RESUMO
Application of functional imaging techniques to animal models is vital to understand pain mechanisms, but is often confounded by the need to limit movement artefacts with anaesthesia, and a focus on evoked responses rather than clinically relevant spontaneous pain and related hyperalgesia. The aim of the present study was to investigate the potential of manganese-enhanced magnetic resonance imaging (MEMRI) to measure neural responses during on-going pain that underpins hyperalgesia in pre-clinical models of nociception. As a proof of concept that MEMRI is sensitive to the neural activity of spontaneous, intermittent behaviour, we studied a separate positive control group undergoing a voluntary running wheel experiment. In the pain models, pain behaviour (weight bearing asymmetry and hindpaw withdrawal thresholds (PWTs)) was measured at baseline and following either intra-articular injection of nerve growth factor (NGF, 10µg/50µl; acute pain model, n=4 rats per group), or the chondrocyte toxin monosodium iodoacetate (MIA, 1mg/50µl; chronic model, n=8 rats per group), or control injection. Separate groups of rats underwent a voluntary wheel running protocol (n=8 rats per group). Rats were administered with paramagnetic ion Mn2+ as soluble MnCl2 over seven days (subcutaneous osmotic pump) to allow cumulative activity-dependent neural accumulation in the models of pain, or over a period of running. T1-weighted MR imaging at 7T was performed under isoflurane anaesthesia using a receive-only rat head coil in combination with a 72mm volume coil for excitation. The pain models resulted in weight bearing asymmetry (NGF: 20.0 ± 5.2%, MIA: 15 ± 3%), and a reduction in PWT in the MIA model (8.3 ± 1.5g) on the final day of assessment before undergoing MR imaging. Voxel-wise and region-based analysis of MEMRI data did not identify group differences in T1 signal. However, MnCl2 accumulation in the VTA, right Ce amygdala, and left cingulate was negatively correlated with pain responses (greater differences in weight bearing), similarly MnCl2 accumulation was reduced in the VTA in line with hyperalgesia (lower PWTs), which suggests reduced regional activation as a result of the intensity and duration of pain experienced during the 7 days of MnCl2 exposure. Motor cortex T1-weighted signal increase was associated with the distance ran in the wheel running study, while no between group difference was seen. Our data suggest that on-going pain related signal changes identified using MEMRI offers a new window to study the neural underpinnings of spontaneous pain in rats.
Assuntos
Dor Aguda/fisiopatologia , Artralgia/fisiopatologia , Comportamento Animal/fisiologia , Cérebro/fisiopatologia , Dor Crônica/fisiopatologia , Aumento da Imagem/métodos , Imageamento por Ressonância Magnética/métodos , Manganês , Dor Aguda/diagnóstico por imagem , Animais , Artralgia/diagnóstico por imagem , Cérebro/diagnóstico por imagem , Dor Crônica/diagnóstico por imagem , Modelos Animais de Doenças , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVES: To describe non-relapse-related emergency consultations of patients with multiple sclerosis (MS): causes, difficulties in the diagnosis, clinical characteristics, and treatments administered. METHODS: We performed a retrospective study of patients who attended a multiple sclerosis day hospital due to suspected relapse and received an alternative diagnosis, over a 2-year period. Demographic data, clinical characteristics, final diagnosis, and treatments administered were evaluated. Patients who were initially diagnosed with pseudo-relapse and ultimately diagnosed with true relapse were evaluated specifically. As an exploratory analysis, patients who consulted with non-inflammatory causes were compared with a randomly selected cohort of patients with true relapses who attended the centre in the same period. RESULTS: The study included 50 patients (33 were women; mean age 41.4⯱â¯11.7 years). Four patients (8%) were initially diagnosed with pseudo-relapse and later diagnosed as having a true relapse. Fever and vertigo were the main confounding factors. The non-inflammatory causes of emergency consultation were: neurological, 43.5% (20 patients); infectious, 15.2% (7); psychiatric, 10.9% (5); vertigo, 8.6% (4); trauma, 10.9% (5); and miscellaneous, 10.9% (5). CONCLUSIONS: MS-related symptoms constituted the most frequent cause of non-inflammatory emergency consultations. Close follow-up of relapse and pseudo-relapse is necessary to detect incorrect initial diagnoses, avoid unnecessary treatments, and relieve patients' symptoms.
