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1.
Neurology ; 60(11): 1761-6, 2003 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-12796527

RESUMO

BACKGROUND: Dietary influences on oxidative stress have been thought to play important role in the etiology of PD. OBJECTIVE: To examine associations of PD with dietary nutrients, including minerals, vitamins, and fats. METHODS: A population-based case-control study was conducted among newly diagnosed case (n = 250) and control subjects (n = 388) identified between 1992 and 2002 from enrollees of the Group Health Cooperative health maintenance organization in western Washington state. Controls were frequency matched to cases on sex and age. In-person interviews elicited data on food frequency habits during most of adult life. Nutrient intakes were calculated and analyzed by adjusting each person's nutrient intake by their total energy intake (the nutrient density technique). RESULTS: Subjects with an iron intake in the highest quartile compared with those in the lowest quartile had an increased risk of PD (odds ratio = 1.7, 95% CI: 1.0, 2.7, trend p = 0.016). There was an apparent joint effect of iron and manganese; dietary intake above median levels of both together conferred a nearly doubled risk compared with lower intakes of each nutrient (odds ratio = 1.9, 95% CI: 1.2, 2.9). No strong associations were found for either antioxidants or fats. CONCLUSION: A high intake of iron, especially in combination with high manganese intake, may be related to risk for PD.


Assuntos
Ferro da Dieta/administração & dosagem , Manganês/administração & dosagem , Doença de Parkinson/epidemiologia , Adulto , Idoso , Antioxidantes/administração & dosagem , Estudos de Casos e Controles , Dieta , Gorduras/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Minerais/administração & dosagem , Doença de Parkinson/diagnóstico , Doença de Parkinson/etiologia , Fatores de Risco , Vitaminas/administração & dosagem
2.
Brain Res ; 884(1--2): 77-86, 2000 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-11082489

RESUMO

Delivery of valproic acid (VPA) to the human brain is relatively inefficient as reflected by a low brain-to-unbound plasma concentration ratio (< or =0.5) at steady state. Previous pharmacokinetic studies suggested that the unfavorable brain-to-plasma gradient is maintained by coupled efflux transport processes at both the brain parenchymal cells and blood-brain barrier (BBB); one or both of the efflux transporters are inhibitable by probenecid. The present study in rabbits utilized microdialysis to measure drug concentration in the brain extracellular fluid (ECF) of the cerebral cortex during steady-state i.v. infusion with VPA alone or with VPA plus probenecid. Probenecid co-infusion elevated VPA concentration in the brain tissue surrounding the tip of the microdialysis probe to a greater extent than in the ECF (230% versus 47%). Brain intracellular compartment (ICC) concentration was estimated. In control rabbits, the ICC concentration was 2.8+/-0.28 times higher than the ECF concentration. Probenecid co-infusion elevated the ICC-to-ECF concentration ratio to 4.2+/-0.44, which confirms the existence of an efflux transport system in brain parenchymal cells. The ECF-to-unbound plasma concentration ratio was well below unity (0.029), indicating an uphill efflux transport of VPA across the BBB. Co-infusion of probenecid did not have a significant effect on VPA efflux at the BBB as evidenced by a minimal change in the ECF-to-unbound plasma concentration ratio. This study suggests the presence of distinctly different organic anion transporters for the efflux of VPA at the parenchymal cells and capillary endothelium in the brain.


Assuntos
Transporte Biológico Ativo/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Interações Medicamentosas/fisiologia , Espaço Extracelular/efeitos dos fármacos , Probenecid/farmacologia , Ácido Valproico/farmacocinética , Animais , Transporte Biológico Ativo/fisiologia , Barreira Hematoencefálica/fisiologia , Encéfalo/citologia , Encéfalo/metabolismo , Proteínas de Transporte/efeitos dos fármacos , Proteínas de Transporte/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Epilepsia/tratamento farmacológico , Espaço Extracelular/metabolismo , Líquido Intracelular/efeitos dos fármacos , Líquido Intracelular/metabolismo , Bombas de Íon/efeitos dos fármacos , Bombas de Íon/metabolismo , Masculino , Microdiálise/estatística & dados numéricos , Neuroglia/citologia , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Coelhos , Ácido Valproico/sangue
3.
Anesth Analg ; 91(2): 362-8, 2000 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-10910849

