RESUMEN
In various clinical guidelines of brain injury, intracranial pressure (ICP), cerebral blood flow (CBF) and brain temperature (BT) are essential targets for precise management for brain resuscitation. In addition, the integrated automatic control of BT, ICP, and CBF is required for improving therapeutic effects and reducing medical costs and staff burden. Thus, a new model of cerebral circulation was developed in this study for integrative automatic control. With this model, the CBF and cerebral perfusion pressure of a normal adult male were regionally calculated according to cerebrovascular structure, blood viscosity, blood distribution, CBF autoregulation, and ICP. The analysis results were consistent with physiological knowledge already obtained with conventional studies. Therefore, the developed model is potentially available for the integrative control of the physiological state of the brain as a reference model of an automatic control system, or as a controlled object in various control simulations.
Asunto(s)
Encéfalo/fisiología , Circulación Cerebrovascular/fisiología , Modelos Biológicos , Adulto , Vasos Sanguíneos/anatomía & histología , Vasos Sanguíneos/fisiología , Encéfalo/fisiopatología , Arterias Cerebrales/fisiología , Homeostasis/fisiología , Humanos , Presión Intracraneal/fisiología , Masculino , Modelos CardiovascularesRESUMEN
An automatic control system of brain temperature by air-surface cooling was developed for therapeutic hypothermia, which is increasingly recommended for hypoxic-ischemic encephalopathy after cardiac arrest and neonatal asphyxia in several guidelines pertinent to resuscitation. Currently, water-surface cooling is the most widespread cooling method in therapeutic hypothermia. However, it requires large electric power for precise control and also needs water-cooling blankets which have potential for compression of patients by its own weight and for water leakage in ICU. Air-surface cooling does not have such problems and is more suitable for clinical use than water-surface cooling, because air has lower specific heat and density as well as the impossibility of the contamination in ICU by its leakage. In the present system, brain temperature of patients is automatically controlled by suitable adjustment of the temperature of the air blowing into the cooling blankets. This adjustment is carried out by the regulation of mixing cool and warm air using proportional control valves. The computer in the developed control apparatus suitably calculates the air temperature and rotation angle of the valves every sampling time on the basis of the optimal-adaptive control algorithm. Thus, the proposed system actualizes automatic control of brain temperature by the inputting only the clinically desired temperature of brain. The control performance of the suggested system was verified by the examination using the mannequin in substitution for an adult patient. In the result, the control error of the head temperature of the mannequin was 0.12 °C on average in spite of the lack of the production capacity of warm air after the re-warming period. Thus, this system serves as a model for the clinically applied system.
Asunto(s)
Encéfalo/fisiología , Hipotermia Inducida/métodos , Aire , Algoritmos , Temperatura Corporal , HumanosRESUMEN
Automatic control systems of brain temperature for water surface-cooling were first-ever applied to the brain hypothermic treatment of patients. A patient in ICU was regarded as a unity controlled system with an input (temperature of water into blanket) and an output (tympanic membrane temperature). The proposed algorithm of optimal-adaptive and fuzzy control laws inclusive of our developed cooling and warming machine were well confirmed during the hypothermic course to keep brain temperature of patients within its allowable range. It was well controlled without much influence due to room temperature, metabolic and circulatory change caused by various medical treatments including the effect of nonlinear and time-varying characteristics of individual patients. The clinical control of brain temperature was almost continuously performed in around 10 days, under the brain temperature between 35 degrees C and 37 degrees C scheduled by physicians according to the state of patients. Their state had been monitored during the therapeutic course of pharmacological treatment with almost everyday examinations by CT imaging, referring various vital signs inclusive of the temperature of urinary bladder with continuous measurement of intracranial pressure by a catheter placement in cerebral sinus. The patients had good recovery to their rehabilitation after mild hypothermia by the proposed automatic control systems.