Assuntos
Esclerose Múltipla , Encaminhamento e Consulta , Adulto , Doença Crônica , Feminino , Humanos , Esclerose Múltipla/diagnóstico , Recidiva , Estudos RetrospectivosRESUMO
Tricyclic antidepressants (TCAs) are an important analgesic treatment for neuropathic pain, though the neural substrates mediating these effects are poorly understood. We have used an integrative approach combining behavioural pharmacology with functional magnetic resonance imaging (fMRI) to investigate the effects of chronic treatment with the TCA desipramine, on touch-evoked pain (mechanical allodynia) and brain regional activity in the selective spinal nerve ligation (SNL) model of neuropathic pain. SNL and sham-operated rats received once daily i.p. administration of 10 mg/kg DMI, or saline, for 14 days. Withdrawal responses to the application of a normally non-noxious (10 g) stimulus were recorded in SNL and sham-operated rats over this period. On the final day of the study, SNL and sham-operated rats received a final challenge dose of DMI (10 mg/kg i.p.) during fMRI scanning. Chronic administration of desipramine (DMI) significantly attenuated mechancial allodynia in SNL rats. DMI challenge in chronic DMI-treated neuropathic rats produced significantly greater activation of the deep mesencephalic nucleus, primary somatosensory cortex, insular cortex, medial globus pallidus, inferior colliculus, perirhinal cortex and cerebellum compared to sham-operated rats and saline controls. By contrast, the spatial pattern of brain regional activation by chronic DMI treatment in sham controls encompassed a number of other areas including those associated with learning and memory processes. These novel findings identify key brain regions implicated in the analgesic and mood altering effects associated with chronic treatment with DMI.
Assuntos
Mapeamento Encefálico , Encéfalo/efeitos dos fármacos , Desipramina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Neuralgia/tratamento farmacológico , Neuralgia/patologia , Animais , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Modelos Animais de Doenças , Esquema de Medicação , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética , Masculino , Oxigênio/sangue , Limiar da Dor/efeitos dos fármacos , Estimulação Física/efeitos adversos , Ratos , Ratos Sprague-Dawley , Nervos Espinhais/fisiopatologiaRESUMO
INTRODUCTION: We aim to describe the use of emergency electroencephalogram (EmEEG) by the on-call neurologist when nonconvulsive status epilepticus (NCSE) is suspected, and in other indications, in a tertiary hospital. SUBJECTS AND METHODS: Observational retrospective cohort study of emergency EEG (EmEEG) recordings with 8-channel systems performed and analysed by the on-call neurologist in the emergency department and in-hospital wards between July 2013 and May 2015. Variables recorded were sex, age, symptoms, first diagnosis, previous seizure and cause, previous stroke, cancer, brain computed tomography, diagnosis after EEG, treatment, patient progress, routine control EEG (rEEG), and final diagnosis. We analysed frequency data, sensitivity, and specificity in the diagnosis of NCSE. RESULTS: The study included 135 EEG recordings performed in 129 patients; 51.4% were men and their median age was 69 years. In 112 cases (83%), doctors ruled out suspected NCSE because of altered level of consciousness in 42 (37.5%), behavioural abnormalities in 38 (33.9%), and aphasia in 32 (28.5%). The EmEEG diagnosis was NCSE in 37 patients (33%), and this was confirmed in 35 (94.6%) as the final diagnosis. In 3 other cases, NCSE was the diagnosis on discharge as confirmed by rEEG although the EmEEG missed this condition at first. EmEEG performed to rule out NCSE showed 92.1% sensitivity, 97.2% specificity, a positive predictive value of 94.6%, and a negative predictive value of 96%. CONCLUSIONS: Our experience finds that, in an appropriate clinical context, EmEEG performed by the on-call neurologist is a sensitive and specific tool for diagnosing NCSE.
