Consenso de expertos españoles sobre el uso de la safinamida en la enfermedad de Parkinson / Spanish expert consensus on the use of safinamide in Parkinson's disease

La safinamida es un nuevo fármaco para el tratamiento de pacientes con enfermedad de Parkinson (EP) con fluctuaciones como tratamiento complementario a levodopa. Dado que por el momento aún no existen estudios de fase IV postautorización debido a la reciente incorporación de la safinamida a la práctica clínica habitual, el interés de este proyecto radica en el desarrollo de una guía de manejo clínico de la safinamida basada en las opiniones de expertos de trastornos del movimiento. Este proyecto se desarrolló en 2 fases: una primera fase que constó de 16 reuniones locales y una segunda fase que consistió en una reunión nacional. Dichas reuniones siguieron un guion de trabajo preestablecido. Tras la reunión nacional se recopilaron las principales conclusiones de los expertos, que han supuesto la base para redactar la presente guía clínica. Se concluyó que la safinamida es eficaz en la reducción de las fluctuaciones motoras y no motoras. Los pacientes con EP con fluctuaciones leves-moderadas son los que más se benefician del tratamiento, si bien el fármaco puede contribuir a mejorar diversos problemas clínicos en pacientes con EP avanzada. Se ha destacado la posibilidad de reducir la dosis de otros fármacos dopaminérgicos tras la introducción de la safinamida, lo cual contribuiría a reducir efectos adversos como el trastorno de control de impulsos. Se hipotetizó sobre el posible efecto de la safinamida sobre la mejoría de las discinesias a dosis más altas de las habitualmente utilizadas. Se ha consensuado que la safinamida es bien tolerada y presenta un perfil de efectos adversos favorable frente a placebo. (AU)

Safinamide is a new add-on drug to levodopa for the treatment of Parkinson's disease (PD) with motor fluctuations. Due to the recent incorporation of safinamide into routine clinical practice, no post-authorisation phase IV studies on the safety of safinamide have been conducted to date. This study provides clinical management guidelines for safinamide based on the opinion of a group of experts in movement disorders. This project was developed in 2 phases: 16 local meetings in phase 1 and a national meeting in phase 2. The meetings followed a pre-established agenda. The present clinical practice guidelines are based on the main conclusions reached during the national meeting. The group concluded that safinamide is effective in reducing motor and non-motor fluctuations. PD patients with mild-to-moderate fluctuations benefit most from treatment, although the drug may also improve the clinical status of patients with advanced PD. The dose of other dopaminergic drugs may be reduced after introducing safinamide, which would contribute to reducing such adverse reactions as impulse control disorder. At doses higher than those usually prescribed, safinamide may also improve dyskinesia. The experts agreed that safinamide is well tolerated and causes few adverse reactions when compared with placebo. (AU)

Hipersexualidad en relación con safinamida / Hypersexuality associated with safinamide

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Anatomical distribution of primary amine oxidase activity in four adipose depots and plasma of severely obese women with or without a dysmetabolic profile

Semicarbazide-sensitive amine oxidase (SSAO), identical to primary amine oxidase or vascular adhesion protein-1, is a membrane enzyme that generates hydrogen peroxide. SSAO is highly expressed at the adipocyte surface, and its plasma levels increase with type 2 diabetes. Since visceral adipose tissue (AT) is more tightly associated with obesity complications than subcutaneous (SC) abdominal fat, we compared SSAO activity in plasma and 4 distinct AT locations in 48 severely obese women (body mass index (BMI), averaging 54 ± 11 kg/m2), with or without a dysmetabolic profile. Higher glucose and triacylglycerol levels vs lower high-density lipoprotein (HDL)-cholesterol characterized dysmetabolic women (DYS; n = 25) from non-dysmetabolic (NDYS; n = 23), age- and weight-matched subjects. SC, mesenteric (ME), omental (OM), and round ligament (RL) fat locations were collected during bariatric surgery. SSAO capacity to oxidize up to 1 mM benzylamine was determined in AT and plasma with radiometric and fluorimetric methods. Plasma SSAO was higher in the DYS group. SSAO activity was higher in fat than in plasma, when expressed as radiolabeled benzaldehyde per milligram of protein. In ATs from DYS women, protein content was 10 % higher, and basal hydrogen peroxide release lower than in NDYS subjects, except for RL location. The SSAO affinity towards benzylamine did not exhibit regional variation and was not altered by a dysmetabolic profile (K m averaging 184 ± 7 μM; n = 183). Although radiometric and fluorimetric methods gave different estimates of oxidase activity, both indicated that AT SSAO activity did not vary according to anatomical location and/or metabolic status in severely obese women

