RESUMEN
Amyloidosis is a rare but devastating condition caused by deposition of misfolded proteins as aggregates in the extracellular tissues of the body, leading to impairment of organ function. High clinical suspicion is required to facilitate early diagnosis. Correct identification of the causal amyloid protein is absolutely crucial for clinical management in order to avoid misdiagnosis and inappropriate, potentially harmful treatment, to assess prognosis, and to offer genetic counselling if relevant. This review summarises the current evidence on which the diagnosis and subtyping of amyloidosis is based, outlines the limitations of various diagnostic techniques, particularly in an Australian and New Zealand context, and discusses optimal strategies for the diagnostic approach to these patients. Recommendations are provided for when particularly to suspect amyloidosis, what investigations are required, as well as an approach to accurate subtyping of amyloidosis.
Asunto(s)
Amiloidosis/diagnóstico , Amiloide/análisis , Amiloidosis/clasificación , Amiloidosis/etiología , Amiloidosis/genética , Amiloidosis/patología , Australasia , Biopsia , Rojo Congo , Pruebas Genéticas , Humanos , Inmunohistoquímica , Inflamación/complicaciones , Especificidad de Órganos , Paraproteinemias/complicaciones , Fenotipo , Coloración y Etiquetado , Espectrometría de Masas en TándemRESUMEN
We report a case of malignant intraventricular meningioma with CSF drop metastases and an implantation metastatic subgaleal nodule in a 53-year-old woman. Malignant intraventricular meningiomas are rare with only seven cases being reported in the literature. These tumours can be very aggressive and one should consider immediate postoperative radiotherapy.
Asunto(s)
Neoplasias del Ventrículo Cerebral/patología , Neoplasias Meníngeas/patología , Meningioma/patología , Neoplasias de la Columna Vertebral/secundario , Craneotomía/métodos , Femenino , Humanos , Imagen por Resonancia Magnética , Neoplasias Meníngeas/cirugía , Meningioma/cirugía , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Neoplasias de la Columna Vertebral/cirugía , Tomografía Computarizada por Rayos X/métodosRESUMEN
High performance liquid chromatography (HPLC), electrospray ionization mass spectrometry (ESI) and high performance liquid chromatography coupled to mass spectrometry (LC-MS) were used to analyze randomly chosen samples from parallel syntheses carried out on derivatized polypropylene crowns compatible with a Multipin solid support system. Side-reactions and by-products were clearly identified, and the yields of the expected molecules were unexpectedly low for most samples. LC-MS was superior to HPLC with absorbance detection or electrospray mass spectrometry alone for determining the identity and purity of each desired combinatorial compounds.
Asunto(s)
Cromatografía Líquida de Alta Presión/métodos , Técnicas Químicas Combinatorias , Acrilamidas/química , Aminoácidos/química , Éteres Cíclicos/química , Fluorenos/química , Espectrometría de Masas/métodos , Estructura Molecular , Biblioteca de Péptidos , Polipropilenos/químicaRESUMEN
The aim of this work was to obtain photoactivatable nonpeptide antagonists of the angiotensin II AT(1) receptor. Based on structure-function relationships, two chemical structures as well as appropriate synthetic schemes were chosen as a frame for the design of radiolabeled azido probes. The feasibility of the strategy was first assessed by the synthesis of two tritiated ligands 21 and 22 possessing a high affinity for the AT(1) receptor and a low nonspecific binding to membrane or cell preparations. We then prepared two unlabeled azido derivatives 7 and 14 which retained a fairly high affinity for the AT(1) receptor. The latter compound proved to be suitable for receptor irreversible labeling and was prepared in its tritiated form 28. This tritiated azido nonpeptide probe displayed a K(d) value of 11.8 nM and a low nonspecific binding. It was suitable for specific and efficient covalent labeling of the recombinant AT(1A) receptor stably expressed in CHO cells. The electrophoretic pattern of the specifically labeled entity was strictly identical to that of purified receptor photolabeled with a biotinylated peptidic photoactivatable probe. This new tool should be useful for the mapping of the nonpeptide receptor binding site. These potential applications are discussed in light of the current knowledge of molecular mechanisms of G-protein coupled receptor activation and inactivation.
