RESUMEN
Successful cytosolic delivery enables opportunities for improved treatment of various genetic disorders, infectious diseases and cancer. Cationic nanoemulsions were designed using alternative excipients and evaluated for particle size, charge, effect of sterilization on its stability, DNA condensation potential and cellular uptake efficiency. Various concentrations of non-ionic and ionic stabilizers were evaluated to design formula for colloidally stable cationic nanoemulsion. The nanoemulsion comprised of 5% Capmul MCM, 0.5% didodecyldimethylammonium bromide (DDAB), 1% phospholipid, 1% Poloxamer 188 and 2.25% glycerol and possessed particle size of 81.6 ± 3.56 nm and 137.1 ± 1.57 nm before and after steam sterilization, respectively. DNA condensation studies were carried out at various nanoemulsion: DNA ratios ranging from 1:1 to 10:1. Cell uptake studies were conducted on human embryonic kidney (HEK) cell lines which are widely reported for transfection studies. The nanoemulsions showed excellent cellular uptake as evaluated by fluorescence microscopy and flow cytometry. Overall, a colloidally stable cationic nanoemulsion with good DNA condensation ability was successfully fabricated for efficient cytosolic delivery and potential for in vivo effectiveness.
RESUMEN
Hepatospecific delivery by ligand based receptor targeting is an established strategy to augment therapy associated with liver diseases and disorders. Previously, we have investigated the effect of ligand headgroup on cellular uptake mediated by the asialoglycoprotein receptor by in silico and in vitro approach. In this paper, we report the design of agarose based liposomes for delivery to liver cancer cells and provide a proof of concept of the targeting efficiency against galactose liposomes using an in vivo approach. Sorafenib Tosylate loaded targeting liposomes were developed and optimized using factorial design. Comparative evaluation including cell cytotoxicity, pharmacokinetics and biodistribution and hepatospecific uptake was performed for both the liposomal systems. The formulations possessed a particle size of 150 - 180 nm and a zeta potential of 30 - 60 mV depending on the amount of ligand and drug loading, with more than 90% entrapment efficiency. A two-fold increase in cytotoxicity was observed with agarose-based liposomes as compared to galactose based liposomes. In vivo PK evaluation indicated a reduction in half life of drug when loaded in agarose ligand loaded system, probably due to greater uptake in the liver as evidenced in biodistribution study. Intrahepatic disposition revealed a higher PC/NPC uptake ratio with the targeted systems as compared to conventional liposomes, although the agarose-based system resulted in highest uptake ratio. A biocompatible platform for specific delivery of drugs to hepatocytes was established validating a rational approach to design liver targeting systems.
Asunto(s)
Galactosa , Liposomas , Sistemas de Liberación de Medicamentos , Ligandos , Liposomas/farmacocinética , Hígado/metabolismo , Monosacáridos/metabolismo , Monosacáridos/farmacología , Tamaño de la Partícula , Polisacáridos/farmacología , Sefarosa/metabolismo , Sefarosa/farmacología , Sorafenib/farmacología , Distribución TisularRESUMEN
Ligands with the polysaccharide headgroups have been recently reported by our group to possess enhanced interaction with asialoglycoprotein receptor (ASGPR) in silico as compared to ligands having galactose moieties. This enhanced interaction is a result of the polymer's backbone support in anchoring the ligand in a specific orientation within the bilayer. In this paper, we have attempted to provide an in vitro proof of concept by performing a comparative evaluation of polysaccharide and monosaccharide-based ligands. Docking was performed to understand interaction with ASGPR in silico. Agarose and galactose conjugates with behenic acid were synthesized, purified, and characterized to yield biocompatible hepatospecific ligands which were incorporated into nanoliposomes. Cellular internalization of these targeted liposomes was studied using confocal microscopy and flow cytometry. The toxicity potential was assessed in vivo. Results indicated that the polysaccharide-based ligand increased cellular uptake due to better interaction with the receptor as compared to ligand bearing a single galactose group. In addition to developing novel liver targeting ligands, the study also established proof of concept that has been suggested by earlier in silico investigations. The approach can be used to design targeting ligands and develop formulations with improved targeting efficacy.