Assuntos
Eletroencefalografia/métodos , Serviço Hospitalar de Emergência , Neurologistas/estatística & dados numéricos , Estado Epiléptico/diagnóstico , Idoso , Eletroencefalografia/instrumentação , Feminino , Humanos , Estudos Longitudinais , Masculino , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
RATIONALE: Functional magnetic resonance imaging (fMRI) in rats can non-invasively identify brain regions activated by physiological stimuli and the effects of pharmacological intervention on these responses. OBJECTIVES: This study was conducted to investigate the effects of systemic administration of the mu-opioid receptor agonist morphine on whole brain functional signal intensity in anaesthetised rats; to investigate whether pre-treatment with the opioid receptor antagonist naloxone blocks the effects of morphine; to determine whether pre-treatment with morphine attenuates noxious-evoked changes in whole brain functional signal intensity. METHODS: Continuous whole brain fMRI scanning was used to study brain signal intensity prior to, and following, systemic administration of morphine (5 mg/kg, n=7), systemic administration of naloxone (1 mg/kg) and morphine (n=8). Effects of pre-treatment with saline (n=5) or morphine (5 mg/kg, n=5) on formalin (5%, intraplantar)-evoked changes in signal intensity were determined. Data were processed using SMP99 with fixed-effects analysis (p<0.05). RESULTS: Morphine produced significant positive bilateral increases in signal intensity in the cingulate cortex, amygdala, thalamus, hypothalamus and PAG (p<0.05), and these effects were blocked by naloxone. Intraplantar injection of formalin produced a significant positive increase in signal intensity in the cingulate cortex, somatosensory cortex, amygdala, thalamus, hypothalamus and PAG (p<0.05). Morphine attenuated formalin-evoked increases in signal intensity in the PAG, amygdala, hypothalamus and cingulate cortex. CONCLUSION: Our data demonstrate that morphine modulates noxious-evoked changes in signal intensity in discrete brain regions. fMRI studies in rats are able to identify specific brain regions involved in the pharmacological modification of physiologically evoked changes in regional brain activation.
Assuntos
Mapeamento Encefálico , Encéfalo/irrigação sanguínea , Encéfalo/fisiologia , Imageamento por Ressonância Magnética , Dor/fisiopatologia , Receptores Opioides/fisiologia , Analgésicos Opioides/farmacologia , Análise de Variância , Animais , Encéfalo/efeitos dos fármacos , Interações Medicamentosas , Formaldeído/efeitos adversos , Processamento de Imagem Assistida por Computador/métodos , Masculino , Morfina/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Dor/induzido quimicamente , Medição da Dor/métodos , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologiaRESUMO
RATIONALE AND OBJECTIVES: Blood oxygen level dependent (BOLD) contrast pharmacological magnetic resonance imaging (phMRI) is an increasingly popular technique that allows the non-invasive investigation of spatial and temporal changes in rat brain function in response to pharmacological stimulation in vivo. Rat brain BOLD contrast phMRI is, at present, established in few neuropharmacological laboratories, and various issues associated with the technique require attention. The present review is primarily aimed at psychopharmacologists with no previous experience of phMRI, who are interested in the practical aspects that phMRI studies entail. RESULTS AND DISCUSSION: Experimental and analytical considerations, including anaesthesia, physiological monitoring, drug dose and delivery, scanning protocols, statistical approaches and the interpretation of phMRI data, are discussed.
Assuntos
Mapeamento Encefálico , Encéfalo/irrigação sanguínea , Imageamento por Ressonância Magnética/métodos , Anestesia , Animais , Encéfalo/efeitos dos fármacos , Circulação Cerebrovascular , Interpretação Estatística de Dados , Esquema de Medicação , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/instrumentação , Monitorização Fisiológica , Oxigênio/sangue , RatosRESUMO
Nitric oxide (NO) synthesized from the inducible isoform of nitric oxide synthase (NOS-2) has been suggested to play both beneficial and deleterious roles in various neuropathologies. To define the role of nitric oxide in traumatic brain injury, we subjected male mice lacking a functional NOS-2 gene (NOS-2-/-) and their wild-type littermates (NOS-2+/+) to mild or severe aseptic cryogenic cerebral injury. Expression of NOS-2 mRNA and protein was observed in NOS-2+/+ animals following injury. Lesion volume (as measured by histology and brain imaging) and neurological outcome (using motor and cognitive behavioral paradigms) were assessed at various times after injury. While magnetic resonance imaging revealed the extent of edema of the 2 genotypes to be similar, histology showed a reduced (32%) lesion volume in severely injured NOS-2-/- compared with NOS-2+/+ mice. In addition, NOS-2-/- mice showed significant improvements in both contralateral sensorimotor deficits (grid test: p = 0.011) and cognitive function (Morris water maze: p = 0.009) after severe injury compared to their wild-type littermates. This indicates that lesion volume is reduced and neurological recovery is improved after acute traumatic injury in mice lacking a functional NOS-2 gene, and strongly suggests that the post-trauma production of NO from this source contributes to neuropathology.