RESUMO

UNLABELLED: When injecting lidocaine into tissues, the mean toxic dose of lidocaine may be increased by adding epinephrine to lidocaine and by decreasing the PaCO(2). In contrast, when lidocaine is introduced directly into an artery or vein, adding epinephrine to lidocaine may decrease the mean toxic dose of lidocaine. Less is known about the effects of decreased PaCO(2) on intravascular lidocaine toxicity. We infused lidocaine in 24 rabbits at 4 mg. kg(-1). min(-1) with/without epinephrine and with/without hypocapnia. We measured the time to onset of lidocaine-induced seizures, total dose of lidocaine at the time of seizures, and concentrations of lidocaine and monoethylglycine xylidide (MEGX), a metabolite of lidocaine, in plasma, brain, and cerebrospinal fluid. Epinephrine decreased onset time by 11% with hypocapnia and by 21% with normocapnia, and it increased plasma MEGX by 1 microg/mL with hypocapnia and 2 microg/mL with normocapnia. Hypocapnia increased onset time by 18% without epinephrine and by 33% with epinephrine, and it increased whole-brain MEGX by 10 microg/mL without epinephrine and by 14 microg/mL with epinephrine. We conclude that, when lidocaine is given intravascularly, hypocapnia increases onset time and lidocaine dose required for seizures. These effects occur with no change in the concentration of lidocaine in plasma or the brain. IMPLICATIONS: Hypocapnia increases the toxic dose of lidocaine given IV without altering lidocaine concentrations in blood, brain, or cerebrospinal fluid. Whole-brain monoethylglycine xylidide concentration is greater during hypocapnia than during normocapnia, and the addition of epinephrine to lidocaine increases the concentration of monoethylglycine xylidide in plasma.


Assuntos
Anestésicos Locais/farmacocinética , Anestésicos Locais/toxicidade , Encéfalo/metabolismo , Eletroencefalografia/efeitos dos fármacos , Epilepsia/metabolismo , Epinefrina/administração & dosagem , Hipocapnia/metabolismo , Lidocaína/análogos & derivados , Lidocaína/farmacocinética , Lidocaína/toxicidade , Anestésicos Locais/administração & dosagem , Animais , Pressão do Líquido Cefalorraquidiano/efeitos dos fármacos , Epilepsia/induzido quimicamente , Epilepsia/complicações , Epilepsia/fisiopatologia , Hipocapnia/complicações , Lidocaína/administração & dosagem , Lidocaína/análise , Coelhos
4.
Am J Kidney Dis ; 35(2): 266-74, 2000 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10676726

RESUMO

Delivered dose of hemodialysis (HD) in large patients with end-stage renal disease is often less than adequate. Fourteen chronic HD patients with weights greater than 80 kg participated in a prospective, cross-over study comparing urea reduction ratio (URR +/- SEM) and the fractional clearance index for urea (eKt/V(urea) +/- SEM) on a single polysulfone dialyzer for a control (HDC) period of 4 weeks versus clearances obtained with two dialyzers in parallel during an intervention (HDP) period of 4 weeks. Clearance of the surrogate middle molecule iohexol (C(Io)) was also measured. Health status was assessed with the SF-36. Blood and dialysate flow rates and duration of HD sessions were constant. URR increased from 0.67 +/- 0.006 during HDC to 0.72 +/- 0.006 with HDP (P < 0.0001). eKt/V(urea) increased from 1.16 +/- 0.021 to 1.34 +/- 0.021 (P < 0.0001). Increased URR and eKt/V(urea) occurred in all 14 during HDP (P < 0.05). C(Io) during HDP averaged 182 +/- 7.7 mL/min compared with 131 +/- 5.4 mL/min in HDC sessions (P < 0.00001). Health status improved in six of eight categories. Expense increased approximately $14.27 per dialysis with HDP. In 11 of 14 patients continued on two dialyzers in parallel for 1 year, monthly eKt/V averaged 1.46 +/- 0.066, and health status further improved in five of eight categories. In large patients, two dialyzers in parallel increased urea and iohexol clearance. Increased urea clearance was maintained for 1 year, and health status improved.