Asunto(s)
Angiotensina II/metabolismo , Antagonistas de Receptores de Angiotensina , Azidas/síntesis química , Benzoatos/síntesis química , Etiquetas de Fotoafinidad/síntesis química , Animales , Aorta/efectos de los fármacos , Aorta/fisiología , Azidas/química , Azidas/metabolismo , Azidas/farmacología , Benzoatos/química , Benzoatos/metabolismo , Benzoatos/farmacología , Células CHO , Cricetinae , Técnicas In Vitro , Ligandos , Hígado/metabolismo , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/fisiología , Mutación , Etiquetas de Fotoafinidad/química , Etiquetas de Fotoafinidad/metabolismo , Etiquetas de Fotoafinidad/farmacología , Conejos , Ratas , Receptor de Angiotensina Tipo 1 , Receptor de Angiotensina Tipo 2 , Receptores de Angiotensina/genética , Receptores de Angiotensina/metabolismo , TritioRESUMEN
A series of new analogues of 15-deoxyspergualin (DSG), an immunosuppressive agent commercialized in Japan, was synthesized and tested in a graft-versus-host disease (GVHD) model in mice. Various substitutions of the spermidine "D" region were made in order to determine its optimum structure in terms of in vivo immunosuppressive activity. Various positions of methylation were first investigated leading to the discovery of the monomethylated malonic derivative 56h in which the pro-R hydrogen of the methylene alpha to the primary amine of the spermidine moiety has been replaced by a methyl group. Synthesis of the similarly methylated analogue of the previously reported glycolic derivative LF 08-0299 afforded 60e which demonstrated a powerful activity at a dose as low as 0.3 mg/kg in the GVHD model and was much more potent than DSG in the demanding heart allotransplantation model in rats. The improvement of in vivo activity was supposed to be related to an increase of the metabolic stability of the methylated analogues compared to the parent molecules. Due to its very low active dose, compatible with a subcutaneous administration in humans, and its favorable pharmacological and toxicological profile, 60e was selected as a candidate for clinical evaluation.
Asunto(s)
Carbamatos/síntesis química , Guanidinas/síntesis química , Inmunosupresores/síntesis química , Espermidina/química , Animales , Carbamatos/química , Carbamatos/farmacología , Evaluación Preclínica de Medicamentos , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Guanidinas/química , Guanidinas/farmacología , Trasplante de Corazón , Inmunosupresores/química , Inmunosupresores/farmacología , Ratones , Ratas , Ratas Endogámicas Lew , Estereoisomerismo , Relación Estructura-Actividad , Trasplante HomólogoRESUMEN
A series of new analogues of 15-deoxyspergualin (DSG), an immunosuppressive agent currently commercialized in Japan, was synthesized and tested in a graft-versus-host disease (GVHD) model in mice. Using the general concept of bioisosteric replacement, variations of the hydroxyglycine central "C" region were made in order to determine its optimum structure in terms of in vivo immunosuppressive activity. By this way, the malonic derivative 13a was discovered as the first example of a new series of potent immunosuppressive agents encompassing a retro-amide bond linked to the hexyl-guanidino moiety. Structure-activity relationships of this series were studied by synthesizing compounds 13g-i and 13k-s. Variation of the "right-amide" of 13a led to the urea 19a and the carbamates 23 and 27a which proved to be equally active as DSG in our GVHD model. Finally 27a was found to be the most potent derivative, being slightly more active than DSG in a heart allotransplantation model in rats. Due to the absence of chiral center in its structure and to its improved chemical stability compared to DSG, 27a was selected as a candidate for clinical evaluation.
Asunto(s)
Glicina/química , Guanidinas/farmacología , Inmunosupresores/farmacología , Animales , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Guanidinas/química , Guanidinas/uso terapéutico , Trasplante de Corazón , Inmunosupresores/química , Inmunosupresores/uso terapéutico , Espectroscopía de Resonancia Magnética , Ratones , Estructura Molecular , Ratas , Relación Estructura-Actividad , Trasplante HomólogoRESUMEN
A (-)-conduritol F derivative was condensed with 4-ethyl-7-hydroxy-2H-1-benzopyran-2-one and converted into (+)-4-ethyl-7-[(1'R,2'S,3'S,4'R)-2',3',4'- trihydroxycyclohexyloxy]-2H-1-benzopyran-2-one ((+)-2). Enantiomer (-)-2 was obtained from a (+)-conduritol F derivative. The carbaxyloside (-)-2 with the L-xylose configuration was more active than (+)-2 in the Wessler's model.