Assuntos
Lesões Encefálicas/enzimologia , Córtex Cerebral/enzimologia , Degeneração Neural/enzimologia , Óxido Nítrico Sintase/fisiologia , Óxido Nítrico/biossíntese , Doença Aguda , Animais , Edema Encefálico/enzimologia , Edema Encefálico/genética , Edema Encefálico/patologia , Lesões Encefálicas/genética , Lesões Encefálicas/patologia , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Transtornos Cognitivos/enzimologia , Transtornos Cognitivos/genética , Transtornos Cognitivos/patologia , Imageamento por Ressonância Magnética , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Knockout , Transtornos dos Movimentos/enzimologia , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/patologia , Degeneração Neural/genética , Degeneração Neural/patologia , Neurônios/enzimologia , Neurônios/patologia , Óxido Nítrico Sintase/biossíntese , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase Tipo II , RNA Mensageiro/metabolismo , Tempo de Reação/genética , Recuperação de Função Fisiológica/genéticaRESUMO
BOLD-contrast functional magnetic resonance imaging (fMRI) was used to investigate the effects of the synthetic cannabinoid agonist HU210 on the rat brain in order to determine potential CNS sites of action for the functional effects of cannabinoids. After obtaining basal data, rats (n=8) were given the cannabinoid agonist HU210 (10 microg/kg i.v.) and volume data sets collected for 85 mins. Significant increases in functional BOLD activity were observed in specific brain regions including those important in pain (PAG), reward (VTA and accumbens) and motor function (striatum). In order to confirm cannabinoid receptor involvement in the HU210 evoked functional BOLD activity, rats (n=8) were pre-treated with the CB1 cannabinoid receptor antagonist SR141716A (100 microg/kg i.v.) prior to HU210. Pretreatment with SR141716A abolished all significant evoked HU210 functional BOLD activity. To exclude the involvement of potential systemic effects induced by the cannabinoid agonist administration on the observed evoked functional BOLD activity a separate experiment investigated the effect of HU210 (10 microg/kg i.v.) on mean arterial pressure and showed that HU210 had no significant effect on pressure under chloral hydrate anaesthesia. In summary, this study demonstrates that the cannabinoid agonist HU210 evokes a significant increase in BOLD functional activity in specific regions and that this was cannabinoid receptor mediated. Furthermore the study indicates the potential value of fMRI in rodents to delineate pharmacologically induced changes in regional brain function.
Assuntos
Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Agonistas de Receptores de Canabinoides , Canabinoides/farmacologia , Dronabinol/análogos & derivados , Imageamento por Ressonância Magnética/métodos , Oxigênio/sangue , Animais , Encéfalo/fisiologia , Dronabinol/farmacologia , Masculino , Ratos , Receptores de Canabinoides/fisiologiaRESUMO
The metabolism of 5-fluorouracil (5FU) and its analogues 2'-deoxy-5-fluorouridine (2'FdURD), 5'-deoxy-5-fluorouridine (5'FdURD) and R,S-1-(tetrahydro-2-furyl)-5-fluorouracil (Ftorafur) has been studied by 19F NMR in rat liver and the rat S. G. Prolactinoma. In experiments using i.v. bolus injections of 0.46 mmol/kg 5FU was cleared more rapidly from the liver than 5'FdURD (t1/2 of 4.7 +/- 0.6 vs 15.8 +/- 0.8 min, P less than 0.001). Alphafluoro-beta-alanine (FBALA) production was almost identical after 5FU or 2'FdURD but slower and more sustained after 5'FdURD and still slower after Ftorafur. Both 5FU and 2'FdURD caused formation of toxic fluoronucleotides in S.G. Prolactinomas when administered i.v. (0.92 mmol/kg bolus). After i.v. infusion (0.23 mmol/kg/hr for 4 hr) 5FU produced fluoronucleotides whereas 2'FdURD did not; however, both 5FU and 2'FdURD (0.19 mmol/kg daily i.p. for 7 days) suppressed tumour growth. FBALA was observed in tumors following 5FU and 2'FdURD. Infusion of FBALA itself (0.17 mmol/kg/hr for 4 hr i.v.) led to signal in the tumour, so this compound could have been formed in the liver. These data demonstrate that 19F NMR can monitor drug metabolism in vivo.