Asunto(s)
Lesiones Encefálicas/terapia , Hipotermia Inducida/instrumentación , Monitoreo Fisiológico/instrumentación , Anciano , Algoritmos , Infarto Cerebral/terapia , Femenino , Lógica Difusa , Humanos , Persona de Mediana EdadRESUMEN
Alzheimer's disease (AD) is characterized by cerebrovascular deposition of the amyloid beta-peptide (A beta), which is derived from a larger beta-amyloid precursor protein (beta APP). Altered metabolism of beta APP, resulting in increased A beta production, appears central in the neuropathology of AD. The processing of the holoprotein beta APP by different "secretase" enzymes results in three major carboxyl-truncated species. One species, which results from the cleavage of beta APP by gamma-secretase, is secreted into the cerebrospinal fluid (CSF) and is called sAPP gamma as it contains an intact A beta domain. Moreover, AD is characterized by cholinergic dysfunction and the loss of synaptic proteins. Reports of an inverse relation between nicotine intake, due to cigarette smoking, and the incidence of AD prompted us to investigate the effects of nicotine on beta APP processing and synaptic proteins in rats and in cell culture. Nicotine, 1 and 8 mg/kg/day, doses commensurate with cigarette smoking, and a higher but well tolerated dose, respectively, was administered over 14 days to rats. Levels of sAPP in the CSF sample were evaluated by Western blot analysis. The higher dose significantly increased levels of total sAPP; however, both doses significantly reduced sAPP gamma, which contains the amyloidogenic portion of A beta. These actions were blocked by nicotinic receptor antagonism. Nicotinic antagonists alone had no effect on either total sAPP or sAPP gamma levels in CSF. Nicotine did not significantly change the intracellular levels of total beta APP in rat brain extracts, which is consistent with neuronal cell culture data. Similarly, levels of vesicular protein, such as synaptophysin, and presynaptic terminal protein SNAP-25 were unaffected by nicotine treatment both in vivo and in cell culture experiments. Taken together, these results suggest that nicotine modifies beta APP processing away from the formation of potentially amyloidogenic products, without altering the levels of synaptic proteins, and that this can potentially offer therapeutic potential for Alzheimer's disease.
Asunto(s)
Precursor de Proteína beta-Amiloide/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Nicotina/farmacología , Sinapsis/fisiología , Precursor de Proteína beta-Amiloide/líquido cefalorraquídeo , Precursor de Proteína beta-Amiloide/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Humanos , Masculino , Proteínas del Tejido Nervioso/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Sinapsis/efectos de los fármacosRESUMEN
The reduction in levels of the potentially toxic amyloid-beta peptide (Abeta) has emerged as one of the most important therapeutic goals in Alzheimer's disease. Key targets for this goal are factors that affect the expression and processing of the Abeta precursor protein (betaAPP). Earlier reports from our laboratory have shown that a novel cholinesterase inhibitor, phenserine, reduces betaAPP levels in vivo. Herein, we studied the mechanism of phenserine's actions to define the regulatory elements in betaAPP processing. Phenserine treatment resulted in decreased secretion of soluble betaAPP and Abeta into the conditioned media of human neuroblastoma cells without cellular toxicity. The regulation of betaAPP protein expression by phenserine was posttranscriptional as it suppressed betaAPP protein expression without altering betaAPP mRNA levels. However, phenserine's action was neither mediated through classical receptor signaling pathways, involving extracellular signal-regulated kinase or phosphatidylinositol 3-kinase activation, nor was it associated with the anticholinesterase activity of the drug. Furthermore, phenserine reduced expression of a chloramphenicol acetyltransferase reporter fused to the 5'-mRNA leader sequence of betaAPP without altering expression of a control chloramphenicol acetyltransferase reporter. These studies suggest that phenserine reduces Abeta levels by regulating betaAPP translation via the recently described iron regulatory element in the 5'-untranslated region of betaAPP mRNA, which has been shown previously to be up-regulated in the presence of interleukin-1. This study identifies an approach for the regulation of betaAPP expression that can result in a substantial reduction in the level of Abeta.