Asunto(s)
MonosacáridosRESUMEN
AIM: Accelerated extracellular matrix breakdown caused by the increased activity of matrix metalloproteinases (MMPs) has been implicated in several rheumatological disorders and systemic vasculitides, especially Takayasu's arteritis and Kawasaki disease. Therefore, the aim of the present study was to investigate the potential role of MMPs in Henoch-Schonlein purpura (HSP), an acute type of systemic vasculitis in children. METHODS: We studied the activity of MMP-2 and MMP-9 in the sera using gelatin zymography and the transcriptional expression in peripheral blood mononuclear cells using semi-quantitative RT-PCR in 20 patients with HSP in acute and convalescent phase and in 20 healthy children, who were siblings of the subjects with same age group. RESULTS: All 20 children with HSP showed increased levels of serum activity of MMP-2 and MMP-9 in acute phase as compared with their convalescent phase [MMP-2 (p > 0.05); MMP-9 (p > 0.05)] and their control counterparts [MMP-2 (p < 0.001); MMP-9 (p < 0.001)]. Similarly, transcriptional expression of MMPs was found to be higher in the acute phase of HSP than in convalescent phase [MMP-2 (p < 0.05); MMP-9 (p < 0.001)] and in their healthy controls [MMP-2 (p < 0.001); MMP-9 (p < 0.01)]. CONCLUSION: The presence of excessive transcriptional expression and gelatinolytic activity of MMPs may be downstream to the actual aetiopathogenetic factors.
Asunto(s)
Vasculitis por IgA/enzimología , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Gelatina/metabolismo , Humanos , Vasculitis por IgA/sangre , Masculino , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Hermanos , Transcripción GenéticaRESUMEN
AIM: To investigate comparative in vitro and in vivo performance of lipid vesicular and particulate systems in escalating oral bioavailability for superior hepatoprotection. MATERIALS AND METHODS: Systems were fabricated using easy to scale up process and novel excipients to deliver Silibinin. In vitro characterization followed by pharmacokinetic and pharmacodynamic evaluation in rats was conducted to establish a correlation. RESULTS: Nanoformulations resulted in 20 fold increase in solubilisation and significant increase in permeation. 2.5 fold increase in bioavailability was evident in vivo. Vesicles demonstrated greatest hepatoprotective potential in efficacy study. CONCLUSION: The findings establish a link between in vitro and in vivo performance to rank order lipid nanoartchitects. Concurrently, a significant potential in therapeutic intervention of hepatotoxicity is envisaged as elucidated.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Excipientes/química , Lípidos/química , Hígado/enzimología , Nanotecnología/métodos , Silibina/química , Administración Oral , Animales , Disponibilidad Biológica , Tetracloruro de Carbono , Liberación de Fármacos , Estabilidad de Medicamentos , Femenino , Técnicas In Vitro , Tamaño de la Partícula , Permeabilidad , Ratas , Silibina/sangre , Silibina/farmacocinética , Silibina/farmacología , Solubilidad , Propiedades de SuperficieRESUMEN
The aim of this paper was to introduce a simple and effective method to aid in isolation and stabilization of Dupuytren cords for collagenase injection. Tongue depressors were used to isolate and stabilize the cord during the injection procedure. The area to be injected was sterilely prepared. An assistant was then directed to place a tongue depressor on both sides of the cord. A total of 35 patients with Dupuytren disease were treated. Follow-up lasted two years. Post-operative Disabilities of the Arm, Shoulder and Hand (DASH) scores was 4±2. Health-related quality of life measured with the EQ-5D index was 0.89±0.4. Recurrence rates of metacarpophalangeal joint and proximal interphalangeal joint were 11% and 14% respectively, using a flexion contracture of 20° to define recurrence. Collagenase treatment using a modified injection method with the aid of tongue depressors are a safe, effective way to treat Dupuytren contractures of the fingers. The technique can isolate the cord, which improves visualization of the cord. It may allow improved accuracy with needle placement and helps to decrease the complications and recurrence.
