RESUMEN
BACKGROUND: Ropivacaine is present in plasma in both protein-bound and free forms. The free form is responsible for the occurrence of toxic side effects. During obstetric epidural analgesia, free ropivacaine enters the fetal circulation depending on various factors. The aim of this study was to analyse a potential association between ropivacaine concentrations in maternal and fetal plasma and hence the extent of fetal exposure to ropivacaine. METHODS: In this prospective monocentre study, parturients who met the following criteria were included in the study: 1. epidural administration as part of obstetric anaesthesia, and 2. subsequent intrapartum caesarean delivery, which 3. was performed after an epidural bolus administration of ropivacaine within the existing epidural analgesia. Total and free ropivacaine concentrations were analysed in maternal blood at baseline, prior to epidural bolus administration for caesarean delivery, and in maternal and fetal (umbilical venous, oxygenated) blood at delivery. The results are presented as mean⯱â¯SD or median (25/75th percentile). RESULTS: We screened 128 parturients who went into labour at term and requested epidural analgesia, of whom 39 were ultimately included in the study. An intrapartum caesarean delivery was performed after the epidural application of 207 (166/276) mg ropivacaine during an epidural treatment period of 577 (360/1010) min. Total and free ropivacaine concentrations were 1402⯱â¯357â¯ng/ml and 53⯱â¯46â¯ng/ml, respectively, in maternal venous blood and 457⯱â¯243â¯ng/ml and 43⯱â¯27â¯ng/ml, respectively, in fetal blood. The maternal total and free ropivacaine concentrations were significantly correlated (râ¯=â¯0.873; Pâ¯<â¯0.0001). CONCLUSION: The results of the present study suggest that determining the concentration of free ropivacaine in maternal blood may be a feasible option for estimating neonatal exposure to ropivacaine.
Asunto(s)
Analgesia Epidural , Analgesia Obstétrica , Anestésicos Locales , Cesárea , Ropivacaína , Humanos , Femenino , Estudios Prospectivos , Embarazo , Anestésicos Locales/administración & dosificación , Analgesia Epidural/métodos , Adulto , Analgesia Obstétrica/métodos , Sangre Fetal/química , Amidas , Recién NacidoRESUMEN
In the present study, over a period of 8 days 12 mg/kg/d quercetin aglycone and 18 mg/kg/d isoquercitrin were orally given to rats, respectively. Four hours after administration, plasma samples were taken as well as tissue samples of liver, lung, heart, kidney and the brain sections hippocampus, cerebellum, striatum, cortex and the remaining brain. A HPLC-FD method with in-line post-column complexation was employed to quantify the quercetin metabolites (QM) in plasma and tissues. Compared to the quercetin gavage the isoquercitrin gavage consistently produced higher levels of QM in tissues (double to five-fold) as well as in plasma (double to three-fold). In body tissues, the highest amounts of QM were observed in the lung. In brain tissue, the highest levels of QM were found in the cerebellum, while the striatum contained the lowest levels of QM. In conclusion, this study clearly demonstrates that orally given isoquercitrin leads to higher levels in plasma and in all investigated tissue than quercetin aglycone.