Assuntos
Falência Renal Crônica/metabolismo , Falência Renal Crônica/terapia , Diálise Renal/instrumentação , Ureia/metabolismo , Adulto , Idoso , Peso Corporal , Estudos Cross-Over , Desenho de Equipamento , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
5.
J Neurosci Methods ; 87(2): 159-65, 1999 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-11230812

RESUMO

We validate a modification of the sedimentation method for measuring fluorescent microspheres (FM) that improves the determination of regional cerebral blood flow (rCBF). Our FM method for rCBF determination is compared to the radioactive microspheres (RM) method for rCBF measurement by simultaneous injection of one radioactive and two fluorescent labeled doses, at two separate time points, into the left ventricle of a pig. The pig was killed, the brain and spinal cord removed, and divided into 92 pieces averaging 0.83 g. Our modifications to FM analysis by sedimentation includes: 2 instead of 1 week of autolysis, pellet washing with 1% Triton X-100 instead of 0.25% Tween 80, phosphate buffer addition during rinse, fluorescent dye extraction using 2-ethoxyethylacetate instead of 2-(2-ethoxyethoxy)ethyl acetate and polypropylene instead of glass tubes. Comparing rCBF using Sc46 RM, to yellow-green and orange FM, yielded mean differences of 0.026 and 0.021 ml/min per piece, respectively. Sn(113) RM compared to blue-green and scarlet FM gave mean differences of -0.010 and 0.137 ml/min per piece, respectively. All RM-FM differences, except those for scarlet FM, are within acceptable limits. This assay provides a reliable method for determining rCBF.


Assuntos
Circulação Cerebrovascular/fisiologia , Corantes Fluorescentes/farmacocinética , Animais , Sistema Nervoso Central/anatomia & histologia , Sistema Nervoso Central/irrigação sanguínea , Sistema Nervoso Central/metabolismo , Microesferas , Análise de Regressão , Reprodutibilidade dos Testes , Suínos
6.
Anesth Analg ; 87(4): 900-6, 1998 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9768791

RESUMO

UNLABELLED: There are no controlled studies to determine whether propofol given after the onset of lidocaine-induced seizures (posttreatment) stops lidocaine-induced seizures. In this study, we determined whether posttreatment with propofol abolishes lidocaine-induced epileptiform electroencephalogram (EEG) activity as effectively as does midazolam, and cerebrospinal fluid (CSF) dynamics during lidocaine-induced epileptiform EEG activity and its treatment. EEG activity and CSF dynamics were determined in two groups of anesthetized rabbits at each of four experimental conditions: baseline, lidocaine-induced epileptiform activity, treatment with midazolam (n = 6) or propofol (n = 6), and return to baseline. The analog EEG signal was converted into a set of digital parameters using aperiodic analysis, and CSF dynamics were determined using ventriculocistemal perfusion. Propofol (3.8 +/- 1.3 mg/kg) stopped epileptiform activity, as did midazolam (2.0 +/- 1.7 mg/kg). The rates of CSF formation or reabsorption and resistances to CSF reabsorption or flow at the arachnoid villi did not differ among conditions or between groups. Our results indicate that propofol and midazolam both terminate epileptiform activity without changing CSF dynamics. IMPLICATIONS: Propofol may be an alternative to benzodiazepines for treating lidocaine-induced epileptiform electroencephalogram activity in patients.


Assuntos
Anestésicos Intravenosos/administração & dosagem , Anestésicos Locais/toxicidade , Líquido Cefalorraquidiano/fisiologia , Eletroencefalografia , Epilepsia/induzido quimicamente , Epilepsia/tratamento farmacológico , Lidocaína/toxicidade , Propofol/administração & dosagem , Animais , Líquido Cefalorraquidiano/efeitos dos fármacos , Midazolam/administração & dosagem , Coelhos
7.
J Trauma ; 43(4): 680-6, 1997 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9356067

RESUMO

BACKGROUND: The purpose of this study was to determine how chronic cocaine exposure affects the hemodynamic response to epinephrine, dopamine, phenylephrine, and ephedrine in awake sheep. METHODS: The hemodynamic response to dopamine (10 microg/kg), phenylephrine (1.5 microg/kg), and ephedrine (0.15 mg/kg) boluses was determined at baseline before low-dosage cocaine exposure and again after 15 and 18 days of cocaine exposure. The hemodynamic response to epinephrine (0.15 microg/kg), phenylephrine (1.5 microg/kg), and ephedrine (0.15 mg/kg) was determined at baseline before high-dosage cocaine exposure and again after 15 and 18 days of cocaine exposure. RESULTS: Chronic cocaine exposure abolished the mean arterial pressure and heart rate responses to dopamine but did not alter the responses to epinephrine, phenylephrine, or ephedrine. CONCLUSION: In awake sheep, chronic cocaine exposure markedly impairs the hemodynamic response to dopamine but not to epinephrine, phenylephrine, or ephedrine.