Asunto(s)
Clostridium histolyticum , Contractura de Dupuytren/terapia , Equipos y Suministros , Inyecciones , Colagenasa Microbiana/administración & dosificación , Adulto , Anciano , Evaluación de la Discapacidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Calidad de Vida , RecurrenciaRESUMEN
Hypertension is a disorder controlled by multiple genes and inflammation and vascular remodelling of arteries have been implicated in pathogenesis of this disease. Green tea polyphenols (GrTPs) are rich in antioxidants and are known to inhibit inflammatory responses. A significant time-dependent increase in mRNA expression of both IL-6 and MMP-9 were observed in THP-1 macrophages when cultured in normocholesterolaemic hypertensive sera (P<0.05).
Asunto(s)
Antioxidantes/farmacología , Flavonoides/farmacología , Hipertensión/sangre , Interleucina-6/genética , Macrófagos/fisiología , Metaloproteinasa 9 de la Matriz/genética , Fenoles/farmacología , Té , Células Cultivadas , Expresión Génica , Humanos , Extractos Vegetales/farmacología , Polifenoles , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
The neural basis for the transition from preclinical to symptomatic Huntington's disease (HD) is unknown. We used serial positron emission tomography (PET) imaging in preclinical HD gene carriers (p-HD) to assess the metabolic changes that occur during this period. Twelve p-HD subjects were followed longitudinally with [11C]-raclopride and [18F]-fluorodeoxyglucose PET imaging, with scans at baseline, 18 and 44 months. Progressive declines in striatal D2-receptor binding were correlated with concurrent changes in regional metabolism and in the activity of an HD-related metabolic network. We found that striatal D2 binding declined over time (P < 0.005). The activity of a reproducible HD-related metabolic covariance pattern increased between baseline and 18 months (P < 0.003) but declined at 44 months (P < 0.04). These network changes coincided with progressive declines in striatal and thalamic metabolic activity (P < 0.01). Striatal metabolism was abnormally low at all time points (P < 0.005). By contrast, thalamic metabolism was elevated at baseline (P < 0.01), but fell to subnormal levels in the p-HD subjects who developed symptoms. These findings were confirmed with an MRI-based atrophy correction for each individual PET scan. Increases in network expression and thalamic glucose metabolism may be compensatory for early neuronal losses in p-HD. Declines in these measures may herald the onset of symptoms in gene carriers.
Asunto(s)
Enfermedad de Huntington/diagnóstico por imagen , Enfermedad de Huntington/metabolismo , Tálamo/metabolismo , Adulto , Análisis de Varianza , Estudios de Casos y Controles , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Progresión de la Enfermedad , Fluorodesoxiglucosa F18/metabolismo , Giro del Cíngulo/diagnóstico por imagen , Giro del Cíngulo/metabolismo , Heterocigoto , Humanos , Enfermedad de Huntington/genética , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Corteza Motora/diagnóstico por imagen , Corteza Motora/metabolismo , Pruebas Neuropsicológicas , Lóbulo Occipital/diagnóstico por imagen , Lóbulo Occipital/metabolismo , Tomografía de Emisión de Positrones , Unión Proteica , Racloprida/metabolismo , Radiofármacos/metabolismo , Receptores de Dopamina D2/metabolismo , Tálamo/diagnóstico por imagenRESUMEN
Rapid identification of Haemophilus influenzae and other bacillary meningitides was attempted by gas-liquid chromatography (GLC) of the metabolic by-products in broth cultures and in cerebrospinal fluid (CSF) samples obtained from experimental meningitis produced in New Zealand White male rabbits. These results were correlated with the GLC of CSF of meningitis patients. A major peak with retention time of succinic acid was found in the broth cultures of all bacilli tested including H. influenzae, Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, Proteus mirabilis, Citrobacter freundii, Pseudomonas aeruginosa, and Listeria monocytogenes. Succinic acid was also found in the CSF of experimental meningitis and in the CSF of all patients with H. influenzae and Esch. coli meningitis. This peak was not detected in the blood samples of experimental animals. It was also absent in the broth cultures of all of the gram-positive and gram-negative cocci tested, such as Streptococcus pneumoniae and Neisseria meningitidis. Succinic acid, which appears to be a by product of fermentation, persisted as a clear cut marker in H. influenzae meningitis for at least 3 d after the initiation of treatment. In one patient, the succinic acid peak disappeared during treatment and reappeared with a clinical relapse. Clearly, the presence of succinic acid that can be rapidly detected by GLC in the CSF excludes pneumococcal or meningococcal meningitis and strongly suggests H. influenzae or other bacillary meningitides.