Benzylamine antihyperglycemic effect is abolished by AOC3 gene invalidation in mice but not rescued by semicarbazide-sensitive amine oxidase expression under the control of aP2 promoter

Semicarbazide-sensitive amine oxidase (SSAO) is a transmembrane enzyme that metabolizes primary amines from endogenous or dietary origin. SSAO is highly expressed in adipose, smooth muscle and endothelial cells. In each of these cell types, SSAO is implicated in different biological functions, such as glucose transport activation, extracellular matrix maturation and leucocyte extravasation, respectively. However, the physiological functions of SSAO and their involvement in pathogenesis remain uncompletely characterized. To better understand the role of adipose tissue SSAO, we investigated whether it was necessary and/or sufficient to produce the antihyperglycemic effect of the SSAO-substrate benzylamine, already reported in mice. Therefore, we crossed SSAO-deficient mice invalidated for AOC3 gene and transgenic mice expected to express human SSAO in an adipocyte-specific manner, under the control of aP2 promoter. The aP2-human AOC3 construct (aP2-hAOC3) was equally expressed in the adipose tissue of mice expressing or not the native murine form and almost absent in other tissues. However, the corresponding SSAO activity found in adipose tissue represented only 20 % that of control mice. As a consequence, the benzylamine antihyperglycemic effect observed during glucose tolerance test in control was abolished in AOC3-KO mice but not rescued in mice expressing aP2-hAOC3. The capacity of benzylamine or methylamine to activate glucose uptake in adipocytes exhibited parallel variations in the corresponding genotypes. Although the aP2-hAOC3 construct did not allow a total rescue of SSAO activity in adipose tissue, it could be assessed from our observations that adipocyte SSAO plays a pivotal role in the increased glucose tolerance promoted by pharmacological doses of benzylamine (AU)

Aportación de los nuevos anticoagulantes orales al tratamiento del síndrome coronario agudo / Contribution of the new oral anticoagulants to the treatment of acute coronary syndrome

El síndrome coronario agudo (SCA) aparece tras la ruptura de una placa aterosclerótica y la consiguiente activación plaquetaria y de la coagulación que conducen a la formación de trombo y la obstrucción coronaria. La trombina y el factor X activado son elementos clave en la cascada de la coagulación. La utilización de anticoagulantes en el síndrome coronario agudo durante la fase aguda y a largo plazo ha mejorado su pronóstico debido a la reducción de episodios trombóticos, pero asociándose a mayor riesgo de sangrado. En los últimos años se han desarrollado nuevos anticoagulantes orales que no requieren monitorización y presentan menor riesgo de sangrado. Rivaroxaban es el único que presenta un perfil de riesgo-beneficio favorable en pacientes con síndrome coronario agudo. El estudio ATLAS ACS 2-TIMI 51 es el primer ensayo de fase III que demuestra que la adición de rivaroxaban a dosis bajas a la terapia antiagregante óptima reduce la mortalidad, la mortalidad cardiovascular, el infarto o el ictus sin un aumento significativo en los sangrados fatales (AU)

Acute coronary syndrome (ACS) occurs as a result of atherosclerotic plaque rupture and subsequent platelet activation and coagulation leading to thrombus formation and coronary occlusion. Thrombin and activated factor X (FXa) are key elements in the coagulation cascade. The use of anticoagulants in ACS, both in the acute phase and in the long term, has improved prognosis by reducing thrombotic events, but is associated with an increased risk of bleeding. In recent years, new oral anticoagulants have been developed that do not require monitoring and produce a lower risk of bleeding. Rivaroxaban is the only drug with a favorable risk-benefit profile in patients with ACS. The ATLAS ACS TIMI 2-51 is the first phase III trial demonstrating that the addition of low-dose rivaroxaban to optimal antiplatelet therapy reduces mortality, cardiovascular mortality, infarct or stroke without significantly increasing fatal bleeding (AU)

Manejo clínico de los nuevos anticoagulantes / Clinical management of the new anticoagulants