Assuntos
Fluoruracila/farmacocinética , Fígado/efeitos dos fármacos , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Tumor Carcinoide/tratamento farmacológico , Tumor Carcinoide/metabolismo , Feminino , Floxuridina/farmacocinética , Floxuridina/uso terapêutico , Fluoruracila/análogos & derivados , Fluoruracila/uso terapêutico , Infusões Intravenosas , Fígado/metabolismo , Espectroscopia de Ressonância Magnética , Neoplasias Experimentais/tratamento farmacológico , Ratos , Ratos Endogâmicos , Tegafur/farmacocinética , beta-Alanina/análogos & derivados , beta-Alanina/análise , beta-Alanina/biossínteseRESUMO
The Early Treatment Diabetic Retinopathy Study (ETDRS), conducted at 22 clinical centers during the period 1980 to 1989, collected baseline data on C-peptide levels after ingestion of Sustacal in 582 patients with diabetes mellitus, prior to enrollment in the trial. Data on several clinical factors associated with diabetes were also collected from all 3711 enrolled patients. C-peptide data were used to develop sets of clinical criteria for the classification of ETDRS patients and to compare and contrast definitions of type of diabetes used in previous studies. The distribution of C-peptide levels was strikingly bimodal, suggesting a division of study participants into two groups--those with levels at 80 pmol/L or less and those with more than 80 pmol/L of C-peptide after Sustacal ingestion. Constellations of clinical characteristics that could serve as proxies for C-peptide level were ascertained. The result was two sets of clinically developed definitions for type of diabetes in the ETDRS. According to the more restrictive set of definitions, three groups were identified, compared to two groups using the "broad" set of definitions. Discriminant analysis was also used to classify ETDRS patients, yielding similar results. A comparison of definitions of type of diabetes used in the ETDRS and in previous studies revealed that even in the absence of C-peptide data, clinically derived definitions provided good discrimination between type I and type II diabetes.
Assuntos
Peptídeo C/sangue , Diabetes Mellitus/classificação , Retinopatia Diabética/terapia , Adulto , Aspirina/administração & dosagem , Terapia Combinada , Diabetes Mellitus/sangue , Retinopatia Diabética/sangue , Análise Discriminante , Feminino , Humanos , Fotocoagulação , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sensibilidade e EspecificidadeRESUMO
This randomized, double-blind, placebo-controlled trial of 48 hours' duration conducted in 13 primary care ambulatory practices in the United States and Mexico was used to compare the efficacy and safety of loperamide with placebo for the treatment of acute diarrhea in children aged 2 through 11 years. Two hundred fifty-eight children with acute nonspecific diarrhea were enrolled. Children were randomly assigned to treatment with loperamide HCl 0.5 mg/5 mL (n = 130) or placebo (n = 128). The first dose of loperamide consisted of either 1.0 mg (children 2 through 5 years of age) or 2.0 mg (children 6 through 11 years of age) of study medication under the observation of study personnel. This was followed by 1 mg after each unformed stool, with a total daily dose of up to 3.0 mg in the children 2-5 years of age, 4.0 mg in the children 6-8 years of age, and 6.0 mg in the children 9-11 years of age. The primary outcome measures were time to last unformed stool, time to first unformed stool, number of unformed stools during six consecutive 8-hour periods, and overall rating of efficacy/acceptability. Secondary outcomes included abdominal pain/cramping, vomiting, and fever. Children who received loperamide had significantly shorter time to last unformed stool (p = 0.0017) and fewer numbers of unformed stools (p = 0.0237) than children who received placebo. The end-of-study overall efficacy/acceptability rating of loperamide was significantly better than for placebo (p = 0.0107). All other clinically important outcome measures related to diarrhea relief favored loperamide. There was no significant difference in the incidence of drug-related adverse events between treatment groups, although total adverse events were reported more frequently (p = 0.048) by the loperamide group (15%) compared with the placebo group (7%). In conclusion, this controlled study provides data demonstrating that at recommend doses, loperamide is well tolerated and significantly shortens the duration and severity of symptoms of acute nonspecific diarrhea in children 2 through 11 years of age.
Assuntos
Diarreia Infantil/tratamento farmacológico , Loperamida/uso terapêutico , Doença Aguda , Criança , Pré-Escolar , Método Duplo-Cego , Feminino , Humanos , Lactente , Loperamida/farmacologia , Masculino , PlacebosRESUMO
The origin and course of the carotid arterial system in the superior mediastinum and neck are remarkably constant. Although variations are rare, they can have important implications in certain clinical problems. In this report, a patient underwent free jejunal graft repair of a cervical oesophageal stricture caused by radiotherapy for a post-cricoid carcinoma. The common carotid artery on the side of the surgical approach was found to cross the midline to the other side of the neck, and created difficulties both with the procedure and future management. This has not been previously reported.