Asunto(s)
Líquido Cefalorraquídeo/microbiología , Cromatografía de Gases/métodos , Meningitis/diagnóstico , Meningitis/microbiología , Animales , Diagnóstico Diferencial , Infecciones por Escherichia coli/diagnóstico , Humanos , Infecciones por Klebsiella/diagnóstico , Klebsiella pneumoniae , Masculino , Meningitis por Haemophilus/diagnóstico , Meningitis Meningocócica/diagnóstico , Meningitis Neumocócica/diagnóstico , Infecciones por Proteus/diagnóstico , Proteus mirabilis , ConejosRESUMEN
In this study we have explored the nature and range of sleep dysfunction that occurs in untreated Parkinson's disease (PD) comparing data obtained from the use of the Parkinson's disease sleep scale (PDSS) in an untreated PD patient group compared to advanced PD and healthy controls. 25 untreated (drug-naive, DNPD) PD patients (mean age 66.9 years, range 53-80, 18 males) completed the validated Parkinson's disease sleep scale (PDSS), mean duration of PD was 2.1 years (1-10, up to 4 years in all except one patient with tremulous PD reporting tremor duration of 10 years) and mean Hoehn and Yahr score 1.9 (1-3). Data were compared to 34 advanced PD (mean age 70.2 years, range 51-88, 23 male), mean duration of PD 11 years (range 4-22), mean Hoehn and Yahr score 3.4 (3-5) and PDSS data obtained from 131 healthy controls (mean age 66.6 years, range 50-93, 56 males). Total PDSS scores and PDSS sub-items, except PDSS item 2, were highly significantly different (p<0.001) between DNPD, advanced PD and controls. Controls reported higher mean PDSS scores than both groups of patients, and advanced cases reported lower (mean+/-S.D.) PDSS scores (86.95+/-20.78) than drug-naive (105.72+/-21.5) (p<0.001). Logistic regression analysis showed that items PDSS8 (nocturia), PDSS11 (cramps), PDSS12 (dystonia), PDSS13 (tremor), and PDSS15 (daytime somnolence) were significantly impaired in DNPD compared to controls while PDSS7 (nighttime hallucinations) additionally separated advanced PD from DNPD. In a subgroup of 11 advanced PD cases (mean age 62 years, range=49-84 years, mean Hoehn and Yahr score 2.5, range=1-3) with high Epworth Sleepiness Scale (ESS) scores (mean 14.5), low item 15 PDSS score (mean 4.7) and complaints of severe daytime sleepiness, underwent detailed overnight polysomnography (PSG) studies, all showing abnormal sleep patterns. We conclude that nocturia, nighttime cramps, dystonia, tremor and daytime somnolence seem to be the important nocturnal disabilities in DNPD and some of these symptoms may be reminiscent of "off" period related symptoms even though patients are untreated. Furthermore, polysomnography in "sleepy" PD patients may help diagnose unrecognised conditions such as periodic limb movement of sleep (PLMS), obstructive sleep apnoea (OSA) and REM Sleep Behaviour Disorder.