Los antagonistas de la vitamina K (AVK) actualmente disponibles para la prevención del ictus en pacientes con fibrilación auricular tienen diversos inconvenientes, por su dificultad de manejo y riesgo de sangrado. Actualmente están en desarrollo diversos fármacos que serían posibles sustitutos de los AVK y que tienen grandes ventajas, siendo las principales la ausencia de necesidad de monitorización y las escasas interacciones farmacológicas y con los alimentos. Presentamos una revisión de los nuevos anticoagulantes orales que están en fases más avanzadas de investigación clínica, sus propiedades farmacológicas, ventajas y desventajas y los resultados en recientes ensayos clínicos (AU)

The vitamin K antagonists (VKA) available for stroke prevention in patients with atrial fibrillation have many drawbacks due to their difficult clinical use and high risk of bleeding. Currently, several drugs are being developed as possible substitutes for VKA that have many advantages such as the lack of monitoring requirement and scarce pharmacologic and food interactions. The present article provides an update on the new oral anticoagulants that are in a more advanced stage of clinical research, their pharmacologic properties, advantages and disadvantages and their results in recent clinical trials (AU)

Influence of acute and chronic administration ofbenzylamine on glucose tolerance in diabetic andobese mice fed on very high-fat diet

The combination of vanadate plus benzylamine has been reported to stimulateglucose transport in rodent adipocytes and to mimic other insulin actions in diversestudies. However, benzylamine alone activates glucose uptake in human fat cells andincreases glucose tolerance in rabbits. The aim of this work was to unravel the benzylamineantihyperglycemic action and to test whether its chronic oral administrationcould restore the defective glucose handling of mice rendered slightly obese anddiabetic by very high-fat diet (VHFD). When VHFD mice were i.p. injected withbenzylamine at 0.7 to 700 ìmol/kg before glucose tolerance test, they exhibitedreduced hyperglycemic response without alteration of insulin secretion. Whole bodyglucose turnover, as assessed by the glucose isotopic dilution technique, wasunchanged in mice perfused with benzylamine (total dose of 75 ìmol/kg). However,their in vivo glycogen synthesis rate was increased. Benzylamine appeared thereforeto directly facilitate glucose utilisation in peripheral tissues. When given chronicallyat 2000 or 4000 ìmol/kg/d in drinking water, benzylamine elicited a slightreduction of water consumption but did not change body weight or adiposity anddid not modify oxidative stress markers. Benzylamine treatment improved glucose tolerance but failed to normalize the elevated glucose fasting plasma levels of VHFDmice. There was no influence of benzylamine ingestion on lipolytic activity, basal andinsulin-stimulated glucose uptake, and on inflammatory adipokine expression inadipocytes. The improvement of glucose tolerance and the lack of adverse effects onadipocyte metabolism, reported here in VHFD mice allow to consider orally givenbenzylamine as a potential antidiabetic strategy which deserves to be further studiedin other diabetic models (AU)

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Influence of high-fat diet on amine oxidase activity in white adipose tissue of mice prone or resistant to diet-induced obesity

Decreased monoamine oxidase (MAO) activity has been observed in adipose tissue of obese patients. Since substrates of MAO and semicarbazide-sensitive amine oxidase (SSAO) can modify adipocyte metabolism, this work investigates whether changes in amine oxidase activity may occur during white adipose tissue (WAT) development. We evaluated MAO and SSAO activities in WAT of high-fat diet (HFD) and low-fat diet fed mice. To distinguish the effect of HFD on its own from the effect of fat mass enlargement, obesity-prone transgenic line of the FVBn strain lacking b3-adrenergic receptors (AR) but expressing human b3-AR and a2-AR (mb3-/-, hb3+/+, ha2+/-) was compared to its obesity-resistant control (mb3-/-, hb3+/+). As already reported, the former mice became obese while the latter resisted to HFD. No significant change in SSAO or MAO activity was found in WAT of both strains after HFD when expressing oxidase activity per milligram of protein. However, when considering the overall capacity of the fat depots to oxidize tyramine or benzylamine, there was an increase in MAO and SSAO activity only in the enlarged WAT of HFD-induced obese mice. Therefore, the comparison of these models allowed to demonstrate that the higher amine oxidase capacity hold in enlarged fat stores of obese mice is more likely the consequence of increased fat cell number rather than the result of an increased expression of MAO or SSAO in the adipocyte

