Asunto(s)
Antihipertensivos/farmacocinética , Diuréticos/farmacocinética , Furosemida/farmacocinética , Hipertensión/tratamiento farmacológico , Pindolol/farmacocinética , Administración Oral , Antihipertensivos/administración & dosificación , Antihipertensivos/sangre , Antihipertensivos/orina , Diuréticos/administración & dosificación , Interacciones Farmacológicas , Femenino , Furosemida/administración & dosificación , Humanos , Parto/sangre , Parto/orina , Pindolol/administración & dosificación , Pindolol/sangre , Pindolol/orina , Embarazo , Complicaciones del Embarazo/tratamiento farmacológico , EstereoisomerismoRESUMEN
A method for the determination of pindolol enantiomers in amniotic fluid and breast milk was developed, validated, and applied to the investigation of six pregnant women treated with rac-pindolol (10 mg/12 h). Biological samples were extracted with tert-methyl-butyl ether, and the pindolol enantiomers were resolved on a Chiralpak AD column. Amniotic fluid/plasma and milk/plasma concentrations ratios ranged from 0.4 to 4.5 and from 0.6 to 3.7, respectively, for (+)-R-pindolol and from 0.5 to 3.5 and from 1.1 to 2.8, respectively, for (-)-S-pindolol. Preliminary data suggest that amniotic fluid and breast milk are routes of fetal exposure to pindolol enantiomers.
Asunto(s)
Líquido Amniótico/química , Antihipertensivos/análisis , Lactancia , Leche Humana/química , Pindolol/análisis , Adulto , Antihipertensivos/farmacocinética , Femenino , Humanos , Pindolol/farmacocinética , Embarazo , Reproducibilidad de los Resultados , Espectrometría de Fluorescencia , EstereoisomerismoRESUMEN
The kinetics and mechanistic aspects of the riboflavin-photosensitised oxidation of the topically administrable ophthalmic drugs Timolol (Tim) and Pindolol (Pin) were investigated in water-MeOH (9:1, v/v) solution employing light of wavelength > 400 nm. riboflavin, belonging to the vitamin B(2) complex, is a known human endogenous photosensitiser. The irradiation of riboflavin in the presence of ophthalmic drugs triggers a complex picture of competitive reactions which produces the photodegradation of both the drugs and the pigment itself. The mechanism was elucidated employing stationary photolysis, polarographic detection of dissolved oxygen, stationary and time-resolved fluorescence spectroscopy, and laser flash photolysis. Ophthalmic drugs quench riboflavin-excited singlet and triplet states. From the quenching of excited triplet riboflavin, the semireduced form of the pigment is generated, through an electron transfer process from the drug, with the subsequent production of superoxide anion radical (O(2)(*-)) by reaction with dissolved molecular oxygen. Through the interaction of dissolved oxygen with excited triplet riboflavin, the species singlet oxygen (O(2)((1)Delta(g))) is also generated to a lesser extent. Both O(2)(*-) and O(2)((1)Delta(g)) induce photodegradation of ophthalmic drugs, Tim being approximately 3-fold more easily photooxidisable than Pin, as estimated by oxygen consumption experiments.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacocinética , Oxígeno/metabolismo , Pindolol/farmacocinética , Riboflavina/química , Timolol/farmacocinética , Animales , Aniones , Electrones , Ojo/metabolismo , Radicales Libres , Cinética , Luz , Modelos Químicos , Oxígeno/química , Consumo de Oxígeno , Fármacos Fotosensibilizantes/farmacología , Especies Reactivas de Oxígeno/química , Espectrofotometría , Factores de Tiempo , Rayos UltravioletaRESUMEN
It has been proposed that anti-myocardial antibodies (Ab) against neurotransmitter (NT) receptors are involved in the immunopathology of chronic Chagas' heart disease. We demonstrated that an anti-Trypanosoma cruzi monoclonal Ab (mAb), CAK20.12, binds to murine cardiac beta-adrenergic and muscarinic acetyl choline (mACh) receptors eliciting abnormal physiological responses on normal heart. No cross-linking requirement for mAb actions was demonstrated using Fab fragment derived from CAK20.12. mAb binding to synthetic peptides from the second extracellular loop of both beta1-adrenergic and mACh receptors, demonstrated by ELISA, identified the region of NT receptors involved. Cross-reactivity between these peptides and T. cruzi antigen was confirmed by binding inhibition assays. These results support the existence of cross-reactivity due to molecular mimicry between a parasite antigen and the major antigenic epitopes present on both beta1-adrenergic and M2-ACh receptors. Its possible relationship with cardiac dysfunction during chronic stage of Chagas' disease is also discussed.