Asunto(s)
Enfermedad de Parkinson/complicaciones , Polisomnografía/métodos , Trastornos del Sueño-Vigilia/diagnóstico , Trastornos del Sueño-Vigilia/etiología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Examen NeurológicoRESUMEN
Restless legs syndrome (RLS), also known as Ekbom syndrome, is a common movement disorder with sensorimotor symptoms occurring during sleep and quiet wakefulness. The underlying cause for RLS is unknown but genetic influences play a strong part in the pathogenesis of RLS, particularly when the condition starts at a young age. This review explores the genetic basis of RLS and related phenotypic variations. Recently, three loci showing vulnerability to RLS have been described in French-Canadian and Italian families in chromosomes 12q, 14q and 9q, emphasising on an autosomal dominant mode of inheritance. These have been labelled RLS1, RLS2 and RLS3, respectively. However, specific causative mutations remain elusive and no linkage analysis has been identified so far in the candidate genes investigated in RLS.
Asunto(s)
Síndrome de las Piernas Inquietas/genética , Mapeo Cromosómico , Predicción , Ligamiento Genético , Humanos , Linaje , Ataxias Espinocerebelosas/genéticaRESUMEN
The effects of high inspired concentrations of xenon and krypton on regional CBF (rCBF) were assessed in the rat using [14C]iodoantipyrine and quantitative autoradiography. Inhalation of 80% xenon for 1 or 2 min and inhalation of 40% xenon for 2 min were found to have significant effects on rCBF, including average increases of 75-96% in cerebral neocortical regions. Inhalation of 40% xenon for 1 min and of 80% krypton for 2 min had no significant effect on rCBF in most brain regions studied. If xenon inhalation produces effects on rCBF in humans similar to those observed in the rat, such effects could be an important source of error in xenon computed tomography rCBF studies.
Asunto(s)
Circulación Cerebrovascular/efectos de los fármacos , Criptón/farmacología , Xenón/farmacología , Animales , Autorradiografía , Masculino , Ratas , Ratas EndogámicasRESUMEN
Although we and others have employed a thresholding strategy to extract "peak" values from positron emission tomographic (PET) regions of interest (ROIs), the effects of peak picking on fitted fluorodeoxyglucose rate constants, regional metabolic rate for glucose (rCMRglc) profiles, patterns of regional metabolic covariation, and PET-neurobehavioral correlations have not been systematically investigated. Our results suggest that under some commonly encountered imaging conditions percent thresholding may increase sensitivity to regional activation; however, the effect of thresholding is determined by a number of factors, including the relative magnitude of regional activation, ROI size, and the specific threshold selected. The difference-annulus concept is proposed as a means to study the effects of different region drawing and thresholding strategies, and to determine if a given ROI contains one and only one source of covarying metabolic activity.
Asunto(s)
Encéfalo/diagnóstico por imagen , Desoxiglucosa/análogos & derivados , Tomografía Computarizada de Emisión/métodos , Complejo SIDA Demencia/metabolismo , Encéfalo/metabolismo , Radioisótopos de Flúor , Fluorodesoxiglucosa F18 , Glucosa/metabolismo , Humanos , CinéticaRESUMEN
L-[18F]6-Fluoro-DOPA (L-[18F]6-fluoro-3,4-dihydroxyphenylalanine; FDOPA) has been used with quantitative positron emission tomography (PET) to assess presynaptic nigrostriatal dopaminergic function in life. The relationship of estimated kinetic rate constants for striatal FDOPA uptake [Ki(FDOPA)] to the normal aging process has been the subject of conflicting reports. Resolution of this issue has been hampered by methodological differences in previous FDOPA/PET investigations. We studied 19 healthy normal subjects (aged 27-77 years) and measured striatal Ki-(FDOPA) according to each of the earlier methods. While significant correlations (p < 0.005) existed between Ki(FDOPA) values estimated by the various techniques, none correlated with normal aging. We conclude that normal striatal Ki(FDOPA) values estimated using quantitative FDOPA/PET are uncorrelated with the aging process.