Asunto(s)
Anticoagulantes/farmacología , Benzopiranos/farmacología , Trombosis/tratamiento farmacológico , Administración Oral , Anticoagulantes/química , Anticoagulantes/uso terapéutico , Benzopiranos/química , Benzopiranos/uso terapéutico , Hidrólisis , Venas/patologíaRESUMEN
2,3-Oxidosqualene lanosterol-cyclase (OSC; EC 5.4.99.7) is an attractive target for the design of compounds that block hepatic cholesterol biosynthesis. (4a alpha, 5 alpha, 6 beta, 8a beta)-Decahydro-5,8a-dimethyl-2-(1,5,9-trimethyldecyl)-6- isoquinolinol (1) and simplified analogs have been devised to inhibit this enzyme by mimicking the postulated pro-C-8 high-energy intermediary carbocation occurring during the cyclization-rearrangement pathway. In order to gain an understanding into the mechanism by which these types of molecules inhibit OSC, we have synthesized a series of substituted isoquinoline derivatives 3 and investigated the structural and stereoelectronic requirements, and their stringency, that make 3 potential high-energy intermediate analogs of OSC. Determination of the IC50 values of the different compounds with rat liver microsomal cyclase, allowed the study of the relative importance of (i) the nature and the stereochemistry of the nitrogen side chain, (ii) the presence of methyl groups at C-5 and C-8a (ring junction), (iii) the presence and stereochemistry of the C-6 hydroxyl group, (iv) the nature of the ring junction, and (v) the absolute configuration of the bicyclic system. The resulting structure-activity relationships seem to validate the mechanism of action of these inhibitors as analogs of a pro-C-8 high-energy intermediate and delineate the minimal requirements for the design of efficient isoquinoline-based, or simplified, OSC inhibitors.
Asunto(s)
Anticolesterolemiantes/química , Inhibidores Enzimáticos/química , Transferasas Intramoleculares , Isomerasas/antagonistas & inhibidores , Isoquinolinas/farmacología , Animales , Anticolesterolemiantes/síntesis química , Anticolesterolemiantes/farmacología , Colesterol/biosíntesis , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Isoquinolinas/síntesis química , Isoquinolinas/química , Cinética , Microsomas Hepáticos/enzimología , Estructura Molecular , Unión Proteica , Ratas , Escualeno/análogos & derivados , Escualeno/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
LF 7-0156 (2-[[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol- 5-yl]methyl]amino]benzoic acid) is a nonpeptide angiotensin II receptor antagonist selective for the type 1 angiotensin receptor. In rabbit aortic rings, LF 7-0156 competitively antagonized angiotensin II-induced contractile responses, with a pA2 value of 8.44. The synthesis of the radiolabeled compound [3H]LF 7-0156 has allowed direct binding studies with several membrane or cell preparations. Consistent with competition experiments, the binding of [3H]LF 7-0156 to purified rat liver membranes was characterized by a Kd value of 12.6 nM and very low pseudospecific or nonspecific binding; this latter characteristic confers to this compound an advantage over the structurally different compound [3H]DuP 753, which is the only commercially available nonpeptide radioligand. [3H]LF 7-0156 also bound to the type 1A angiotensin receptor expressed in Chinese hamster ovary cells, with high affinity (Kd = 3.5 nM) and a total absence of nonspecific binding. Functional antagonism in this cell system was assessed by the ability of LF 7-0156 to reverse angiotensin II-induced inositol phosphate production. These properties make [3H]LF 7-0156 an interesting pharmacological tool and should allow future evaluation of recognition of the nonpeptide ligand by mutated receptors expressed in Chinese hamster ovary cells; it will facilitate the analysis of possible differences in receptor amino acids involved in the binding of peptide and nonpeptide ligands, as well as the extent of spatial overlap between several nonpeptide antagonists displaying different structural properties.