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Background: Autotaxin-lysophosphatidic acid (ATX-LPA) signaling has a predominant role in immunological and fibrotic processes, including cancer. Several ATX inhibitors and LPA receptor antagonists have been clinically evaluated, but none in patients with solid tumors. Many cancers are burdened with a high degree of fibrosis and an immune desert phenotype (so-called 'cold' tumors). In these cold tumors, the fibrotic stroma provides an intrinsic cancer-supporting mechanism. Furthermore, the stroma prevents penetration and limits the effectiveness of existing therapies. IOA-289 is a novel ATX inhibitor with a unique chemical structure, excellent potency and an attractive safety profile. Materials and methods: In vitro and in vivo pharmacology studies have been carried out to elucidate the pharmaceutical properties and mechanism of action of IOA-289. A phase I clinical study in healthy volunteers was carried out to determine the pharmacokinetics and pharmacodynamics of IOA-289 following a single oral dose. Results: In vitro and in vivo studies showed that IOA-289 is a potent inhibitor of ATX and, as a monotherapy, is able to slow progression of lung fibrosis and tumor growth in mouse models. In a clinical study, IOA-289 showed a dose-dependent increase in plasma exposure levels and a corresponding decrease in circulating LPA. Conclusions: Our data show that IOA-289 is a novel ATX inhibitor with a unique chemical structure, excellent potency and an attractive safety profile. Our data support the further development of IOA-289 as a novel therapeutic approach for the treatment of cancer, particularly those with a high fibrotic and immunologically cold phenotype.
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The objective of the present study was to determine the anxiety and stress levels of liver transplant candidates during the preoperative period. A cross-sectional, prospective study was conducted on 52 liver transplantation candidates seen at a specialized public hospital outpatient clinic in the interior of the state of São Paulo, Brazil. Data were collected from November 2014 to April 2015 using a self-applicable questionnaire for the assessment of anxiety (State-Trait Anxiety Inventory, short version) and stress (Perceived Stress Scale), in addition to sociodemographic and clinic characterization. The mean (±SD) anxiety level detected was 23.06 ± 5.51 points, with 1.92% of the subjects showing minimum levels (0 to 12 points), 59.62% a medium level (12 to 24 points), 36.54% a moderate level (24 to 36 points), and 1.92% a severe level (36 to 48 points) of anxiety. The mean level on the stress scale was 12.10 ± 5.62 points, with 7.69% of the subjects showing high stress levels. When individuals with good and poor stress levels were compared, a significant difference was observed between them (P = .0004). The Spearman correlation test showed that the higher the stress, the higher the levels of anxiety (r = 0.4258), P < .0001. The present study contributes to the analysis of the mental health of liver transplantation candidates in view of the need for interventions for the improvement of anxiety and stress levels since the waiting period for the organ generates emotional changes that can affect the quality of life of the patient and the success of this complex therapeutic modality.
Assuntos
Ansiedade/psicologia , Cirrose Hepática/psicologia , Transplante de Fígado/psicologia , Estresse Psicológico/psicologia , Adolescente , Adulto , Idoso , Brasil , Estudos Transversais , Feminino , Hepatite Viral Humana/complicações , Humanos , Cirrose Hepática/etiologia , Cirrose Hepática/cirurgia , Cirrose Hepática Alcoólica/psicologia , Cirrose Hepática Alcoólica/cirurgia , Masculino , Saúde Mental , Pessoa de Meia-Idade , Período Pré-Operatório , Estudos Prospectivos , Qualidade de Vida , Inquéritos e Questionários , Listas de Espera , Adulto JovemRESUMO
OBJECTIVE: The goal of this study was to evaluate the sleep quality and daytime sleepiness of patients eligible for liver transplants. METHODS: A cross-sectional prospective study was conducted on liver transplant candidates from a transplant center in the interior of São Paulo State. The Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale questionnaires were applied to obtain demographic and clinical characteristics and to assess sleep quality and daytime sleepiness. RESULTS: The mean (±SD) score on the Epworth Sleepiness Scale of the 45 liver transplantation candidates was 7.00 ± 2.83 points, with 28.89% having scores >10 points, indicating excessive daytime sleepiness. The mean score on the Pittsburgh Sleep Quality Index was 6.64 ± 4.95 points, with 60% of the subjects showing impaired sleep quality, with scores >5 points. The average sleep duration was 07:16 h. Regarding sleep quality self-classification, 31.11% reported poor or very poor quality. It is noteworthy that 73.33% of patients had to go to the bathroom, 53.33% woke up in the middle of the night, and 40.00% reported pain related to sleeping difficulties. Comparison of subjects with good and poor sleep quality revealed a significant difference in time to sleep (P = .0002), sleep hours (P = .0003), and sleep quality self-classification (P = .000072). CONCLUSION: Liver transplant candidates have a compromised quality of sleep and excessive daytime sleepiness. In clinical practice, we recommend the evaluation and implementation of interventions aimed at improving the sleep and wakefulness cycle, contributing to a better quality of life.