Asunto(s)
Precursor de Proteína beta-Amiloide/genética , Inhibidores de la Colinesterasa/farmacología , Interleucina-1/farmacología , Fisostigmina/farmacología , Biosíntesis de Proteínas/efectos de los fármacos , ARN Mensajero/genética , Regiones no Traducidas 5'/genética , Astrocitoma , Supervivencia Celular/efectos de los fármacos , Cloranfenicol O-Acetiltransferasa/análisis , Cloranfenicol O-Acetiltransferasa/genética , Cromonas/farmacología , Medios de Cultivo Condicionados , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Flavonoides/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Interleucina-1/fisiología , L-Lactato Deshidrogenasa/análisis , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Morfolinas/farmacología , Neuroblastoma , Fosfatidilinositol 3-Quinasas/metabolismo , Fisostigmina/análogos & derivados , ARN Mensajero/metabolismo , Proteínas Recombinantes/biosíntesis , Transfección , Células Tumorales CultivadasRESUMEN
In order to clarify the pathological outcome of congenital diaphragmatic hernia (CDH), we devised an animal model of CDH by administration of 2,4-dichlorophenyl-p-nitrophenyl ether (nitrofen) to pregnant rats, and determined the level and distribution of lung surfactant using the monoclonal antibody toward sphingomyelin and disaturated phosphatidylcholine (disat-PC). In control rats, the concentration of disat-PC was found to increase greatly from 16 to 18 days of gestation. Intragastric administration of nitrofen to pregnant rats at day 9 of gestation resulted in CDH in 42.7% of fetuses delivered after 20 days of gestation. In nitrofen-treated fetuses, the concentration of disat-PC in the lungs was lower than those in control fetuses, and surfactant apoprotein SP-A was similarly reduced in nitrofen-treated fetuses. However, the concentration of disat-PC in nitrofen-treated fetuses was higher than that in control fetuses at 18 days of gestation, indicating a synthetic potential of surfactant in nitrofen-treated fetuses comparable to that at the late stage of normal gestation. Immunohistochemical study with the antibody revealed that surfactant phospholipid was mainly in the form of intracellular granules in nitrofen-treated fetuses, probably causing the hypoplastic lungs and then CDH, in contrast to the uniform distribution on the pulmonary alveolar surface in control fetuses.
Asunto(s)
Hernias Diafragmáticas Congénitas , Pulmón/metabolismo , Surfactantes Pulmonares/metabolismo , Líquido Amniótico/metabolismo , Animales , Animales Recién Nacidos , Western Blotting , Peso Corporal , Cromatografía en Capa Delgada , Modelos Animales de Enfermedad , Electroforesis en Gel de Poliacrilamida , Herbicidas , Hernia Diafragmática/inducido químicamente , Inmunohistoquímica , Pulmón/anomalías , Pulmón/química , Tamaño de los Órganos , Éteres Fenílicos , Fosfatidilcolinas/análisis , Surfactantes Pulmonares/química , Ratas , Ratas Sprague-Dawley , Esfingomielinas/análisisRESUMEN
Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the elderly, characterised by widespread loss of central cholinergic function. The only symptomatic treatment proven effective to date is the use of cholinesterase (ChE) inhibitors to augment surviving cholinergic activity. ChE inhibitors act on the enzymes that hydrolyse acetylcholine (ACh) following synaptic release. In the healthy brain, acetylcholinesterase (AChE) predominates (80%) and butyrylcholinesterase (BuChE) is considered to play a minor role in regulating brain ACh levels. In the AD brain, BuChE activity rises while AChE activity remains unchanged or declines. Therefore both enzymes are likely to have involvement in regulating ACh levels and represent legitimate therapeutic targets to ameliorate the cholinergic deficit. The two enzymes differ in location, substrate specificity and kinetics. Recent evidence suggests that BuChE may also have a role in the aetiology and progression of AD beyond regulation of synaptic ACh levels. Experimental evidence from the use of agents with enhanced selectivity for BuChE (cymserine, MF-8622) and ChE inhibitors such as rivastigmine, which have a dual inhibitory action on both AChE and BuChE, indicate potential therapeutic benefits of inhibiting both AChE and BuChE in AD and related dementias. The development of specific BuChE inhibitors and the continued use of ChE inhibitors with the ability to inhibit BuChE in addition to AChE should lead to improved clinical outcomes.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/enzimología , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/uso terapéutico , HumanosRESUMEN
