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INTRODUCTION: Kidney transplantation (KTx) necessarily conveys an ischemia/reperfusion (I/R) process, which impacts on allograft outcomes. Delayed graft function (DGF) is defined as a non-decrease of serum creatinine by at least 10% daily on 3 consecutive days during the first 7 days post-KTx. DGF significantly conditions both short- and long-term graft outcomes. Still there is a lack of DGF predictive biomarkers. OBJECTIVES: This study aimed to explore the potential of kidney graft perfusate metabolomics to predict DGF occurrence. METHODS: 49 human perfusates from grafts categorized upon donor type [donation after brain death (DBD)/donation after circulatory death (DCD)] and DGF occurrence and 19 perfusates from a murine model classified upon death type (DBD/DCD) were collected and analyzed by NMR-based metabolomics. RESULTS: The multivariate analysis of the murine data highlighted significant differences between perfusate metabolomes of DBD versus DCD. These differences were similarly observed in the human perfusates. After correcting for the type of donor, multivariate analysis of human data demonstrated a metabolomics signature that could be correlated with DGF occurrence. CONCLUSIONS: The metabolome of kidney grafts is influenced by the donor's type in both human and pre-clinical studies and could be correlated with DGF in the human DBD cohort. Thus, metabolomic analysis of perfusate applied prior to KTx may represent a new predictive tool for clinicians in a more personalized management of DGF. Moreover, our data paves the way to better understand the impact of donor's types on the biochemical events occurring between death and the hypothermic storage.
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Funcionamiento Retardado del Injerto , Supervivencia de Injerto , Humanos , Animales , Ratones , Metabolómica , Riñón , AloinjertosRESUMEN
The US FDA approval of broad-spectrum histone deacetylase (HDAC) inhibitors has firmly laid the cancer community to explore HDAC inhibition as a therapeutic approach for cancer treatment. Hitting one HDAC member could yield clinical benefit but this required a complete understanding of the functions of the different HDAC members. Here we explored the consequences of specific HDAC5 inhibition in cancer cells. We demonstrated that HDAC5 inhibition induces an iron-dependent reactive oxygen species (ROS) production, ultimately leading to apoptotic cell death as well as mechanisms of mitochondria quality control (mitophagy and mitobiogenesis). Interestingly, adaptation of HDAC5-depleted cells to oxidative stress passes through reprogramming of metabolic pathways towards glucose and glutamine. Therefore, interference with both glucose and glutamine supply in HDAC5-inhibited cancer cells significantly increases apoptotic cell death and reduces tumour growth in vivo; providing insight into a valuable clinical strategy combining the selective inhibition of HDAC5 with various inhibitors of metabolism as a new therapy to kill cancer cells.
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Antineoplásicos/farmacología , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Glucosa/metabolismo , Glutamina/metabolismo , Humanos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Myoferlin is a multiple C2-domain-containing protein that regulates membrane repair, tyrosine kinase receptor function and endocytosis in myoblasts and endothelial cells. Recently it has been reported as overexpressed in several cancers and shown to contribute to proliferation, migration and invasion of cancer cells. We have previously demonstrated that myoferlin regulates epidermal growth factor receptor activity in breast cancer. In the current study, we report a consistent overexpression of myoferlin in triple-negative breast cancer cells (TNBC) over cells originating from other breast cancer subtypes. Using a combination of proteomics, metabolomics and electron microscopy, we demonstrate that myoferlin depletion results in marked alteration of endosomal system and metabolism. Mechanistically, myoferlin depletion caused impaired vesicle traffic that led to a misbalance of saturated/unsaturated fatty acids. This provoked mitochondrial dysfunction in TNBC cells. As a consequence of the major metabolic stress, TNBC cells rapidly triggered AMP activated protein kinase-mediated metabolic reprogramming to glycolysis. This reduced their ability to balance between oxidative phosphorylation and glycolysis, rendering TNBC cells metabolically inflexible, and more sensitive to metabolic drug targeting in vitro. In line with this, our in vivo findings demonstrated a significantly reduced capacity of myoferlin-deficient TNBC cells to metastasise to lungs. The significance of this observation was further supported by clinical data, showing that TNBC patients whose tumors overexpress myoferlin have worst distant metastasis-free and overall survivals. This novel insight into myoferlin function establishes an important link between vesicle traffic, cancer metabolism and progression, offering new diagnostic and therapeutic concepts to develop treatments for TNBC patients.