Assuntos
Artéria Carótida Primitiva/anormalidades , Idoso , Estenose Esofágica/cirurgia , Esôfago/cirurgia , Feminino , Humanos , Jejuno/transplanteAssuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Ibuprofeno/uso terapêutico , Síndrome de Reye/epidemiologia , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Aspirina/efeitos adversos , Criança , Humanos , Síndrome de Reye/induzido quimicamente , Estados Unidos/epidemiologiaRESUMO
1,3-Dinitrobenzene (1,3-DNB), an intermediate used in the chemical industry, has toxic effects in the brain and testes. It produces focal lesions with marked astroglial necrosis in the rat brain upon repeated administration. Astrocytic death occurs in parallel with elevated local blood flow and is followed by damage to the cerebral vasculature and neurones. (1)H-nuclear magnetic resonance spectroscopic analysis before the onset of astrocytic damage, showed a global elevation of lactate, whereas choline containing compounds increased in the non-vulnerable cerebral cortex, yet decreased in the vulnerable brainstem. Similarly, glutamate increased in the cerebral cortex, cerebellum and midbrain, but decreased in the susceptible brainstem. In vivo T2-weighted NMR imaging showed high signal intensities in brain nuclei shown to develop astroglial loss by conventional neuropathology at 24 hours after completion of dosing, but not at 6-10 hours. Hence the early neurochemical changes in susceptible areas contribute to the aetiology of degeneration, and those seen elsewhere may represent adaptive responses dependent on the particular phenotype of different cell groups and underlying metabolic relationships.
Assuntos
Astrócitos/patologia , Química Encefálica/efeitos dos fármacos , Edema Encefálico/induzido quimicamente , Edema Encefálico/patologia , Dinitrobenzenos , Neuroglia/patologia , Síndromes Neurotóxicas/patologia , Anestesia , Anestésicos Inalatórios , Animais , Encéfalo/patologia , Isoflurano , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Ratos , Ratos Endogâmicos F344RESUMO
5-fluorouracil (5FU) is activated intracellularly to cytotoxic 5-fluoronucleotides (FNuct). These were detected non-invasively in rats bearing the Walker carcinosarcoma by 19F-magnetic resonance spectroscopy (MRS) following an i.v. bolus dose of 5FU (50 mg kg-1). Pre-treatment of the rats (3 to 24 h earlier) by methotrexate (MTX) (20 or 50 mg kg-1) did not affect the rate of 5FU disappearance but did significantly increase the rate of FNuct formation (P less than 0.002) and the final amount formed (P less than 0.02) as assessed by MRS in vivo. MTX (20 mg kg-1) caused substantially the same effects on FNuct formation (P less than 0.002 for rate and P less than 0.05 for the amount) when 5FU was administered i.p. although higher doses of 5FU (120 mg kg-1) were necessary to observe the 19F-signals. Quantitative analysis by MRS in vitro of extracts from the freeze-clamped tumours treated by 5FU i.v. confirmed that MTX pre-treatment increased FNuct formation 3-fold (P less than 0.05). Hplc quantitative analysis demonstrated that 50% of the FNuct was the cytotoxic nucleotide FUTP which was also increased 3-fold in MTX treated animals (P less than 0.05). Since the Walker tumour is probably sensitive to 5FU action via FUTP incorporation into RNA, these results suggested that drug regimes in which MTX preceded 5FU (MTX-5FU schedule) would be more cytotoxic that 5FU alone. At an MTX dose of 20 mg kg-1 24 h prior to 5FU there was significant inhibition of growth (P less than 0.05) compared to no treatment, MTX alone or the reverse schedule of 5FU-MTX. These results suggest MRS may be of clinical value in optimising chemotherapy using schedules where MTX precedes 5FU.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Carcinoma 256 de Walker/tratamento farmacológico , Fluoruracila/uso terapêutico , Metotrexato/uso terapêutico , Animais , Divisão Celular/efeitos dos fármacos , Esquema de Medicação , Feminino , Fluoruracila/metabolismo , Injeções Intraperitoneais , Injeções Intravenosas , Espectroscopia de Ressonância Magnética , Ratos , Ratos Endogâmicos , Fatores de TempoRESUMO