The extracellular deposition of amyloid beta-peptide (Abeta) in the form of cerebrovascular amyloid and extracellular plaques is one of the major neuropathological manifestations of Alzheimer's disease (AD). Abeta is generated proteolytically from the large beta-amyloid precursor protein (APP). APP is cleaved by a group of proteases called "secretase" to generate soluble derivatives of APP (sAPP), which are secreted in human plasma, CSF and cultured cells. Neurochemically, there is a severe loss of cholinergic neurons and a decreased synthesis of acetylcholine in neocortex in AD. Current approved AD drugs, such as aricept and tacrine, are based on the use of cholinesterase inhibitors (ChEIs) and have been reported to improve memory deficits and cognitive decline in some patients with AD. To compare the effects of ChEIs on APP processing, we have tested a series of ChEIs such as tacrine, physostigmine, metrifonate, phenserine and cymserine in cultured human neuroblastoma cells. We analyzed levels of sAPP by immunochemical techniques with APP-specific antibodies and assayed levels of Abeta by a sensitive sandwich ELISA. Based on these results, ChEIs can be divided into three groups: the first group of ChEIs had no effect on sAPP secretion, the second decreased the sAPP secretion only, and third group affected the secretion of sAPP and Abeta. The difference in the action of metrifonate, physostigmine, phenserine and tacrine on APP processing is independent of their selectivity for the cholinesterase enzymes. This possibly is due to the different targets that are used by ChEIs. Studying the effects of ChEIs on different targets is useful to maximize the benefit of ChEIs for the treatment of AD subjects.
Asunto(s)
Enfermedad de Alzheimer/fisiopatología , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Inhibidores de la Colinesterasa/farmacología , Humanos , Inmunohistoquímica , Neuroblastoma , Células Tumorales CultivadasRESUMEN
Phenserine, a phenylcarbamate of physostigmine, is a new potent and highly selective acetylcholinesterase (AChE) inhibitor, with a > 50-fold activity versus butyrylcholinesterase (BChE), in clinical trials for the treatment of Alzheimer's disease (AD). Compared to physostigmine and tacrine, it is less toxic and robustly enhances cognition in animal models. To determine the time-dependent effects of phenserine on cholinergic function, AChE activity, brain and plasma drug levels and brain extracellular acetylcholine (ACh) concentrations were measured in rats before and after phenserine administration. Additionally, its maximum tolerated dose, compared to physostigmine and tacrine, was determined. Following i.v. dosing, brain drug levels were 10-fold higher than those achieved in plasma, peaked within 5 min and rapidly declined with half-lives of 8.5 and 12.6 min, respectively. In contrast, a high (> 70%) and long-lasting inhibition of AChE was achieved (half-life > 8.25 h). A comparison between the time-dependent plasma AChE inhibition achieved after similar oral and i.v. doses provided an estimate of oral bioavailability of 100%. Striatal, in vivo microdialysis in conscious, freely-moving phenserine-treated rats demonstrated > 3-fold rise in brain ACh levels. Phenserine thus is rapidly absorbed and cleared from the body, but produces a long-lasting stimulation of brain cholinergic function at well tolerated doses and hence has superior properties as a drug candidate for AD. It selectively inhibits AChE, minimizing potential BChE side effects. Its long duration of action, coupled with its short pharmacokinetic half-life, reduces dosing frequency, decreases body drug exposure and minimizes the dependence of drug action on the individual variations of drug metabolism commonly found in the elderly.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/farmacología , Inhibidores de la Colinesterasa/farmacocinética , Fisostigmina/farmacología , Fisostigmina/farmacocinética , Administración Oral , Enfermedad de Alzheimer/patología , Animales , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Inhibidores de la Colinesterasa/administración & dosificación , Modelos Animales de Enfermedad , Semivida , Infusiones Intravenosas , Masculino , Fisostigmina/administración & dosificación , Fisostigmina/análogos & derivados , Ratas , Ratas Endogámicas F344 , Tacrina/administración & dosificación , Tacrina/farmacocinética , Tacrina/farmacologíaRESUMEN
Four novel analogues (8-11) of cymserine (2) were synthesized by methods similar to those recently developed for the total syntheses of N8-norphenserine (Yu, Q. S.; et al. J. Med. Chem. 1997, 40, 2895-2901) and N1,N8-bisnorphenserine (Yu, Q. S.; et al. J. Med. Chem. 1998, 41, 2371-2379). As our structure-activity studies predicted, these compounds are highly potent and selective inhibitors of human butyrylcholinesterase (BChE) and will test the novel hypothesis that BChE inhibitors are useful in the treatment of Alzheimer's disease. In a similar manner, the same modifications that provided BChE selectivity were applied to the acetylcholinesterase (AChE)-selective inhibitor, tolserine (5), to provide the novel tolserine analogues 12-15. As predicted, these modifications altered the AChE-selective action of tolserine (5) to favor a lack of cholinesterase enzyme subtype selectivity.
