ current density, which may contribute to the secretory phenotype in sympathetic peripheral neurons.

Biomass fire consumption and carbon release rates of rainforest-clearing experiments conducted in northern Mato Grosso, Brazil

Biomass consumption and carbon release rates during the process of forest clearing by fire in five test plots are presented and discussed. The experiments were conducted at the Caiabi Farm near the town of Alta Floresta, state of Mato Grosso, Brazil, in five square plots of 1 ha each designated A, B, C, D, and E, with different locations and timing of fire. Plot A was located in the interface with a pasture, with three edges bordering on the forest, and was cut and burned in 1997. Plots B,C, D, and E were located inside the forest. Plot B was cut and burned in 1997. Plot C was inside a deforested 9-ha area, which was cut and burned in 1998. Plot D was inside a deforested 4-ha area, which was cut in 1998 and burned in 1999. Plot E was inside a deforested 4-ha area which was cut and burned in 1999. Biomass consumption was 22.7%, 19.5%, 47.5%, 61.5% and 41.8%, for A, B, C, D, and E, respectively. The effects of an extended curing period and of increasing the deforested area surrounding the plots could be clearly observed. The consumption for areas cut and burned during the same year, tended toward a value of nearly 50% when presented as a function of the total area burned. The aboveground biomass of the test site and the amount of carbon before the fire were 496 Mg ha-1 and 138 Mg ha-1, respectively. Considering that the biomass that remains unburned keeps about the same average carbon content of fresh biomass, which is supported by the fact that the unburned material consists mainly of large logs and considering the value of 50% for consumption, the amount of carbon released to the atmosphere as gases was 69 Mg ha-1. The amounts of CO2 and CO released to the atmosphere by the burning process were then estimated as 228 Mg ha-1 and 15.9 Mg ha-1, respectively. Observations on fire propagation and general features of the slash burnings in the test areas complete the paper. Copyright 2001 by the American Geophysical Union.