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Proteínas de Unión al Calcio/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas Musculares/metabolismo , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Animales , Proteínas de Unión al Calcio/biosíntesis , Línea Celular Tumoral , Vesículas Citoplasmáticas/metabolismo , Femenino , Glucólisis , Xenoinjertos , Humanos , Metabolismo de los Lípidos , Proteínas de la Membrana/biosíntesis , Ratones , Ratones Endogámicos NOD , Ratones SCID , Proteínas Musculares/biosíntesis , Metástasis de la Neoplasia , Fosforilación OxidativaRESUMEN
REASONS FOR PERFORMING STUDY: It is hypothesised that European atypical myopathy (AM) has a similar basis as seasonal pasture myopathy in North America, which is now known to be caused by ingestion of hypoglycin A contained in seeds from the tree Acer negundo. Serum from horses with seasonal pasture myopathy contained the conjugated toxic metabolite of hypoglycin A, methylenecyclopropyl acetic acid (MCPA). STUDY DESIGN: Retrospective study on archived samples. OBJECTIVES: 1) To determine whether MCPA-carnitine was present in serum of European horses confirmed to have AM; 2) to determine whether Acer negundo or related Acer species were present on AM pastures in Europe. METHODS: Concentrations of MCPA-carnitine were analysed in banked serum samples of 17 AM horses from Europe and 3 diseased controls (tetanus, neoplasia and exertional rhabdomyolysis) using tandem mass spectrometry. Atypical myopathy was diagnosed by characteristic serum acylcarnitine profiles. Pastures of 12 AM farms were visited by experienced botanists and plant species were documented. RESULTS: Methylenecyclopropyl acetic acid-carnitine at high concentrations (20.39 ± 17.24 nmol/l; range 0.95-57.63 nmol/l; reference: <0.01 nmol/l) was identified in serum of AM but not disease controls (0.00 ± 0.00 nmol/l). Acer pseudoplatanus but not Acer negundo was present on all AM farms. CONCLUSIONS: Atypical myopathy in Europe, like seasonal pasture myopathy in North America, is highly associated with the toxic metabolite of hypoglycin A, MCPA-carnitine. This finding coupled with the presence of a tree of which seeds are known to also contain hypoglycin A indicates that ingestion of Acer pseudoplatanus is the probable cause of AM. This finding has major implications for the prevention of AM.
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Ciclopropanos/sangre , Enfermedades de los Caballos/sangre , Enfermedades Musculares/veterinaria , Acer/química , Animales , Europa (Continente)/epidemiología , Femenino , Enfermedades de los Caballos/inducido químicamente , Enfermedades de los Caballos/diagnóstico , Enfermedades de los Caballos/epidemiología , Caballos , Hipoglicinas/sangre , Hipoglicinas/toxicidad , Masculino , Enfermedades Musculares/sangre , Enfermedades Musculares/inducido químicamente , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/epidemiología , Intoxicación por Plantas/diagnóstico , Intoxicación por Plantas/veterinaria , Plantas Tóxicas , Estudios Retrospectivos , Estaciones del AñoRESUMEN
BACKGROUND: 2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography (FDG-PET/CT) was carried out before and after neoadjuvant chemoradiotherapy (NCRT) followed by radical surgery for locally advanced rectal cancer (LARC). The aim of this study was to define its predictive and prognostic values. PATIENTS AND METHODS: Patients with cT3-T4 N-/+ carcinoma of medium/low rectum received daily 5-fluorouracil-based chemotherapy infusion and radiation therapy on 6-week period followed by surgery 7-8 weeks later. Tumour metabolic activity, expressed as maximum standardised uptake value (SUV-1 = at baseline and SUV-2 = pre-surgery), was calculated in the most active tumour site. Predictive and prognostic values of SUV-1, SUV-2 and Δ-SUV (percentage change of SUV-1 - SUV-2) were analysed towards pathological response (pR) in the surgical specimen and disease recurrence, respectively. RESULTS: Eighty consecutive patients entered the study. SUV-1, SUV-2 and Δ-SUV appeared singly correlated with pR, but not one of them resulted an independent predictive factor at multivariate analysis. After a median follow-up of 44 months, 13 patients (16.2%) presented local and/or distant recurrence. SUV-2 ≤5 was associated with lower incidence of disease recurrence and resulted prognostic factor at multivariate analysis. CONCLUSIONS: Dual-time FDG-PET/CT in patients with LARC treated with NCRT and radical surgery supplies limited predictive information. However, an optimal metabolic response appears associated with a favourable patient outcome.