Asunto(s)
Envejecimiento/metabolismo , Cuerpo Estriado/metabolismo , Dihidroxifenilalanina/análogos & derivados , Adulto , Anciano , Cuerpo Estriado/diagnóstico por imagen , Dihidroxifenilalanina/sangre , Dihidroxifenilalanina/farmacocinética , Dihidroxifenilalanina/farmacología , Femenino , Radioisótopos de Flúor , Humanos , Masculino , Persona de Mediana Edad , Valores de Referencia , Tomografía Computarizada de EmisiónRESUMEN
We used [18F]fluorodeoxyglucose/positron emission tomography (18F-FDG/PET) and a statistical model of regional covariation to study brain topographic organization in parkinsonism. We studied 22 patients with Parkinson's disease (PD), 20 age-matched normal volunteers, and 10 age- and severity-matched patients with presumed striatonigral degeneration (SND). We used FDG/PET to calculate global, regional, and normalized metabolic rates for glucose (GMR, rCMRglc, rCMRglc/GMR). Metabolic parameters in the three groups were compared using an analysis of variance, with a correction for multiple comparisons, and discriminant analysis. The scaled subprofile model (SSM) was applied to the combined rCMRglc dataset to identify topographic covariance profiles that distinguish PD patients from SND patients and normals. GMR, rCMRglc, and rCMRglc/GMR were normal in PD; caudate and lentiform rCMRglc/GMR was reduced in the SND group (p < 0.01). SSM analysis of the combined group of patients and normals revealed a significant topographic profile characterized by increased metabolic activity in the lentiform nucleus and thalamus associated with decreased activity in the lateral frontal, paracentral, inferior parietal, and parietooccipital areas. Individual subject scores for this profile were significantly elevated in PD patients compared with normals and SND patients (p < 0.001) and discriminated the three groups. In the PD group, subject scores for this factor correlated with individual subject Hoehn and Yahr (H & Y) scores (p < 0.02), and with quantitative rigidity (p < 0.01) and bradykinesia (p < 0.03) ratings, but not with tremor ratings. SSM analysis of right-left metabolic asymmetries yielded a topographic contrast profile that accurately discriminated mildly affected PD patients (H & Y Stage I) from normals. Our findings demonstrate that abnormal topographic covariance profiles exist in parkinsonism. These profiles have potential clinical application as neuroimaging markers in parkinsonism.
Asunto(s)
Encéfalo/fisiopatología , Enfermedad de Parkinson/diagnóstico por imagen , Adulto , Anciano , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Encefalopatías/fisiopatología , Mapeo Encefálico , Cuerpo Estriado/fisiopatología , Femenino , Glucosa/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/fisiopatología , Sustancia Negra/fisiopatología , Tomografía Computarizada de EmisiónRESUMEN
This article addresses the question posed in the title by examining the effects of parameters traditionally associated with improved absolute quantitation, on the analysis of 12 acquired immune deficiency syndrome dementia complex (ADC) patients compared to a normal control group. Results are discussed within the framework of the subprofile scaling model (SSM) for analyzing patterns of regional covariation. It is demonstrated that the ability to extract measures of group discrimination and disease progression are unaffected by (1) limited improvements in image resolution, (2) the use of transmission scan smoothing, (3) the application of a scatter deconvolution correction, and (4) converting region-of-interest measurements of counts per voxel to measurements of regional CMRglc. This "robustness" of the SSM approach is partly due to the extraction of disease-related subject weights, independent of any subject's global scaling effects. It is argued that other analysis techniques that initially reduce intersubject variation (e.g., using regional ratios or normalizing by global metabolic rates before applying traditional multivariate procedures) lack analytic features that may be important to identify multidimensional, disease-related image patterns. Based on the ADC patient data, it is concluded that measures of group discrimination and disease progression will not necessarily benefit from the organization of parameters traditionally associated with improved absolute quantitation.
