RESUMO
Prior to its total synthesis, a new vanadium coordination compound, called TSAG0101, was computationally designed to inhibit the enzyme protein tyrosine phosphatase 1B (PTP1B). The PTP1B acts as a negative regulator of insulin signaling by blocking the active site where phosphate hydrolysis of the insulin receptor takes place. TSAG001, [V(V)O(2)(OH)(picolinamide)], was characterized by infrared (IR) and nuclear magnetic resonance (NMR) spectroscopy; IR: ν/cm(-1) 3,570 (NH), 1,627 (C=O, coordinated), 1,417 (C-N), 970/842 (O=V=O), 727 δ̣ (pyridine ring); (13)C NMR: 5 bands between 122 and 151 ppm and carbonyl C shifted to 180 ppm; and (1)H NMR: 4 broad bands from 7.6 to 8.2 ppm and NH(2) shifted to 8.8 ppm. In aqueous solution, in presence or absence of sodium citrate as a biologically relevant and ubiquitous chelator, TSAG0101 undergoes neither ligand exchange nor reduction of its central vanadium atom during 24 hours. TSAG0101 shows blood glucose lowering effects in rats but it produced no alteration of basal- or glucose-induced insulin secretion on ß cells during in vitro tests, all of which excludes a direct mechanism evidencing the extrapancreatic nature of its activity. The lethal dose (LD(50)) of TSAG0101 was determined in Wistar mice yielding a value of 412 mg/kg. This value is one of the highest among vanadium compounds and classifies it as a mild toxicity agent when compared with literature data. Due to its nonsubstituted, small-sized scaffold design, its remarkable complex stability, and low toxicity; TSAG0101 should be considered as an innovative insulin-mimetic principle with promising properties and, therefore, could become a new lead compound for potential nonpeptide PTP1B inhibitors in antidiabetic drug research. In view of the present work, the inhibitory concentration (IC(50)) and extended solution stability will be tested.
Assuntos
Glicemia/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Inibidores Enzimáticos/farmacologia , Ácidos Picolínicos/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Animais , Biologia Computacional , Complexos de Coordenação/síntese química , Complexos de Coordenação/toxicidade , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/toxicidade , Feminino , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Dose Letal Mediana , Espectroscopia de Ressonância Magnética , Camundongos , Ácidos Picolínicos/síntese química , Ácidos Picolínicos/toxicidade , Ratos , Ratos Endogâmicos LewRESUMO
Jehovah's Witnesses (J.W.) can undergo successful cardiac operations. We have operated five J.W. patients. Of these patients, two had coronary artery bypass surgery and three had correction of congenital anomalies. These included an atrial septal defect with infundibular pulmonic stenosis, a tetralogy of Fallot and a patient with a ventricular septal defect. Our treatment protocol includes a meticulous surgery, the use of early heparinization to collect all shed blood into the pump oxygenator, observation in the operating room for early exploration if the patient bleeds and administration of iron preparations. Recombinant human erythropoietin, although available and in our treatment protocol, has not been used yet. All patients survived the operation and left the hospital with an excellent hemoglobin and hematocrit. The length of stay varied from 7 to 15 days.