Asunto(s)
Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Fisostigmina/análogos & derivados , Acetilcolinesterasa/sangre , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Butirilcolinesterasa/sangre , Inhibidores de la Colinesterasa/química , Inhibidores de la Colinesterasa/farmacología , Eritrocitos/enzimología , Humanos , Fisostigmina/síntesis química , Fisostigmina/química , Fisostigmina/farmacología , Relación Estructura-ActividadRESUMEN
Abnormal deposition and accumulation of Alzheimer's amyloid beta-protein (A beta) and degeneration of forebrain cholinergic neurons are among the principal features of Alzheimer's disease. Studies in rat model systems have shown that forebrain cholinergic deficits are accompanied by induction of cortical beta-amyloid precursor protein (beta-APP) mRNAs and increased levels of secreted beta-APP in the CSF. The studies reported here determined whether the CSF levels of secreted beta-APP could be altered pharmacologically. In different experiments, rats with lesions of the forebrain cholinergic system received injections of vehicle, a muscarinic receptor antagonist scopolamine, or one of two cholinesterase inhibitors - diisopropyl phosphorofluoridate (DFP) or phenserine. Scopolamine was administered to determine whether the levels of beta-APP in the CSF could be increased by anticholinergic agents. The cholinesterase inhibitors were administered to determine whether the forebrain cholinergic system lesion-induced increases in CSF beta-APP could be reduced by cholinergic augmentation. Scopolamine administration led to a significant increase in the CSF levels of secreted beta-APP in sham-lesioned rats. Phenserine, a novel, reversible acetyl-selective cholinesterase inhibitor, significantly decreased the levels of secreted beta-APP in the CSF of forebrain cholinergic system-lesioned rats whereas DFP, a relatively non-specific cholinesterase inhibitor, failed to affect CSF levels of secreted beta-APP. These results suggest that the levels of secreted beta-APP in the CSF can be pharmacologically modulated but that this modulation is dependent upon the status of the forebrain cholinergic system and the pharmacological properties of the drugs used to influence it.
Asunto(s)
Precursor de Proteína beta-Amiloide/líquido cefalorraquídeo , Precursor de Proteína beta-Amiloide/efectos de los fármacos , Inhibidores de la Colinesterasa/farmacología , Prosencéfalo/efectos de los fármacos , Prosencéfalo/metabolismo , Enfermedad de Alzheimer/metabolismo , Animales , Isoflurofato/farmacología , Masculino , Antagonistas Muscarínicos/farmacología , Fisostigmina/análogos & derivados , Fisostigmina/farmacología , Ratas , Ratas Sprague-Dawley , Escopolamina/farmacologíaRESUMEN
BACKGROUND/PURPOSE: The intussusception-type antireflux valve is a mechanism introduced by Nakajo, who reported the results of his initial 17 cases in 1990. This report summarizes our further experience with new patients, together with follow-up results of the cases previously reported by Nakajo. METHODS: In total, 46 new patients who had biliary atresia underwent portoenterostomy at the authors' two units. The authors hoped to construct the intussuscepted antireflux valve in the Roux-en-Y loop, whenever possible, at the time of hepatic portoenterostomy. RESULTS: Among the 46 patients, one case each was found to be too young or too old to have the valve constructed during the surgery. In another case, the Roux-en-Y loop became too short after repeated revisions of the portoenterostomy. In another patient, the valve was first constructed but later removed because of jejunal perforation near the valve. In the last patient, the valve was not constructed for unspecified reasons. The authors constructed the antireflux valve in 42 patients, but it was maintained in 41. In one case, the valve truly prevented reflux of the intestinal juice during an episode of intestinal obstruction. The valve was found to be incompetent in one patient 5 years after the initial surgery. CONCLUSION: The incidence of cholangitis was high in patients with postoperative cystic dilatation of the intrahepatic bile ducts, and low in those without it.