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Fluorodesoxiglucosa F18 , Radiofármacos , Neoplasias del Recto/diagnóstico por imagen , Neoplasias del Recto/terapia , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/uso terapéutico , Terapia Combinada , Femenino , Fluorouracilo/uso terapéutico , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Terapia Neoadyuvante , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Tomografía de Emisión de Positrones , Pronóstico , Estudios Prospectivos , Curva ROC , Neoplasias del Recto/patología , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Amongst ionotropic glutamatergic receptors, the AMPA receptor subtype has been recognized as a major contributor to the fast excitatory neurotransmission in the central nervous system and the expression and maintenance of longterm potentiation. This receptor subtype also represents an interesting target to develop innovative therapeutic drugs such as positive allosteric modulators (AMPA receptor potentiators) since the enhancement of AMPA signals is expected to be beneficial in the management of several neurological disorders such as depression, schizophrenia, Parkinson's disease and learning-memory deficits linked to Alzheimer's disease. This article is dedicated to the use of (hetero) aromatic ring-fused thiadiazines (i.e. benzo- pyrido- and thienothiadiazines) as core structures for the discovery of new positive allosteric modulators of AMPA receptors. Recent advances exploring other chemotypes in the field of AMPA potentiators is the object of a separate review of the present issue.
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Receptores AMPA/química , Tiadiazinas/química , Regulación Alostérica , Humanos , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Receptores AMPA/metabolismo , Tiadiazinas/uso terapéuticoRESUMEN
First described by Alois Alzheimer in 1907, Alzheimer's disease (AD) is the most common dementia type, affecting approximately 20 million people worldwide. As the population is getting older, AD is a growing health problem. AD is currently treated by symptomatic drugs, the acetylcholinesterase inhibitors, based on the cholinergic hypothesis (1976). During the past decade, advances in neurobiology have conducted to the identification of new targets. Although some of these innovative approaches tend to delay onset of AD, others are still symptomatic. In this review, we present an overview of the several strategies and new classes of compounds against AD.
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Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/prevención & control , Aminoácidos/farmacología , Aminoácidos/uso terapéutico , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Colinérgicos/farmacología , Colinérgicos/uso terapéutico , Diseño de Fármacos , Industria Farmacéutica , Quimioterapia/tendencias , Humanos , Estrés OxidativoRESUMEN
Potassium channels play a crucial role in controlling the cell membrane potential. Among the different varieties of K(+) channels, the ATP-sensitive potassium channels (K(ATP) channels) have been characterized in numerous cell types, such as skeletal and smooth muscle cells, endocrine cells, cardiac cells and central neurons. Several molecules are known to activate K(ATP) channels and have been named "potassium channel openers" (PCOs). Such compounds may have a wide therapeutic potential and a few drugs are currently used as antihypertensive agents. Different chemical series of PCOs have been explored. This heterogeneous group of organic compounds comprises the benzopyran series including potent vasorelaxant drugs, such as cromakalim. The latter compound, a typical example of potassium channel opener, exerts its biological effect by activating K(ATP) channels. This review presents recent developments in the chemistry of cromakalim analoges and reports chemical aspects governing their potency and tissue selectivity.
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Cromakalim/análogos & derivados , Canales de Potasio/agonistas , Vasodilatadores/farmacología , Animales , Bronquios/efectos de los fármacos , Cromakalim/farmacología , Humanos , Activación del Canal Iónico/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Miocitos Cardíacos/efectos de los fármacos , Canales de Potasio/efectos de los fármacos , Relación Estructura-Actividad , Vejiga Urinaria/efectos de los fármacosRESUMEN
7-Chloro-3-pyridyl(alkyl)amino-4H-1,2,4-benzothiadiazine 1,1-dioxides and 3-alkylamino-7-chloro-4H-1,2,4-benzothiadiazine 1,1-dioxides containing one or more heteroatoms on the side chain in the 3 position have been synthesized in an attempt to discover new potent KATP-channel openers. The compounds were tested as putative pancreatic B-cells KATP channel openers by measuring their inhibitory activity on the insulin releasing process. The influence on the biological activity of the nature of the side chain in the 3 position is discussed.