Asunto(s)
Complejo SIDA Demencia/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Tomografía Computarizada de Emisión , Complejo SIDA Demencia/fisiopatología , Adulto , Encéfalo/fisiopatología , Desoxiglucosa/análogos & derivados , Fluorodesoxiglucosa F18 , Glucosa/metabolismo , Humanos , CinéticaRESUMEN
Flurodopa (FDOPA) is an analogue of L-di-hydroxyphenylalanine (L-dopa) used to assess the nigrostriatal dopamine system in vivo with positron emission tomography (PET). However, FDOPA/PET quantitation is complicated by the presence of the 3-O-methyl-FDOPA (3OMFD) fraction in brain and plasma. Pretreatment with entacapone (OR-611), a peripheral catechol O-methyl-transferase (COMT) inhibitor, greatly reduces the plasma 3OMFD fraction and provides an ideal situation to evaluate the contribution of the plasma 3OMFD fraction in several kinetic models of FDOPA uptake. We performed FDOPA/PET with and without the OR-611 preadministration in six Parkinson's disease (PD) patients. We measured the time-course of the plasma FDOPA and 3OMFD fractions using high-pressure liquid chromatography (HPLC). We calculated striato-occipital ratios (SOR), and estimated the striatal FDOPA uptake rate constant graphically using the plasma FDOPA and occipital tissue time activity curves (KiFD and KiOCC, respectively). We also estimated striatal dopa decarboxylase (DDC) activity (k3D) using a model incorporating independent measurements of 3OMFD transport kinetic rate constants. With the preadministration of OR-611, the pharmacological efficiency in plasma was prolonged significantly (21.1-37.7%; p < 0.01). We also observed significant mean elevations in SOR and KiOCC by 21.8 and 53.5%, respectively (p < 0.05). KiFD and k3D did not show significant change. We conclude that OR-611 prolongs the circulation time of FDOPA in the plasma but does not alter rate constants for striatal FDOPA uptake or decarboxylation.
Asunto(s)
Inhibidores de Catecol O-Metiltransferasa , Dihidroxifenilalanina/análogos & derivados , Enfermedad de Parkinson/sangre , Tomografía Computarizada de Emisión/métodos , Tirosina/análogos & derivados , Adulto , Anciano , Catecoles/farmacología , Cromatografía Líquida de Alta Presión , Cuerpo Estriado/metabolismo , Dihidroxifenilalanina/sangre , Inhibidores Enzimáticos/farmacología , Femenino , Radioisótopos de Flúor , Humanos , Cinética , Masculino , Persona de Mediana Edad , Nitrilos , Lóbulo Occipital/metabolismo , Control de Calidad , Sensibilidad y Especificidad , Tomografía Computarizada de Emisión/estadística & datos numéricos , Tirosina/sangreRESUMEN
Normal aging is associated with the degeneration of specific neural systems. We used [18F] fluorodeoxyglucose (FDG)/positron emission tomography (PET) and a statistical model of regional covariation to explore the metabolic topography of this process. We calculated global and regional metabolic rates for glucose (GMR and rCMRglc) in two groups of normal subjects studied independently on different tomographs: Group 1--130 normal subjects (62 men and 68 women; range 21-90 years); Group 2--20 normal subjects (10 men and 10 women; range 24-78 years). In each of the two groups, the Scaled Subprofile Model (SSM) was applied to rCMRglc data to identify specific age-related profiles. The validity of these profiles as aging markers was assessed by correlating the associated subject scores with chronological age in both normal populations. SSM analysis disclosed two significant topographic profiles associated with aging. The first topographic profile, extracted in an analysis of group 1 normals, was characterized by relative frontal hypometabolism associated with covariate metabolic increases in the parietooccipital association areas, basal ganglia, mid-brain, and cerebellum. Subject scores for this profile correlated significantly with age in both normal groups (R2 = 0.48 and 0.33, p < 0.0001 for groups 1 and 2, respectively). Because of clinical similarities between normal motoric aging and parkinsonism, we explored the possibility of shared elements in the metabolic topography of both processes. We performed a combined group SSM analysis of the 20 group 2 normals and 22 age-matched Parkinson's disease patients, and identified another aging-related topographic profile. This profile was characterized by relative basal ganglia hypermetabolism associated with covariate decreases in frontal premotor cortex. Subject scores for this profile also correlated significantly with age in both normal groups (group 1: R2 = 0.30, p < 0.00001; group 2: R2 = 0.59, p < 0.01). Healthy aging is associated with reproducible topographic covariation profiles associated with specific neural systems. FDG/PET may provide a useful metabolic marker of the normal aging process.