Asunto(s)
Atresia Biliar/complicaciones , Colangitis/complicaciones , Colangitis/prevención & control , Reflujo Gastroesofágico/prevención & control , Reflujo Gastroesofágico/cirugía , Implantación de Prótesis , Estudios de Seguimiento , Humanos , Lactante , Recién Nacido , Portoenterostomía Hepática/métodos , Estudios RetrospectivosRESUMEN
By TLC-immunostaining with the monoclonal antibody VJ-41, which preferentially reacted with sphingomyelin (Sm) and disaturated fatty acid-containing phosphatidyl choline (DSPC), Sm and surfactant phospholipid dipalmitoyl PC were only detected in the lipid extracts from human amniotic fluid. The method was useful in the selective and simultaneous determination of surfactant phospholipid and Sm concentrations in the amniotic fluids to determine the level of maturity of the lungs of the fetus. By measuring the density of spots visualized by TLC-immunostaining, we detected Sm at a sensitivity two times higher than that for dipalmitoyl PC using the antibody. More than 50 ng of dipalmitoyl PC and Sm was detected on the same TLC plate and the standard curves were linear up to 1 microgram of phospholipids. The method was applied to determine the surfactant phospholipid/Sm ratio in 20 microliter of the amniotic fluids obtained at delivery, and the amniotic fluids from the women who delivered a baby suffering from respiratory distress syndrome (RDS) were easily discriminated from the normal amniotic fluids. In an analysis of 200 microliter of amniotic fluids from 4 RDS cases and 16 normal baby cases, the mean DSPC/Sm ratios were 0.97 +/- 0.53 and 5.75 +/- 1.29, respectively.
Asunto(s)
Líquido Amniótico/química , Cromatografía en Capa Delgada/métodos , Fosfolípidos/análisis , Surfactantes Pulmonares/química , Síndrome de Dificultad Respiratoria del Recién Nacido/diagnóstico , Esfingomielinas/análisis , Amniocentesis , Anticuerpos Monoclonales , Reacciones Antígeno-Anticuerpo , Ácidos Grasos/análisis , Femenino , Humanos , Técnicas para Inmunoenzimas , Recién Nacido , Fosfatidilcolinas/química , Síndrome de Dificultad Respiratoria del Recién Nacido/metabolismo , Sensibilidad y EspecificidadRESUMEN
A dramatic change in the glycosphingolipid composition in murine lung occurred between 1 day and 1 week after birth. GlcCer and LacCer were the predominant neutral glycosphingolipids prenatally and 1 day after birth, and the concentrations of globo- and ganglio-series glycosphingolipids increased abruptly from 1 week after birth, reaching maxima at 2-3 weeks. To explore the functional significance of the change, we examined the role of neutral glycosphingolipids as receptors for the murine pulmonary surfactant protein, SP-A, and found that SP-A bound to LacCer, Gg3Cer, and Gg1Cer, but not to Gb3Cer, Gb4Cer, IV3GalNAc alpha-Gb4Cer, sulfatide, or several gangliosides. On TLC-blotting with 125I-labeled SP-A, the binding of SP-A to Gg3Cer and Gg4Cer was 5 times higher than that to LacCer, and on immunohistochemical staining Gg4Cer and Gg3Cer was mainly observed in the alveolar epithelium. Thus, the capacity to retain SP-A of glycolipid receptors per gram dry weight of lung at 1 week after birth was 1.6 times higher than that at 1 day after birth, and reached a maximum 3 weeks after birth. These findings suggest that the enhanced synthesis of the ganglio-series neutral glycosphingolipids 1 week after birth results in an increase in the binding capacity for SP-A on the epithelial cell surface of alveoli.