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Benzotiadiazinas/farmacología , Diazóxido/análogos & derivados , Diazóxido/farmacología , Insulina/metabolismo , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Animales , Benzotiadiazinas/química , Diazóxido/química , Femenino , Antagonistas de Insulina/química , Antagonistas de Insulina/farmacología , Secreción de Insulina , Bloqueadores de los Canales de Potasio , Ratas , Ratas WistarRESUMEN
A series of 6-substituted 2-alkylaminoquinazolin-4(3H)-ones structurally related to 3-alkylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides were synthesized and tested as putative K(ATP) channel openers on isolated pancreatic endocrine tissue as well as on isolated vascular, intestinal, and uterine smooth muscle. Most of the 6-halogeno-2-alkylaminoquinazolin-4(3H)-ones were found to inhibit insulin release from pancreatic B-cells and to exhibit vasorelaxant properties. In contrast to their pyridothiadiazine dioxide isosteres previously described as more active on the endocrine than on the smooth muscle tissue, quinazolinones cannot be considered as tissue selective compounds. Biological investigations, including measurements of (86)Rb, (45)Ca efflux from pancreatic islet cells and measurements of vasodilator potency in rat aortic rings exposed to 30 or 80 mM KCl in the presence or the absence of glibenclamide, were carried out with 6-chloro- and 6-iodo-3-isopropylaminoquinazolin-4(3H)-ones. Such experiments showed that, depending on the tissue, these new compounds did not always express the pharmacological profile of pure K(ATP) channel openers. Analyzed by X-ray crystallography, one example of quinazolinones appeared to adopt a double conformation. This only suggests a partial analogy between the 2-alkylaminoquinazolin-4(3H)-ones and the 3-alkylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxides. In conclusion, the newly synthesized quinazolinones interfere with insulin secretion and smooth muscle contractile activity. Most of the compounds lack tissue selectivity, and further investigations are required to fully elucidate their mechanism(s) of action.
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Adenosina Trifosfato/metabolismo , Canales de Potasio/efectos de los fármacos , Quinazolinas/síntesis química , Animales , Aorta/efectos de los fármacos , Aorta/fisiología , Calcio , Cristalografía por Rayos X , Femenino , Gliburida/farmacología , Cobayas , Íleon/efectos de los fármacos , Íleon/fisiología , Técnicas In Vitro , Insulina/metabolismo , Secreción de Insulina , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Cloruro de Potasio/farmacología , Quinazolinas/química , Quinazolinas/farmacología , Ratas , Ratas Wistar , Rubidio , Relación Estructura-Actividad , Contracción Uterina/efectos de los fármacos , Útero/efectos de los fármacos , Útero/fisiologíaRESUMEN
Cholecystokinin (CCK) is an important 'brain-gut' hormone located both in the gastrointestinal (GI) system and in the CNS. At least two different G-coupled high affinity receptors have been identified: the CCK-A and the CCK-B receptors. Although the complex biological role of CCK is, as yet, not fully understood, its connection with many different physiological processes both at the GI level and at the CNS level is now well established. There is much potential for therapeutic use of CCK receptor ligands, however, clear investigations have yet to be completed. Several chemical families have been investigated over the last 20 years to find potent, subtype selective and stable CCK receptor agonists and antagonists. The main goal was to discover new therapeutic drugs acting on GI and/or on CNS diseases and also, to obtain powerful pharmacological tools that could permit a better understanding of the biological role of CCK. Despite promising results from investigations into medicinal chemistry of CCK receptor ligands, the therapeutical applications of these ligands still remains to be defined. This article reviews the main biological role of CCK, the therapeutic potential of CCK-A and CCK-B receptor agonists and antagonists and the common compounds from the different families of ligands.
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Drogas en Investigación , Fármacos Gastrointestinales , Receptores de Colecistoquinina , Animales , Enfermedades del Sistema Nervioso Central/tratamiento farmacológico , Fármacos Gastrointestinales/farmacología , Fármacos Gastrointestinales/uso terapéutico , Enfermedades Gastrointestinales/tratamiento farmacológico , Humanos , Ligandos , Receptor de Colecistoquinina A , Receptor de Colecistoquinina B , Receptores de Colecistoquinina/agonistas , Receptores de Colecistoquinina/antagonistas & inhibidores , Receptores de Colecistoquinina/efectos de los fármacos , Receptores de Colecistoquinina/fisiologíaRESUMEN
Cyclooxygenase is the key enzyme in the biosynthesis of prostanoids, biologically active substances that are involved in several physiological processes but also in pathological conditions such as inflammation. Since ten years now, it is well known that this enzyme exists under two forms: a constitutive (COX-1) and an inducible form (COX-2). Both enzymes are sensitive to inhibition by conventional nonsteroidal anti-inflammatory drugs (NSAIDs). Observations that COX-1, involved in several homeostatic processes, played a housekeeping role while COX-2 expression was associated with inflammation and other pathologies such as cancer proliferation have led to the development of COX-2 selective inhibitors in order to reduce the classical side-effects, of which gastric irritation is the most common, associated with the use of conventional NSAIDs.