En trabajos previos se describe que la actividad monoamino oxidasa (MAO) en el tejido adiposo disminuye en pacientes obesos. Dado que los sustratos de la MAO y de la amino oxidasa sensible a semicarbazida (SSAO) pueden modificar el metabolismo de los adipocitos, se investiga en este trabajo si se producen cambios en la actividad amino oxidasa durante el desarrollo del tejido adiposo blanco. Para ello, se evalúa el efecto de la dieta rica en grasa (HFD) respecto de la dieta control sobre la actividad MAO y SSAO en tejido adiposo de ratones transgénicos que no expresan sus propios receptores adrenérgicos b3 y que son de dos líneas diferentes: los que expresan los receptores adrenérgicos humanos b3 Y a2 (mb3 -/-, hb3+/+, ha2+/-) y que son no susceptibles a la obesidad y los que sólo expresan los b3 humanos (mb3 -/-, hb3+/+) y que son resistentes a la obesidad. Los resultados no muestran cambios significativos por efecto de la dieta en ninguno de los dos grupos de ratones sobre la actividad MAO y SSAO cuando se expresa referida a mg de proteína. Sin embargo, cuando se considera la capacidad total de los depósitos grasos para oxidar tiramina o benzilamina, so observa un aumento significativo en ambas actividades MAO y SSAO sólo en el incrementado tejido adiposo blanco de los ratones obesos por efecto de la dieta HFD. Por tanto, estos datos indican que la mayor actividad amino oxidasa de los depósitos grasos de los ratones obesos es probablemente debida al aumento del número de células adiposas, mas que a un incremento de la expresión de MAO y SSAO en los adipocitos

Effects of oral administration of benzylamine on glucose tolerance and lipid metabolism in rats

Repeated administration of benzylamine plus vanadate have been reported to exhibit anti-hyperglycemic effects in different models of diabetic rats. Likewise oral treatment with Moringa oleifera extracts which contain the alkaloïd moringine, identical to benzylamine, has also been shown to prevent hyperglycemia in alloxan-induced diabetic rats. With these observations we tested whether prolonged oral administration of benzylamine could interact with glucose and/or lipid metabolism. Seven week old male Wistar rats were treated for seven weeks with benzylamine 2.9 g/l in drinking water and were submitted to glucose tolerance tests. A slight decrease in water consumption was observed in benzylamine-treated animals while there was no change in body and adipose tissue weights at the end of treatment. Blood glucose and plasma insulin, triacylglycerol or cholesterol levels were not modified. However, benzylamine treatment resulted in a decrease in plasma free fatty acids in both fed and fasted conditions. Benzylamine treatment improved glucose tolerance as shown by the reduction of hyperglycemic response to intra-peritoneal glucose load. Oral benzylamine treatment did not alter the response of adipocytes to insulin nor to insulin-like actions of benzylamine plus vanadate, via in vitro activation of glucose transport or inhibition of lipolysis. This work demonstrates for the first time that oral administration of benzylamine alone influences glucose and lipid metabolism. However, these results obtained in normoglycemic rats require to be confirmed in diabetic models

En ratas diabéticas, la administración crónica de la combinación benzilamina más vanadato ejerce un efecto antidiabético. Recientemente se ha descrito en ratas diabéticas inducidas por aloxan una reducción de la glucemia tras el tratamiento oral con extracto de Moringa oleifera, que contiene el alcaloide moringina, idéntico a la benzilamina. Por ello, se investiga en este trabajo el efecto del tratamiento prolongado por via oral con sólo benzilamina sobre el metabolismo de la glucosa y/o los lípidos. Ratas macho Wistar de 7 semanas se trataron durante 7 semanas con benzilamina 2.9 g/l en el agua de la bebida. Al finalizar el tratamiento, las ratas fueron sometidos a un test de tolerancia a la glucosa, inyectada por via intraperitoneal. Se recogió plasma para la determinación bioquímica y se aislaron adipocitos para estudiar la lipólisis y la captación de glucosa. El tratamiento oral con benzilamina no modifica el peso corporal ni el de la grasa, ni los niveles plasmáticos de glucosa, insulina, triacilglicerol y colesterol. Sin embargo, mejora la tolerancia a la glucosa, pues reduce la respuesta hiperglucémica a la inyección intra-peritoneal de glucosa y reduce los niveles de acidos grasos, tanto en situación de ayuno como tras la ingesta. El tratamiento oral con benzilamina no modifica en el adipocito los efectos de insulina o benzilamina más vanadato sobre la activación del transporte de glucosa o la inhibición de la lipolisis. Este trabajo demuestra por vez primera que la administración oral de benzilamina influye sobre el metabolismo de los lípidos y de la glucosa. Sin embargo, estos resultados obtenidos en ratas normoglicémicas deben ser confirmados en modelos diabéticos