Assuntos
Cocaína/farmacologia , Hemodinâmica/efeitos dos fármacos , Vasoconstritores/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Dopamina/farmacologia , Interações Medicamentosas , Efedrina/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Masculino , Fenilefrina/farmacologia , Ovinos
8.
J Neurosurg Anesthesiol ; 9(2): 166-74, 1997 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9100189

RESUMO

Previous studies suggest that desflurane may increase cerebrospinal fluid (CSF) formation rate (Vf) and volume, particularly during conditions of hypocapnia combined with elevated CSF pressure. The present study was designed to determine whether treatments routinely used in patients during anesthesia for neurological surgery would decrease Vf during desflurane anesthesia in rabbits. Three groups of six rabbits each were examined at four experimental conditions. Condition 1 was the combination of isoflurane, normocapnia, and normal CSF pressure (baseline, all groups). Condition 2 was the combination of isoflurane (group 1) or desflurane (groups 2 and 3), hypocapnia, and elevated CSF pressure (27 and 33 cm H2O). Conditions 3 and 4 were the same as condition 2 with the addition of furosemide, dexamethasone, mannitol, or fentanyl in groups 2 and 3. Vf, resistance to reabsorption of CSF (Ra), and systemic values were determined at each experimental condition, and brain water content was determined at the end of the study. Mean baseline Vf was 9.8 +/- 2.6 microliters.min-1. During the combination of desflurane, hypocapnia, and elevated CSF pressure, furosemide decreased Vf to 3.2 +/- 1.7 microliters.min-1, mannitol increased plasma osmolality and decreased plasma sodium concentration, and fentanyl decreased heart rate and increased plasma potassium concentration. Values for Ra and brain water content did not differ between groups. Of the four treatments examined, only furosemide decreased Vf during the combination of desflurane, hypocapnia, and elevated CSF pressure.


Assuntos
Anestésicos Inalatórios , Pressão do Líquido Cefalorraquidiano/efeitos dos fármacos , Furosemida/farmacologia , Isoflurano/análogos & derivados , Animais , Bicarbonatos/sangue , Água Corporal , Química Encefálica/efeitos dos fármacos , Dióxido de Carbono/sangue , Ventrículos Cerebrais/efeitos dos fármacos , Ventrículos Cerebrais/fisiologia , Desflurano , Dexametasona/farmacologia , Fentanila/farmacologia , Manitol/farmacologia , Neurocirurgia , Oxigênio/sangue , Pressão Parcial , Potássio/sangue , Coelhos , Sódio/sangue
9.
J Neurosurg Anesthesiol ; 9(1): 31-43, 1997 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9016439

RESUMO

Considering that adrenergic stimulation was reported to decrease the rate of cerebrospinal fluid (CSF) formation (Vf), it was hypothesized that cocaine might exert a similar effect. Accordingly, the present study was designed to examine the effects of low, moderate, and high doses of cocaine on Vf and resistance to reabsorption of CSF (Ra). Because cocaine possesses both adrenergic-stimulating and local anesthetic properties, the present study examined the effects of lidocaine, a local anesthetic without adrenergic-stimulating properties, as a comparison treatment to cocaine. New Zealand white rabbits (n = 17) weighing 3.5-4.3 kg were anesthetized with halothane. A needle was inserted into the left lateral cerebral ventricle and a catheter was inserted into the cisterna magna to permit ventriculocisternal perfusion with mock CSF labeled with blue dextran. A1 each of four experimental conditions, control and three doses of cocaine or lidocaine, fluid volumes and concentrations of blue dextran in timed samples of cisternal outflow were used to determine Vf and the rate of reabsorption of CSF (Va). In turn, Va at normal and elevated CSF pressures (+6 cmH2O) were used to determine Ra. For both the cocaine group (n = 9) and the lidocaine group (n = 8) the three drug doses were 0.5 mg.kg-1 followed by 1.0 microgram.kg-1.min-1, 1.5 mg.kg-1 followed by 3.0 micrograms.kg-1.min-1, and 4.5 mg.kg-1 followed by 9.0 micrograms.kg-1.min-1 i.v. Cocaine caused no significant change of Vf or Ra. In the lidocaine group there was a dose/time-related decrease of Vf (although the slope relating Vf to dose/time was not significantly different from that in the cocaine group), but no significant change of Ra. It is concluded that during halothane anesthesia cocaine does not decrease Vf, a finding not consistent with previous reports that adrenergic stimulation decreases Vf. Decrease of Vf with lidocaine is consistent with previous reports of similar dose-related effects of thiopental, etomidate, midazolam, and fentanyl on Vf.