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Inhibidores Enzimáticos/farmacología , Isoenzimas/antagonistas & inhibidores , Prostaglandina-Endoperóxido Sintasas/farmacología , Animales , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/farmacología , Ensayos Clínicos como Asunto , Ciclooxigenasa 1 , Ciclooxigenasa 2 , Inducción Enzimática , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/uso terapéutico , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Proteínas de la Membrana , Estructura Molecular , Prostaglandina-Endoperóxido Sintasas/genética , Prostaglandina-Endoperóxido Sintasas/metabolismo , Prostaglandinas/química , Prostaglandinas/fisiología , Especificidad por SustratoRESUMEN
BACKGROUND/AIMS: Management of patients with heavily pretreated malignant lymphoma failing frontline treatment and salvage high-dose chemotherapy and autologous peripheral stem cell rescue, is problematic. A pilot study was conducted to evaluate isolated thoracic perfusion of drugs by means of stopflow technique. METHODOLOGY: Six patients were enrolled in the study; diagnoses included 4 advanced Hodgkin's disease, 1 primary mediastinal B-cell lymphoma, and 1 anaplastic large cell lymphoma. Patients were aged 18-37 years; 4 presented with bulky mediastinum. They had never achieved a complete response since all had progressed from front-line treatment, and 3 had even failed salvage high-dose chemotherapy with autologous peripheral stem cell rescue. Cisplatin (100 mg/m2) and melphalan (35 mg/m2) were used. Carmustine (100 mg/m2) were added to these 2 drugs and cytarabine (2000 mg/m2) in patients not previously treated by carmustine, etoposide, cytarabine, and melphalan. Epidoxorubicin (70 mg/m2) was added in patients who previously received a suboptimal dosage of antracycline. Drugs were delivered monthly via aortic perfusion performed by means of Aigner's stop-flow technique. RESULTS: Overall 13 cycles of perfusional chemotherapy were administered with a median number of 2 cycles. During the procedures there were no technical, hemodynamic, or vascular complications, and no deaths occurred during surgery. After 1 month, 6 (100%) objective responses after isolated thoracic perfusion were recorded, 3 (50%) of which were complete. Tolerance to therapy was excellent. Hematological toxicity was mild and transfusional support was needed only in one course. At the last follow-up, 2 patients are alive (1 complete response and 1 very good partial response, maintained). CONCLUSIONS: This new therapeutical approach seems very active in recurrent/refractory malignant lymphoma and may play an important role in this setting.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia del Cáncer por Perfusión Regional/instrumentación , Enfermedad de Hodgkin/tratamiento farmacológico , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Neoplasias del Mediastino/tratamiento farmacológico , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carmustina/administración & dosificación , Carmustina/efectos adversos , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Citarabina/administración & dosificación , Citarabina/efectos adversos , Esquema de Medicación , Epirrubicina/administración & dosificación , Epirrubicina/efectos adversos , Femenino , Enfermedad de Hodgkin/diagnóstico por imagen , Humanos , Linfoma de Células B/diagnóstico por imagen , Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Masculino , Neoplasias del Mediastino/diagnóstico por imagen , Melfalán/administración & dosificación , Melfalán/efectos adversos , Terapia Recuperativa , Tomografía Computarizada por Rayos XRESUMEN
A series of 3-alkylamino-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxides structurally related to diazoxide and pinacidil were synthesized and tested as possible K(ATP) channel openers on isolated pancreatic endocrine tissue as well as on isolated vascular, intestinal, and uterine smooth muscle. In contrast to previously described 3-alkylamino-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1, 1-dioxides, most of the new compounds were found to be poorly active on B-cells but exhibited clear vasorelaxant properties. 3-(3, 3-Dimethyl-2-butylamino)-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxide (4d) and 7-chloro-3-(3, 3-dimethyl-2-butylamino)-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxide (5d), two compounds bearing the alkyl side chain of pinacidil, were found to be the most active representatives of their respective series on rat aorta rings. 3-Cycloalkylalkylamino- and 3-aralkylamino-7-chloro-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxides also expressed myorelaxant activity on electrically stimulated guinea pig ileum and on oxytocin-induced contractions of the rat uterus. Further biological investigations ((86)Rb efflux measurements, vasodilator potency on 30 and 80 mM KCl-induced contractions in the absence and presence of glibenclamide) revealed that compounds 4d and 5d, but not compound 5f, expressed the pharmacological profile of classical K(ATP) channel openers. In conclusion, by changing the position of the nitrogen atom in the pyridine ring, we now have obtained a family of drugs expressing an opposite tissue selectivity. Taken as a whole, the present findings also suggest that 3-alkylamino-4H-pyrido[2,3-e]-1,2,4-thiadiazine 1, 1-dioxides such as 4c, 4d, 5c, and 5d may be considered as new examples of K(ATP) channel openers expressing a pharmacological profile similar to that of pinacidil and diazoxide.