Asunto(s)
Envejecimiento/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Tomografía Computarizada de Emisión , Adulto , Anciano , Anciano de 80 o más Años , Mapeo Encefálico , Desoxiglucosa/análogos & derivados , Desoxiglucosa/metabolismo , Femenino , Radioisótopos de Flúor , Fluorodesoxiglucosa F18 , Humanos , Masculino , Persona de Mediana Edad , Modelos Neurológicos , Enfermedad de Parkinson/metabolismo , Valores de Referencia , Análisis de Regresión , Tomografía Computarizada de Emisión/métodosRESUMEN
OBJECTIVE: This study investigated prefrontal cortex function in the manic state of bipolar disorder. METHOD: High-sensitivity [15O]H2O positron emission tomography and a word generation activation paradigm were used to study regional cerebral blood flow in five manic and six euthymic individuals with bipolar disorder and in five healthy individuals. RESULTS: Decreased right rostral and orbital prefrontal cortex activation during word generation and decreased orbitofrontal activity during rest were associated with mania. CONCLUSIONS: The data support the presence of rostral and orbital prefrontal dysfunction in primary mania. These findings, when seen in the context of the human brain lesion and the behavioral neuroanatomic literatures, may help to explain some of the neurobehavioral abnormalities characteristic of the manic state.
Asunto(s)
Trastorno Bipolar/fisiopatología , Pruebas Neuropsicológicas , Corteza Prefrontal/fisiopatología , Tomografía Computarizada de Emisión , Adulto , Trastorno Bipolar/diagnóstico por imagen , Femenino , Humanos , Masculino , Radioisótopos de Oxígeno , Corteza Prefrontal/irrigación sanguínea , Corteza Prefrontal/diagnóstico por imagen , Flujo Sanguíneo Regional , AguaRESUMEN
We used 18F-fluorodeoxyglucose and PET to study a 23-year-old woman with alternating hemichorea and primary antiphospholipid syndrome. There were three PET studies: (1) during an episode of right hemichorea, (2) during an asymptomatic period 6 months later, and (3) during an episode of left hemichorea occurring 2 months after that. In each study, we calculated normalized regional glucose metabolism for the caudate and lentiform nuclei and compared these values with those calculated in 12 normal volunteer subjects (mean age, 35.3 +/- 9.0). The following results were obtained: (1) during right hemichorea, left lentiform metabolism was increased by 19% (> 3 SD); (2) during the asymptomatic period, right caudate metabolism was increased by 20% (> 3 SD), and right lentiform and left striatal metabolism were normal; and (3) during left hemichorea, right caudate and lentiform metabolism were both elevated by 33% (> 3 SD). During this episode, left caudate metabolism was elevated by 20% (> 2 SD); left lentiform metabolism was normal. These results suggest that hemichorea in primary antiphospholipid syndrome may be associated with contralateral striatal hypermetabolism that may also be present during asymptomatic periods.