Asunto(s)
Glicoesfingolípidos/metabolismo , Proteolípidos/metabolismo , Alveolos Pulmonares/metabolismo , Surfactantes Pulmonares/metabolismo , Receptores de Superficie Celular/metabolismo , Animales , Animales Recién Nacidos , Western Blotting , Epitelio/metabolismo , Femenino , Glicoesfingolípidos/química , Inmunohistoquímica , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos DBA , Embarazo , Alveolos Pulmonares/embriología , Alveolos Pulmonares/crecimiento & desarrollo , Proteína A Asociada a Surfactante Pulmonar , Proteínas Asociadas a Surfactante PulmonarRESUMEN
PURPOSE: Carboplatin has shown promise experimentally as an antineoplastic agent against both primary central nervous system (CNS) tumors and several solid tumors that frequently metastasize to the brain. Unfortunately, carboplatin is limited in its clinical use for tumors in the CNS by systemic toxicity and poor penetration through the blood brain barrier. Recent advances in polymer technology have made feasible the intracranial implantation of a biodegradable polymer capable of local sustained delivery of chemotherapy for brain neoplasms. This study assessed the toxicity and efficacy of carboplatin delivered from intracranial sustained release polymers in the treatment of experimental gliomas in rodents. METHODS: Two biodegradable anhydride polymer systems were tested: a copolymer of 1,3-bis-(p-carboxyphenoxy propane) and sebacic acid, and a copolymer of fatty acid dimer and sebacic acid. The polymers were loaded with carboplatin and dose escalation studies evaluating toxicity were performed by implanting carboplatin-loaded polymers into the brains of rats. Next, efficacy was tested. F-98 glioma cells were injected intracranially into rats, and 5 days later polymers containing the highest tolerated doses were implanted at the site of tumor growth. The survival of animals receiving carboplatin-loaded polymer was compared with that of animals receiving intraperitoneal doses of the same agent. RESULTS: Carboplatin-polymer was well tolerated at doses up to 5% loading in both polymer systems. Locally delivered carboplatin effectively prolonged survival of rats with F98 gliomas. Maximal treatment effect was seen with 5% loading of either polymer, with median survival increased threefold over control (P < 0.004). Systemic carboplatin also significantly prolonged survival, but the best intracranial polymer dose was significantly more effective than the best systemic dose tested. CONCLUSIONS: Carboplatin can be safely delivered intracranially by biodegradable sustained- release polymers. This treatment improves survival in rodents with experimental gliomas, with locally delivered carboplatin being more effective than systemic carboplatin.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/toxicidad , Neoplasias Encefálicas/tratamiento farmacológico , Carboplatino/administración & dosificación , Carboplatino/toxicidad , Glioma/tratamiento farmacológico , Neoplasias Experimentales/tratamiento farmacológico , Animales , Neoplasias Encefálicas/mortalidad , Relación Dosis-Respuesta a Droga , Sistemas de Liberación de Medicamentos , Glioma/mortalidad , Masculino , Polímeros , Ratas , Ratas Endogámicas F344RESUMEN
Infants with hemangiomas of the eyelid and orbit are at risk for amblyopia and refractive errors. Several methods of treatment for these tumors have been associated with complications and limitations. Five infants with these hemangiomas were treated by intralesional corticosteroid injection combined with short-term oral prednisolone. In an attempt to eliminate complications, corticosteroid injections were administered. In the cases of orbital hemangioma, ultrasonography guidance was used to assist the injection. This treatment is safe, simple, and effective for infants. In addition, complications are minimized.