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Óxidos S-Cíclicos/síntesis química , Diazóxido/química , Músculo Liso Vascular/efectos de los fármacos , Pinacidilo/química , Canales de Potasio/efectos de los fármacos , Tiadiazinas/síntesis química , Animales , Aorta/citología , Aorta/efectos de los fármacos , Aorta/fisiología , Óxidos S-Cíclicos/química , Óxidos S-Cíclicos/farmacología , Diseño de Fármacos , Femenino , Cobayas , Íleon/citología , Íleon/efectos de los fármacos , Íleon/fisiología , Técnicas In Vitro , Insulina/metabolismo , Secreción de Insulina , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Contracción Muscular/efectos de los fármacos , Músculo Liso Vascular/citología , Ratas , Ratas Wistar , Relación Estructura-Actividad , Tiadiazinas/química , Tiadiazinas/farmacología , Contracción Uterina/efectos de los fármacos , Vasodilatadores/síntesis química , Vasodilatadores/química , Vasodilatadores/farmacologíaRESUMEN
Albendazole is a benzimidazole derivative with a broad-spectrum activity against human and animal helminth parasites. In order to determine the main pharmacokinetic parameters in sheep after oral and intravenous administration of a new formulation of albendazole (an aqueous solution), a fully automated method was developed for the determination of this drug and its main metabolites, albendazole sulfoxide (active metabolite) and sulfone in ovine plasma. This method involves dialysis as purification step, followed by enrichment of the dialysate on a precolumn and liquid chromatography (LC). All sample handling operations were executed automatically by means of an ASTED XL system. After conditioning of the trace enrichment column (TEC) packed with octadecyl silica with pH 6.0 phosphate buffer containing sodium azide, the plasma sample, in which a protein releasing reagent (1 M HCl) containing Triton X-100 was automatically added, was loaded in the donor channel and dialysed on a cellulose acetate membrane in the static-pulsed mode. The dialysis liquid consisted of pH 2.5 phosphate buffer. By rotation of a switching valve, the analytes were eluted from the TEC in the back-flush mode by the LC mobile phase and transferred to the analytical column, packed with octyl silica. The chromatographic separation was performed at 35 degrees C and the analytes were monitored photometrically at 295 nm. Due to the differences in hydrophobic character between albendazole and its metabolites, a gradient elution was applied. The mobile phase consisted of a mixture of acetonitrile and pH 6.0 phosphate buffer. The proportion of organic modifier was increased from 10.0 to 50.1% in 12.30 min, then from 50.1 to 66.9% in 1.70 min. First, the gradient conditions and the temperature were optimised for the LC separation using the DryLab software. Then, the influence of some parameters of the dialysis process on analyte recovery was investigated. Finally, the method developed was validated. The mean recoveries for albendazole and its metabolites were about 70 and 65%, respectively. The limits of quantification for albendazole and its metabolites were 10 and 7.5 ng/ml, respectively.