19F-magnetic resonance spectroscopy (MRS) can be used to non-invasively monitor metabolism of 5-fluorouracil (5FU) to cytotoxic fluoronucleotides (FNuct). We investigated whether the levels of FNuct formed from 5FU and observed in vivo by MRS in the Walker carcinosarcoma predicted cytotoxicity. Fifty mg kg-1 5FU caused tumour FNuct formation and, when repeated daily for 1 week, significant tumour growth inhibition (P less than 5%). Twenty-five mg kg-1 5FU produced less tumour FNuct (P less than 5%) and did not cause significant tumour regression. Tumour regression and tumour FNuct formation were also suppressed by 50 mg kg-1 5FU combined with a molar equivalent dose of allopurinol (P less than 2%). Tumour extracts were analysed by hplc and MRS confirming the observations in vivo and demonstrating that peak integrals in vivo were directly proportional to 5FU and FNuct concentrations. Hplc analysis of extracts showed that 50% of FNuct in tumours treated with 5FU was the cytotoxic nucleotide FUTP; this was lowered to 5% by a molar equivalent dose of allopurinol (P less than 2%). Twenty-five mg kg-1 5FU also produced significantly less FUTP (36%) than the 50 mg kg-1 dose (P less than 5%). These results suggest that MRS-detectable changes in tumour FNuct (mostly in FUTP) can be used to predict 5FU cytotoxicity.
Assuntos
Carcinoma 256 de Walker/tratamento farmacológico , Nucleotídeos de Desoxiuracil/análise , Fluordesoxiuridilato/análise , Fluoruracila/metabolismo , Animais , Carcinoma 256 de Walker/metabolismo , Feminino , Fluoruracila/uso terapêutico , Espectroscopia de Ressonância Magnética , Ratos , Ratos Endogâmicos , Uridina Trifosfato/análiseRESUMO
Day case surgery should be confined to those procedures where less than 3% of patients require admission. The aim of this study was to establish the admission rates, early readmission rates and patient acceptability of 142 consecutive cases of day case septoplasty. Data acquisition was by retrospective postal questionnaire. One hundred and fifty-three patients were studied and data was acquired on 142. Ninety per cent (128/142) of patients had operations on afternoon lists. Admissions were 7/142 (5%), the early readmission rate (within 24 h) was 0% and 25/142 (17%) of patients felt they would rather have stayed in hospital for the first night after surgery. The conclusion of this work is that day case septoplasty is an acceptable practice in appropriately selected patients who are operated upon in the morning and when the technique described here is applied. An acceptably small proportion of planned day cases may require admission.
Assuntos
Procedimentos Cirúrgicos Ambulatórios , Obstrução Nasal/cirurgia , Septo Nasal/cirurgia , Aceitação pelo Paciente de Cuidados de Saúde , Admissão do Paciente/estatística & dados numéricos , Satisfação do Paciente , Adulto , Feminino , Humanos , Masculino , Complicações Pós-Operatórias/diagnóstico , Estudos Retrospectivos , Inquéritos e Questionários , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate the efficacy and safety of ibuprofen, 200 mg and 400 mg, compared with placebo and each other for the treatment of pain of migraine headache. BACKGROUND: Migraine headache is a common illness with significant social and economic impact. DESIGN: Randomized, placebo-controlled, double-blind trial of 6 hours' treatment duration. METHODS: Fifteen investigators at 17 private practice and referral centers in the United States participated in this study of 660 outpatient adults aged 18 to 84 years with migraine headache of moderate to severe intensity. Each patient was randomly assigned to a single dose of study medication: ibuprofen 200 mg (n = 216) or 400 mg (n = 223), or placebo (n = 221). The percentage of patients with a reduction in baseline headache intensity from severe or moderate to mild or none 2 hours after treatment and the headache pain intensity difference from baseline at 2 hours were the primary efficacy measures. Secondary outcomes included other measures of pain relief, severity differences from baseline for migraine-associated symptoms of nausea, photophobia, phonophobia, and functional disability, and percentage of patients with migraine-associated symptoms reduced to none. RESULTS: Significantly (P < or = .006) more patients treated with ibuprofen, 200 mg or 400 mg, reported mild to no pain after 2 hours (41.7% and 40.8%, respectively), compared with those treated with placebo (28.1%). The mean pain intensity difference from baseline measured at 2 hours was significantly (P < or = .001) greater for patients treated with ibuprofen 200 mg or 400 mg (0.68 and 0.65, respectively), compared with those treated with placebo (0.39). Statistically significant differences in favor of both doses of ibuprofen over placebo were observed for mean pain intensity difference at 1 hour after treatment. In patients with severe baseline pain intensity, ibuprofen, 400 mg, was significantly (P < or = .048) superior to placebo for the primary efficacy end points, while ibuprofen, 200 mg, was not. Ibuprofen, 200 mg and 400 mg, were statistically significantly more effective than placebo for all clinically important secondary pain relief outcomes. Mean