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Anticuerpos Antiprotozoarios/farmacología , Contracción Miocárdica/efectos de los fármacos , Pindolol/análogos & derivados , Receptor Muscarínico M2/inmunología , Receptores Adrenérgicos beta 1/inmunología , Trypanosoma cruzi/inmunología , Antagonistas Adrenérgicos beta , Análisis de Varianza , Animales , Unión Competitiva/efectos de los fármacos , Unión Competitiva/fisiología , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Ensayo de Inmunoadsorción Enzimática/métodos , Epítopos/metabolismo , Epítopos/farmacología , Fragmentos Fab de Inmunoglobulinas/metabolismo , Técnicas In Vitro , Isótopos de Yodo/farmacocinética , Ratones , Ratones Endogámicos BALB C , Antagonistas Muscarínicos/farmacocinética , Contracción Miocárdica/fisiología , Pindolol/farmacocinética , Quinuclidinil Bencilato/farmacocinética , Radioinmunoensayo/métodos , Ensayo de Unión Radioligante/métodos , Receptor Muscarínico M2/química , Receptores Adrenérgicos beta 1/química , Volumetría/métodos , Trypanosoma cruzi/químicaRESUMEN
Nine patients taking oral doses of 10 mg/12 h rac-pindolol as part of their treatment for hypertension in pregnancy were recruited for the study. Maternal and fetal gestational age ranged from 20-38 years and 28-41 weeks, respectively. Blood was collected from the umbilical cord vein and from the mother from zero to 12 h after drug administration. Urine was collected for 12 h after rac-pindolol administration at the following intervals: 0-3, 3-6, 6-9, and 9-12 h. Plasma and urine concentrations of the pindolol enantiomers were determined by HPLC using a Chiralpak AD chiral column and fluorescence detection. The data were fitted to a one-compartment model and differences between (+)-R and (-)-S enantiomers were compared by the paired t-test (P < 0.05). Mean results are reported. The disposition of pindolol in maternal plasma was stereoselective, with higher AUC(SS)0-12 (84.34 vs. 95.69 ng.h/ml) and Cl(R) values (9.16 vs. 10.85 L/h) and lower Vd/f (251.38 vs. 225.17 L) and Cl/f (62.48 vs. 55.74 L/h) for the (+)-R pindolol. The transplacental distribution of pindolol was not stereoselective. Cord, plasma, and presumably fetal, concentrations of the pindolol enantiomers were 56% of the maternal plasma concentrations up to 6 h after the last dose.
Asunto(s)
Antagonistas Adrenérgicos beta/farmacocinética , Antihipertensivos/farmacocinética , Hipertensión/tratamiento farmacológico , Pindolol/farmacocinética , Placenta/metabolismo , Complicaciones Cardiovasculares del Embarazo/tratamiento farmacológico , Adulto , Femenino , Humanos , Hipertensión/metabolismo , Embarazo , Complicaciones Cardiovasculares del Embarazo/metabolismo , EstereoisomerismoRESUMEN
Os efeitos agudos do Propranolol usado na dose de 3mg em 22 pacientes, e do Pindolol, na dose de 0,5mg em 24 pacientes foram estudados em situaçäo basal e 5 minutos após sua administraçäo. A análise comparativa das variáveis demonstrou näo ter havido diferença significativa no efeito de ambas as drogas sobre a pressäo máxima e a pressäo diastólica final de ventrículo esquerdo, as pressöes máxima, mínima e média de aorta, sobre o índice sistólico, e diastólico finais de ventrículo esquerdo, dp/dt máxima e mínima de ventrículo esquerdo e resistência vascular sistêmica (P > 0,05). O Propranolol elevou a pressäo diastólica final de ventrículo direito, reduziu o índice e a freqüência cardíaca, a fraçäo de ejeçäo e a velocidade de encurtamento circunferencial do ventrículo esquerdo (P < 0,05), alteraçöes näo observadas após o Pindolol. O Pindolol determinou elevaçöes significativas nas pressöes máximas de ventrículo direito, máxima, mínima e média de artéria pulmonar (P < 0,05), alteraçöes näo observadas após o Propranolol. A presssäo média do átrio direito aumentou significativamente após uso dos dois medicamentos (P < 0,05). As propriedades simpaticomiméticas do pindolol foram identificadas no presente trabalho, pela tendência que este demonstrou para aumentar o débito cardíaco, reduzir a resistência periférica e melhorar a motilidade segmentar do miocárdio isquêmico