Assuntos
Anestésicos Locais/farmacologia , Líquido Cefalorraquidiano/fisiologia , Cocaína/farmacologia , Lidocaína/farmacologia , Análise de Variância , Anestésicos Locais/administração & dosagem , Animais , Pressão Sanguínea/efeitos dos fármacos , Ventrículos Cerebrais/efeitos dos fármacos , Ventrículos Cerebrais/fisiologia , Líquido Cefalorraquidiano/efeitos dos fármacos , Cocaína/administração & dosagem , Relação Dose-Resposta a Droga , Eletroencefalografia/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Infusões Intravenosas , Pressão Intracraniana/efeitos dos fármacos , Lidocaína/administração & dosagem , Coelhos , Análise de Regressão
10.
J Trauma ; 42(1): 42-8, 1997 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-9003256

RESUMO

BACKGROUND: Although Cocaine use is common in trauma victims, little is known about how cocaine affects the cardiovascular response to trauma and associated blood loss. This study determined the effect of chronic cocaine use on the cardiovascular response to hemorrhage in awake and anesthetized sheep. METHODS: The hemodynamic and acid-base responses to graded hemorrhage were determined in awake and anesthetized sheep at baseline and after 15 and 18 days of chronic cocaine exposure. RESULTS: Chronic cocaine exposure resulted in a moderate paradoxical bradycardic response to hemorrhage in awake sheep, but did not otherwise alter the hemodynamic response to hemorrhage. In anesthetized animals, cocaine exposure impaired the ability to maintain mean arterial pressure and cardiac output during hemorrhage, and resulted in a marked paradoxical bradycardic response to hemorrhage. CONCLUSIONS: Chronic cocaine exposure did not have an important effect on the cardiovascular response to hemorrhage in awake sheep. However, in anesthetized sheep, chronic cocaine exposure diminished the compensatory cardiovascular response to graded hemorrhage.


Assuntos
Anestesia Geral , Cocaína/farmacologia , Hemodinâmica/efeitos dos fármacos , Hemorragia/sangue , Isoflurano , Animais , Cocaína/administração & dosagem , Cocaína/sangue , Relação Dose-Resposta a Droga , Infusões Intravenosas , Masculino , Ovinos
11.
Drug Metab Dispos ; 25(12): 1337-46, 1997 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-9394022

RESUMO

E-Delta 2-valproic acid (E-Delta 2-VPA), a major active metabolite of VPA, has been proposed as an alternative to VPA because it is less hepatotoxic and is nonteratogenic. In rodents, VPA and E-Delta 2-VPA have a brain tissue/free plasma concentration ratio less than unity, which suggests rapid removal of the alkanoate anticonvulsants from the central nervous system. This study in rabbits employed a simultaneous iv infusion-ventriculocisternal (VC) perfusion technique to investigate the steady-state kinetics of E-Delta 2-VPA transport at the blood-brain barrier, the blood-cerebrospinal fluid (CSF) barrier, and the neural cell membrane. Probenecid (PBD) was coadministered to probe the mediation of transport by organic anion transporter(s). Rabbits in the control group (N = 6) received an iv infusion of E-Delta 2-VPA to achieve a steady-state plasma concentration of 50 to 60 microg/ml. Blood and cisternal outflow of mock CSF perfusate were continuously sampled. Midway through the experiment, the VC perfusate was switched to one containing [3H]E-Delta 2-VPA. At 225 min, the rabbits were sacrificed, and each brain was removed and dissected into ten regions. Rabbits in the PBD group (N = 9) received an iv infusion and VC perfusion as in the control group as well as concomitant iv infusion of the inhibitor. The mean steady-state VC extraction ratio for [3H]E-Delta 2-VPA did not differ between the control and PBD groups (63.7 +/- 8.3% vs. 60. 6 +/- 9.6%), indicating the lack of a significant PBD-sensitive transport at the choroidal epithelium. Coadministration of PBD elevated brain concentration of cold E-Delta 2-VPA in the absence of a significant change in total or free steady-state plasma concentration. Mean E-Delta 2-VPA brain tissue/free plasma concentration ratios in the various brain regions were 3.5- to 5.2-fold higher in PBD-treated animals than in the controls. Significant increases (3.0- to 4.5-fold) in the mean brain tissue/cisternal perfusate concentration ratios were also observed. Compartmental modeling of the steady-state distribution data suggested that clearance of E-Delta 2-VPA from the brain parenchyma is governed jointly by efflux transporters at the neural cell membrane and brain capillary endothelium. Moreover, PBD-induced elevation of E-Delta 2-VPA tissue concentrations is attributed primarily to inhibition of E-Delta 2-VPA efflux transport at the neural cell membrane, resulting in both intracellular trapping and greater tissue retention of E-Delta 2-VPA.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ácidos Graxos Monoinsaturados/farmacocinética , Probenecid/farmacologia , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Ventrículos Cerebrais/efeitos dos fármacos , Ventrículos Cerebrais/metabolismo , Cisterna Magna/efeitos dos fármacos , Cisterna Magna/metabolismo , Interações Medicamentosas , Ácidos Graxos Monoinsaturados/sangue , Ácidos Graxos Monoinsaturados/líquido cefalorraquidiano , Infusões Intravenosas , Injeções Intraventriculares , Cinética , Masculino , Perfusão , Probenecid/administração & dosagem , Coelhos , Distribuição Tecidual/efeitos dos fármacos
12.
Epilepsy Res ; 23(2): 95-104, 1996 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-8964279