Asunto(s)
Corticoesteroides/administración & dosificación , Neoplasias de los Párpados/tratamiento farmacológico , Hemangioma/tratamiento farmacológico , Neoplasias Orbitales/tratamiento farmacológico , Prednisolona/administración & dosificación , Administración Oral , Neoplasias de los Párpados/diagnóstico por imagen , Femenino , Hemangioma/diagnóstico por imagen , Humanos , Lactante , Inyecciones Intralesiones/métodos , Masculino , Neoplasias Orbitales/diagnóstico por imagen , Tomografía Computarizada por Rayos X , UltrasonografíaRESUMEN
Partial liver transplantation (PLTR) was studied experimentally, using 60 monkeys (20 recipients, 20 donors, 20 blood donors). The left lobe of the donors was transplanted orthotopically, using a veno-venous bypass catheter that was inserted in the portal vein and the other side passed through the hepatic portion of the inferior vena cava. The donor survival rate at 1 week was 70%. Seven recipients survived for more than 58 hours (58, 60, 64, 68, 72, 110, and 252 hours), and 13 died within 48 hours of surgery because of postoperative complications. Clinical living related liver transplantation (LRLT) was performed between June 1990 and March 1992 on six patients with biliary atresia and on one with liver cirrhosis and hepatocellular carcinoma. In all, the father's left lobe was transplanted orthotopically. Cyclosporine, azathioprine, and methyl prednisolone were administered. In addition, FK-506 was given to two patients in whom rejection was observed; one died 37 days after surgery because of acute rejection followed by systemic cytomegalovirus infection. The other six patients have survived for 8 to 29 months since transplantation. All six have been discharged from the hospital and are enjoying normal daily life. The postoperative course of all donors was uneventful. They were discharged 2 weeks after the operation and returned to their jobs in 2 months. The authors conclude that PLTR from a living donor is a promising therapeutic alternative to liver transplantation from a cadaver.
Asunto(s)
Trasplante de Hígado , Donantes de Tejidos , Adulto , Animales , Niño , Femenino , Haplorrinos , Humanos , Terapia de Inmunosupresión , Lactante , Trasplante de Hígado/métodos , Trasplante de Hígado/mortalidad , Masculino , Persona de Mediana Edad , Tasa de SupervivenciaRESUMEN
To obtain a transparent and effective solution of p-hydroxybenzoic acid esters (parabens), the use of 2-hydroxypropyl-beta-cyclodextrins (2-HP-beta-CyDs) as solubilizers with different degrees of substitution (D.S.) was surveyed. 2-HP-beta-CyDs significantly increased the aqueous solubility of four kinds of parabens (methyl < ethyl < propyl < butyl esters), where the solubilizing ability decreased with an increase in the D.S. of the 2-hydroxypropyl group in beta-CyD. The antimicrobial activity of the parabens tended to decrease by complexation with 2-HP-beta-CyDs. However, the activity could be maintained by lengthening the alkyl chain of the parabens. 1H- and 13C-nuclear magnetic resonance and circular dichroism spectroscopic studies suggest that the hydrophobic alkyl moiety of butyl paraben is preferably included in the cavity, and the phenol group extrudes from the cavity. The present results suggest that a suitable combination of 2-HP-beta-CyDs and hydrophobic, longer alkyl parabens is useful for the preservation of liquid formulations.
Asunto(s)
Antifúngicos/farmacología , Ciclodextrinas/química , Parabenos/química , beta-Ciclodextrinas , 2-Hidroxipropil-beta-Ciclodextrina , Candida albicans/efectos de los fármacos , Ciclodextrinas/farmacología , Pruebas de Sensibilidad Microbiana , Parabenos/farmacología , SolubilidadRESUMEN
Heptakis(2,6-di-O-ethyl)-beta-cyclodextrin (DE-beta-CyD) was prepared and its 1H and 13C nuclear magnetic resonance (NMR) signals in DMSO-d6 were unequivocally assigned by two-dimensional COSY and ROESY. The results on 1H coupling constants indicated that all ethylated glucose units are in a 4C1 chair conformation. The average spin-lattice relaxation times (T1) of ring carbons of DE-beta-CyD were only slightly shorter, and their standard deviations from the mean T1 value were larger, than those of beta-cyclodextrin (beta-CyD) and heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DM-beta-CyD), suggesting the presence of slightly irregular internal motion in the ethylated glucose units. The temperature dependence of chemical shift of DE-beta-CyD in DMSO-d6 suggested that the C3 hydroxyl protons may participate as proton donor in the intramolecular hydrogen bond to the C2 ethoxyl groups of neighboring glucose, and the intramolecular hydrogen bond of DE- and DM-beta-CyDs is much stronger than that of beta-CyD, suggesting the stable macrocyclic ring structure of DE-beta-CyD.