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Albendazol/sangre , Antihelmínticos/sangre , Cromatografía Liquida/métodos , Animales , Automatización , Diálisis , Concentración de Iones de Hidrógeno , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Ovinos , Espectrofotometría UltravioletaRESUMEN
The preparation and the pharmacological evaluation of the R- and S-isomers of 3-(2-butylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide (BPDZ 42) and 3-(3-methyl-2-butylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide (BPDZ 44), two potassium channel openers, is described. Their optical purity was estimated by means of capillary electrophoresis (R- and S-BPDZ 42) and chiral HPLC (R- and S-BPDZ 44). The absolute configuration of each isomer of BPDZ 44 was deduced from crystallographic data. Pharmacological assays performed with the R- and S-isomers of BPDZ 44 revealed only slight differences in their activity on pancreatic B-cells but significant differences in their activity on vascular smooth muscle cells: the R-isomer being sixfold more potent than its corresponding S-isomer. The R-isomer of BPDZ 42 was shown to be more potent than its corresponding S-isomer on the endocrine pancreas. S-BPDZ 44 as well as R- and S-BPDZ 42 were found to exhibit tissue selectivity for the pancreatic versus the vascular smooth muscle tissue.
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Adenosina Trifosfato/farmacología , Óxidos N-Cíclicos , Óxidos S-Cíclicos/síntesis química , Óxidos S-Cíclicos/farmacología , Canales de Potasio/efectos de los fármacos , Piridinas/síntesis química , Piridinas/farmacología , Tiadiazinas/síntesis química , Tiadiazinas/farmacología , Animales , Aorta/efectos de los fármacos , Células Cultivadas , Óxidos S-Cíclicos/química , Evaluación de Medicamentos , Técnicas In Vitro , Activación del Canal Iónico , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Espectroscopía de Resonancia Magnética , Piridinas/química , Ratas , Ratas Wistar , Espectrofotometría Infrarroja , Estereoisomerismo , Tiadiazinas/químicaRESUMEN
During the last few years, cholecystokinin (CCK) has emerged as an important hormone. This polypeptide has been located either in peripheral tissues such as the gastro-intestinal tract and the pancreas as well as in the central nervous system. High affinity CCK receptors are divided in two main subtypes: the CCK-A (A for (A for "alimentary") and the CCK-B (B for "brain") receptors. The latters are currently associated with the gastrin receptors. Since CCK is involved in many different biological processes such as gut function, digestive processes, control of feeding behaviour and neurotransmitter release, the therapeutical potential of cholecystokinin receptor ligands seems to be extremely broad and promising. Several families of CCK receptor ligands (peptides, peptidomimetics, peptoids or non-peptides) were prepared during the last twenty years. The main goal of these researches was to improve agonistic or antagonistic potency but also to find selective compounds for a specific CCK receptor subtype. This review presents the recent developments (since 1995) in the chemistry of CCK receptor ligands.
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Benzodiazepinas/química , Receptores de Colecistoquinina/agonistas , Receptores de Colecistoquinina/antagonistas & inhibidores , Tetragastrina/análogos & derivados , Animales , Ansiolíticos/química , Ansiolíticos/farmacología , Benzodiazepinas/farmacología , Benzodiazepinonas/química , Benzodiazepinonas/farmacología , Humanos , Indoles/química , Indoles/farmacología , Cetoácidos/química , Cetoácidos/farmacología , Ligandos , Meglumina/análogos & derivados , Meglumina/química , Meglumina/farmacología , Peptoides , Proglumida/análogos & derivados , Proglumida/química , Proglumida/farmacología , Receptor de Colecistoquinina A , Receptor de Colecistoquinina B , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
The synthesis of 3-aralkyl-4-aryl-4H-, 3-aralkylamino-4-aryl-4H- and 3-aralkylsulfanyl-4-aryl-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1, 1-dioxides is described. Moreover, the affinity of the different compounds towards the cholecystokinin CCK-A and CCK-B receptors was evaluated. For selected compounds, affinity on the two receptor subtypes was expressed in the micromolar range. This was comparable to the affinity observed with the naturally occurring CCK receptor antagonist asperlicin.