RESUMO

Recently we investigated the mechanisms mediating the transport of valproic acid (VPA) between blood and brain. In one study efflux of valproic acid (VPA) from rabbit brain was inhibited by probenecid. Efflux of VPA decreased when probenecid was given intravenously but not when probenecid was given by ventriculocisternal (VC) perfusion indicating that the major site of probenecid-sensitive transport was at the brain capillary endothelium and not at the choroid plexus. In another study VPA transport into rat brain was inhibited by para-aminohippurate (PAH). The purpose of the present study were to determine (a) if the efflux of VPA from rabbit brain was also inhibited by PAH, and (b) whether efflux of VPA could occur at the choroid plexus via an PAH-selective transport system. Six control rabbits received VPA by intravenous infusion and tracer concentrations of [3H]VPA and [14C]PAH by VC perfusion. Rabbits in the PAH group (n = 6) received identical treatment with VPA, tracer concentrations of [3H]VPA and [14C]PAH and, in addition, received 20 mM PAH by VC perfusion. PAH had no effect on the VC extraction ratio of [3H]VPA or the steady-state brain concentration of intravenously administered VPA. It is concluded that the efflux of VPA at the rabbit blood-brain barrier is mediated by a transporter different from the PAH-like transporter responsible for the uptake of VPA into rat brain. In addition, the finding that VC perfusion with PAH had no effect on the VC extraction of [3H]VPA provides further evidence that the choroid plexus plays a negligible role in removal of VPA from the CNS.


Assuntos
Sistema Nervoso Central/metabolismo , Transporte de Íons/efeitos dos fármacos , Ácido Valproico/metabolismo , Ácido p-Aminoipúrico/farmacologia , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Masculino , Coelhos , Ratos , Distribuição Tecidual
13.
Epilepsy Res ; 20(3): 185-92, 1995 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-7796790

RESUMO

Previous experiments suggest the primary route of valproic acid (VPA) removal from the rabbit central nervous system (CNS) is by probenecid-sensitive transporters at the blood-brain barrier but not at the choroid plexus. The purpose of this study was to determine if other transport mechanisms at the choroid plexus played a significant role in the removal of VPA from the CNS. In six rabbits, silicone oil was perfused into both cerebral ventricles and out through the cisterna magna to physically block exchange of VPA between cerebrospinal fluid (CSF) and blood and between brain and CSF. In six control rabbits, perfusion was performed with mock CSF. Both groups received a loading dose followed by continuous intravenous infusion of VPA for 210 min. Ventriculocisternal perfusion with silicone oil had no significant effect on the steady-state brain concentrations or brain-to-plasma concentration ratios of VPA, further confirming that efflux of VPA at the choroid plexus is negligible.