severity changes of migraine-associated symptoms of nausea, photophobia, phonophobia, and functional disability at 2 and 6 hours were significantly (P < or = .03) in favor of both doses of ibuprofen over placebo, and results for the percentage of patients with symptoms reduced to none consistently, although less often statistically significant, favored ibuprofen. No statistically significant differences in adverse events were found among treatment groups. CONCLUSIONS: Ibuprofen at doses of 200 mg and 400 mg is an efficacious, cost-effective, well-tolerated, single-ingredient nonprescription treatment for pain of migraine headache. In addition, while not always statistically significant, ibuprofen provided a beneficial effect on associated symptoms of migraine including nausea, photophobia, phonophobia, and functional disability.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Ibuprofeno/administração & dosagem , Transtornos de Enxaqueca/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Inflamatórios não Esteroides/uso terapêutico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Ibuprofeno/uso terapêutico , Masculino , Pessoa de Meia-IdadeRESUMO
Blood-brain barrier (BBB) integrity is lost in several neurological conditions in which astrocytes are damaged. We studied 3-chloropropanediol-induced focal lesions, a toxicant that induces early astrocytic (but not neuronal) death followed by BBB leakage. T2-weighted images illustrate regional selectivity of the lesions, affected areas including the inferior colliculi and red nuclei. Gd-DTPA intensity quantified the degree of vascular leakage in the lesioned areas. MRI intensity in lesioned areas peaked at 2 days, correlating with BBB breakdown, and diminished thereafter, returning to pre-injection levels by 30 days in parallel with the return of astrocytes. T2 measurements were unchanged at 6 h, a time when astrocyte swelling is marked but the vasculature is intact, but increased at 2 days, consistent with cellular damage and BBB leakage. Gd-DTPA enhancement was also greatest at 2 days then decreased over the next 28 days, indicating a tracer-size-dependent rate of BBB repair. A simple model based on experimentally acquired data indicated that the vascular breakdown was the result of leakage of only a small percentage of blood vessels in the affected areas. Loss of astrocytes contributes to barrier loss, and restoration of astrocytes is needed for full barrier recovery.
Assuntos
Astrócitos/patologia , Barreira Hematoencefálica/patologia , Transtornos Cerebrovasculares/patologia , Modelos Animais de Doenças , Gadolínio DTPA , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Animais , Astrócitos/efeitos dos fármacos , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/irrigação sanguínea , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Circulação Cerebrovascular/efeitos dos fármacos , Transtornos Cerebrovasculares/induzido quimicamente , Homens , Microcirculação/efeitos dos fármacos , Microcirculação/patologia , Ratos , Ratos Endogâmicos F344 , Índice de Gravidade de Doença , alfa-CloridrinaRESUMO
Those responsible for managing and overseeing multicenter clinical trials often express concern that differential rates of patients enrollment among participating clinical centers may be reflected in poorer compliance with study protocols or poorer patient care in the centers enrolling fewer patients. The purposes of the present investigation were (1) to determine whether rate of patient enrollment was related to other measures of clinical center performance in two multicenter clinical trials in ophthalmology, the Macular Photocoagulation Study (MPS) and the Early Treatment Diabetic Retinopathy Study (ETDRS), and (2) to compare findings from these two studies with findings reported from cooperative oncology groups. Percent of major data forms ever failing computerized edit was the only measure of performance examined that demonstrated a strong positive relationship to rate of patient enrollment in both studies under both analytic approaches employed (F test for linear trend in means and Spearman's rank correlation). In the MPS, but not in the ETDRS, percent of patients who had missed all visits scheduled during the past 12 months (inactive patients) also was related to rate of patient enrollment. However, the major finding from this investigation has been that it is not possible to predict overall performance of an individual clinical center based on rate of patient enrollment. Clinical centers enrolling fewer patients in these multicenter clinical trials performed in some areas as well as or better than centers enrolling larger numbers of patients.