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Receptores de Colecistoquinina/metabolismo , Tiadiazinas/síntesis química , Tiadiazinas/metabolismo , Animales , Fenómenos Químicos , Química Física , Cinética , Ligandos , Masculino , Quinazolinas/química , Ratas , Ratas Wistar , Receptor de Colecistoquinina A , Receptor de Colecistoquinina B , Sincalida/metabolismo , Relación Estructura-Actividad , Tiadiazinas/farmacologíaRESUMEN
A series of 4H-1,2,4-pyridothiadiazine 1,1-dioxides and 2, 3-dihydro-4H-1,2,4-pyridothiadiazine 1,1-dioxides bearing various alkyl and aryl substituents on the 2-, 3-, and 4-positions was synthesized and tested as possible positive allosteric modulators of the (R/S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors. Many compounds were found to be more potent than the reference compounds diazoxide and aniracetam as potentiators of the AMPA current in rat cortex mRNA-injected Xenopus oocytes. The most active compound, 4-ethyl-2,3-dihydro-4H-pyrido[3,2-e]-1,2, 4-thiadiazine 1,1-dioxide (31b), revealed an in vitro activity on Xenopus oocytes not far from that of cyclothiazide, the most potent allosteric modulator of AMPA receptors reported to date. Moreover, 31b, but not cyclothiazide, was found to potentiate the duration and the amplitude of the excitatory postsynaptic field potentials induced by electric stimulation in rat hippocampal slices. Such an effect could indicate, for 31b, but not for cyclothiazide, a possible interaction with postsynaptic AMPA receptor binding sites located on hippocampal CA1 neurons. Structure-activity relationships indicated that the structural requirements responsible for a biological activity on AMPA receptors are different from those responsible for an inhibitory activity on the insulin releasing process (putative ATP-sensitive K+-channel openers). For instance, 31b and other related dihydropyridothiadiazines were found to be ineffective as inhibitors of insulin release from rat pancreatic B-cells, in contrast to diazoxide and known pyridothiadiazines reported as ATP-sensitive K+-channel openers. Conversely, the pyridothiadiazines active on B-cells were found to be ineffective as potentiators of the AMPA currents in Xenopus oocytes. Thus, 31b appeared to be more specific than diazoxide as an AMPA receptor modulator. This compound may be considered as a new pharmacological tool, different from diazoxide and cyclothiazide, for studying AMPA receptors. Moreover, 31b can also constitute a new therapeutic agent for the treatment of cognitive disorders.
Asunto(s)
Benzotiadiazinas/farmacología , Óxidos S-Cíclicos , Diazóxido/farmacología , Diseño de Fármacos , Receptores AMPA/efectos de los fármacos , Tiadiazinas , Adenosina Trifosfato/metabolismo , Regulación Alostérica , Animales , Benzotiadiazinas/química , Corteza Cerebral/metabolismo , Óxidos S-Cíclicos/síntesis química , Óxidos S-Cíclicos/química , Óxidos S-Cíclicos/farmacología , Diazóxido/química , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/fisiología , Técnicas In Vitro , Insulina/metabolismo , Antagonistas de Insulina/síntesis química , Antagonistas de Insulina/química , Antagonistas de Insulina/farmacología , Secreción de Insulina , Islotes Pancreáticos/efectos de los fármacos , Islotes Pancreáticos/metabolismo , Masculino , Ratones , Ratones Endogámicos DBA , Oocitos/efectos de los fármacos , Oocitos/metabolismo , Canales de Potasio/efectos de los fármacos , ARN Mensajero/biosíntesis , Ratas , Ratas Wistar , Receptores AMPA/biosíntesis , Receptores AMPA/genética , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , Tiadiazinas/síntesis química , Tiadiazinas/química , Tiadiazinas/farmacología , Xenopus laevisRESUMEN
The enantioseparation of pirlindole by liquid chromatography (LC) was investigated using three different chiral stationary phases (CSPs) containing either cellulose tris-(3,5-dimethylphenylcarbamate) (Chiralcel OD-R), ovomucoid (OVM) or beta-cyclodextrin (beta-CD). The effects of the mobile phase pH on retention, enantioselectivity and resolution were studied. Methanol and acetonitrile were tested as organic modifiers while the influence of the addition to the mobile phase of sodium alkanesulfonates or sodium perchlorate was also investigated. Sodium perchlorate was only used on the Chiralcel OD-R column while sodium alkanesulfonates were tested as mobile phase additives on the three kinds of CSPs. The enantioseparation of pirlindole could be obtained on all CSPs tested, the best results with respect to chiral resolution being achieved on the Chiralcel OD-R and the OVM columns. The use of sodium octanesulfonate (NaOS) was found to improve the enantioseparation of pirlindole on the OVM column while enantioselectivity was considerably enhanced by addition of sodium perchlorate on the Chiralcel OD-R column.