Assuntos
Plexo Corióideo/metabolismo , Ácido Valproico/farmacocinética , Animais , Barreira Hematoencefálica/fisiologia , Sistema Nervoso Central/metabolismo , Eletroencefalografia/efeitos dos fármacos , Epitélio/metabolismo , Infusões Intravenosas , Masculino , Coelhos , Distribuição Aleatória , Ácido Valproico/administração & dosagem , Ácido Valproico/líquido cefalorraquidiano
14.
J Neurosurg Anesthesiol ; 6(3): 193-200, 1994 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-7521700

RESUMO

Clearance of valproic acid from brain tissue is believed to occur via a carrier-mediated system(s). The present study was designed to determine whether clearance was capacity-limited (saturable) and whether it occurred primarily at the choroid plexus. Ten rabbits were anesthetized with halothane and surgically prepared for ventriculocisternal perfusion. In group 1 (n = 5) valproic acid was added to blue dextran-containing mock cerebrospinal fluid (CSF) to achieve concentrations of 5, 20, 100, and 500 micrograms.ml-1. The mixture was infused through needles in both cerebral ventricles. The purpose of this group was to determine whether over a large range (100x) of valproic acid concentrations, clearance from CSF was capacity limited (saturable). In group 2 (n = 5) valproic acid concentrations were 3, 10, and 30 microgram.ml-1 and infusion was into the left cerebral ventricle only. The purposes of this group were to determine (a) the magnitude of valproic acid clearance for the "clinical" range of valproic acid in CSF (10-30 micrograms.ml-1), and (b) whether clearance of valproic acid was changed by perfusion across a portion of the choroid plexus surface area (group 2) as compared with perfusion across the entire choroid plexus surface area (group 1). In both groups the percent extraction of valproic acid was calculated from the concentration ratio (valproic acid)out/(valproic acid)in corrected for the rate of CSF formation. In group 1 the percent extraction of valproic acid was 93 +/- 2% (mean +/- SD) at 5 micrograms.ml-1 and stabilized within the range of 58-70% (individual values) at the higher inflow concentrations of valproic acid.(ABSTRACT TRUNCATED AT 250 WORDS)


Assuntos
Anestesia por Inalação , Ácido Valproico/líquido cefalorraquidiano , Animais , Encéfalo/irrigação sanguínea , Química Encefálica , Capilares/metabolismo , Ventrículos Cerebrais/metabolismo , Líquido Cefalorraquidiano/metabolismo , Plexo Corióideo/metabolismo , Cisterna Magna/metabolismo , Corantes , Dextranos , Endotélio Vascular/metabolismo , Taxa de Depuração Metabólica , Coelhos , Solubilidade , Ácido Valproico/administração & dosagem , Ácido Valproico/análise , Ácido Valproico/sangue , Ácido Valproico/farmacocinética
15.
J Pharmacol Exp Ther ; 268(2): 797-805, 1994 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-8113992

RESUMO

The steady-state brain-to-free plasma concentration ratio of valproic acid (VPA) is well below unity, which suggests that it is efficiently removed from the central nervous system (CNS) by specialized transport processes. The purpose of this study was to determine whether probenecid (PBD)-sensitive anion transporters at the choroidal epithelium and brain capillary endothelium are involved in the clearance of VPA from the CNS of the rabbit. Unlabeled VPA was infused i.v. to achieve a steady-state plasma concentration while a tracer concentration of 3H-VPA was introduced into the ventricles by ventriculocisternal (VC) perfusion. In two treatment groups, PBD was administered by direct placement into the VC perfusate or by a combination of an i.v. priming dose and continuous infusion. In the control group, no other treatments were given. PBD administered by either route had no effect on the steady-state VC extraction of 3H-VPA (approximately 57%). Coadministration of PBD through the VC perfusate had no apparent effect on the blood-brain distribution of unlabeled VPA. In the i.v. PBD group, the concentration in the brain of systemically administered VPA increased 1.5- to 2-fold in all regions compared with that in control animals. Because neither the total nor the free plasma concentration of VPA was affected by PBD, the increase in brain VPA concentration reflected a blockade of VPA efflux across the brain capillary endothelium. These results suggest that PBD-sensitive transport at the brain capillary endothelium is the main route of VPA efflux from the CNS.


Assuntos
Encéfalo/metabolismo , Plexo Corióideo/metabolismo , Endotélio Vascular/metabolismo , Probenecid/farmacologia , Ácido Valproico/farmacocinética , Animais , Transporte Biológico , Masculino , Probenecid/farmacocinética , Coelhos
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