Asunto(s)
Hipnóticos y Sedantes/farmacocinética , Quercetina/análogos & derivados , Administración Oral , Animales , Disponibilidad Biológica , Encéfalo/metabolismo , Cromatografía Líquida de Alta Presión , Masculino , Quercetina/análisis , Quercetina/metabolismo , Quercetina/farmacocinética , Ratas , Ratas Wistar , Estándares de Referencia , Distribución TisularRESUMEN
BACKGROUND AND PURPOSE Arachidonic acid derivatives play a central role in inflammation processes. Arachidonic acid is metabolized by several enzymes, particularly cyclooxygenases (COX), 5-lipoxygenase (5-LOX) and microsomal prostaglandin E-synthase-1 (mPGES-1) to pro-inflammatory mediators. EXPERIMENTAL APPROACH We determined the effect of LP105, a pirinixic acid derivative which acts as inhibitor of 5-LOX, COX and mPGES-1, on aortic aneurysm development in mice and on 5-LOX activity in murine monocytes. KEY RESULTS In a monocyte cell line (RAW264.7), LP105 inhibited 5-LOX in whole cells (IC(50) : 1-3 µM) and in supernatants (IC(50) : â¼10 µM). Oral administration of LP105 to mice resulted in therapeutic tissue and plasma levels. Aortic aneurysms were induced in ApoE(-/-) mice by angiotensin II (AngII) and LP105 (5 mg·day(-1) per animal) was co-administered to a subgroup. Compared with animals receiving AngII alone, the LP105+AngII group showed a lower heart rate, a trend towards reduced heart to body weight ratio but similar hypertensive responses. AngII alone significantly increased aortic weight and diameter but co-treatment with LP105+AngII prevented these changes. LC/MS-MS studies revealed increased 15-hydroxytetraenoic acid (15-HETE) and 14,15-epoxyeicosatrienoic acid (14,15-EET) plasma levels in LP105-treated animals. In the murine kidney, mRNAs of EET-generating or metabolizing enzymes and of 5-LOX and 15-LOX were unaffected by LP105. LP105 also did not inhibit the EET-metabolizing soluble epoxide hydrolase. CONCLUSIONS AND IMPLICATIONS LP105 was a potent inhibitor of monocyte 5-LOX and reduced AngII-induced vascular remodelling in mice. A shift of arachidonic acid metabolism to the protective EET pathway may contribute to the beneficial effects of LP105.
Asunto(s)
Aneurisma de la Aorta/patología , Araquidonato 5-Lipooxigenasa/metabolismo , Cardiotónicos/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Oxidorreductasas Intramoleculares/antagonistas & inhibidores , Inhibidores de la Lipooxigenasa/farmacología , Pirimidinas/farmacología , Administración Oral , Angiotensina II/administración & dosificación , Angiotensina II/toxicidad , Animales , Aorta/patología , Aneurisma de la Aorta/metabolismo , Araquidonato 5-Lipooxigenasa/sangre , Cardiotónicos/farmacocinética , Cardiotónicos/uso terapéutico , Sistema Cardiovascular/efectos de los fármacos , Línea Celular , Inhibidores de la Ciclooxigenasa/uso terapéutico , Modelos Animales de Enfermedad , Epóxido Hidrolasas/sangre , Epóxido Hidrolasas/metabolismo , Inyecciones Subcutáneas , Inhibidores de la Lipooxigenasa/uso terapéutico , Macrófagos/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Prostaglandina-E Sintasas , Pirimidinas/metabolismo , Pirimidinas/uso terapéuticoRESUMEN
Over the last few years many data have been published suggesting a participation of quercetin flavonoids in the antidepressive effect of St. John's wort (SJW) extract. To elucidate these data more deeply we performed two animal behavioural studies examining the antidepressant effects of SJW extract, rutin and, in addition, the quercetin metabolite isorhamnetin. The substances were in all cases compared to imipramine using Porsolt's forced swimming test (FST) after oral gavage of the substances over a 9 day period. All three compounds were found to be effective, with isorhamnetin exhibiting the strongest effect. In addition to this pharmacological study, we carried out two pharmacokinetic studies to examine the CNS level time-curve of the quercetin flavonoids after a single oral dose of SJW extract (1600 mg/kg) and isoquercitrin (100 mg/kg), respectively, and to observe the cumulative effects after daily repeated oral doses of SJW extract over 8 days. After a single dose the maximal CNS levels for quercetin (340 ng/g) and isorhamnetin/tamarixetin (50 ng/g) were found at 4 h. With repeated doses the maximal cumulation for quercetin (367 ng/g) occurred after 5 days whilst isorhamnetin/tamarixetin (640 ng/g) did not reach its maximal cumulation level within the 8 day test period.