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Hepatopatias/complicações , Transplante de Fígado , Transtornos do Sono-Vigília/etiologia , Sono , Adulto , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Qualidade de Vida , Transtornos do Sono-Vigília/epidemiologia , Inquéritos e QuestionáriosRESUMO
The neuroprotective activity of GV150526 (3-[2-(Phenylaminocarbonyl)ethenyl]-4,6-dichloroindole-2-carboxylic acid sodium salt), a selective glycine receptor antagonist of the NMDA receptor, has been evaluated by magnetic resonance imaging (MRI) in a rat model of middle cerebral artery occlusion. The aim of the work was to evaluate, using an in vivo method, whether GV150526 was able to reduce the extent of ischemic brain damage when administered both before and after (6 h) middle cerebral artery occlusion. GV150526 was administered at a dose of 3 mg/kg i.v. T2-weighted (T2W) and diffusion weighted (DW) images were acquired at 6, 24 and 144 h after the establishment of the cerebral ischemia. Substantial neuroprotection was demonstrated at all investigated time points when GV150526 was administered before the ischemic insult. The ischemic volume was reduced by 84% and 72%, compared to control values, when measured from T2W and DW images, acquired 24 h after middle cerebral artery occlusion. Administration of the same dose of GV150526, 6 h post-ischemia, also resulted in a significant (p < 0.05) neuroprotection. The ischemic volume was reduced by 48% from control values when measured from T2W images and by 45% when measured from DW images. No significant difference was found between volumes of brain ischemia obtained by either MRI or triphenyltetrazolium chloride staining. These data confirm the potential neuroprotective activity of the glycine receptor antagonist GV150526 when administered either before or up to 6 h after ischemia.
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Isquemia Encefálica/prevenção & controle , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Indóis/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Receptores de Glicina/antagonistas & inibidores , Animais , Isquemia Encefálica/patologia , Imageamento por Ressonância Magnética , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Fluticasone propionate pressurized metered dose inhalers (pMDIs) containing the hydrofluoroalkane (HFA) propellant, HFA 134a, are being developed to replace existing chlorofluorocarbon (CFC) pMDIs. This is part of the ongoing worldwide project to limit the damage to the earth's ozone layer. The in vivo performance and dose proportionality of fluticasone propionate HFA 134a pMDIs was examined for fluticasone propionate doses of 400, 1000 and 2000 microg using the 50, 125 and 250 microg strength pMDIs, respectively. The 125 and 250 microg strength HFA 134a pMDIs were compared with corresponding fluticasone propionate CFC pMDIs. Twenty-three healthy subjects participated in this single dose, randomized, five-way, cross-over study. Serial blood samples were collected 24 h post-dose to measure fluticasone propionate plasma concentrations. Twenty-four hour urinary-free cortisol was also measured before and after dosing. A dose-proportional increase in plasma fluticasone propionate concentrations was observed with increasing dose for the HFA 134a pMDIs. This was associated with a dose-related decrease in urinary cortisol excretion. Similar or lower fluticasone propionate systemic exposure was observed with the HFA 134a pMDIs compared to the corresponding CFC inhalers. The differences in systemic exposure observed for the HFA 134a and CFC pMDIs were too small to produce a differential effect on urinary cortisol excretion. Since fluticasone propionate has negligible oral bioavailability, the systemic exposure, which arises only from pulmonary absorption, is a measure of lung deposition. There was a good correlation between the in vitro fine particle mass produced by the different strengths and types of pMDI and the systemic exposure to fluticasone propionate. Therefore, the fluticasone propionate HFA 134a pMDI is an acceptable pharmaceutical alternative to the current CFC pMDI, producing similar lung deposition and no increase in systemic exposure at microgram equivalent doses.
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Propelentes de Aerossol/farmacologia , Androstadienos/administração & dosagem , Antiasmáticos/administração & dosagem , Clorofluorcarbonetos/farmacologia , Hidrocarbonetos Fluorados/farmacologia , Adulto , Androstadienos/sangue , Antiasmáticos/sangue , Estudos Cross-Over , Feminino , Fluticasona , Humanos , Hidrocortisona/urina , MasculinoRESUMO
Magnetic resonance imaging has proved to be the best technique to visualise the sella and juxtasellar area and it is used successfully to evaluate children with hypopituitarism or other endocraniological disorders in this area. The Authors present two cases of "empty sella syndrome", both characterized by growth hormone deficiency associated with precocious puberty in one case and with delayed puberty in the other one. The Authors stress the importance of magnetic resonance imaging in defining the morphological aspects of the hypothalamo-pituitary region and that empty sella can be associated either with pituitary hypofunction or hyperfunction.
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Síndrome da Sela Vazia , Hormônio do Crescimento Humano/deficiência , Puberdade Tardia/etiologia , Puberdade Precoce/etiologia , Adolescente , Criança , Gonadotropina Coriônica/uso terapêutico , Síndrome da Sela Vazia/complicações , Síndrome da Sela Vazia/diagnóstico , Feminino , Seguimentos , Hormônio Liberador de Gonadotropina/uso terapêutico , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Imageamento por Ressonância Magnética , Masculino , Polimorfismo Genético , Puberdade Tardia/tratamento farmacológico , Fatores de TempoRESUMO
The goal of this study was to assess the effects of anxiety and stress on sleep quality in liver transplantation recipients. A prospective cross-sectional study was performed including 45 recipients enrolled at a liver transplantation program at Ribeirão Preto, State of São Paulo, Brazil. Anxiety and stress were evaluated by using a reduced version of the State-Trait Anxiety Inventory and the Perceived Stress Scale, respectively. Sleep quality and excessive daytime sleepiness were evaluated by using the Brazilian Portuguese versions of the Pittsburgh Sleep Quality Index and the Epworth Sleepiness Scale. Thirty-two (71.11%) recipients presented with compromised sleep quality and 5 (11.11%) presented with excessive daytime sleepiness. Recipients with bad sleep quality had anxiety (mean, 26.91 points) and stress (mean, 17.88 points) levels that were higher than the levels of patients with normal sleep quality patterns, with anxiety levels presenting with statistically significant differences (P = .0420). Patients with above-average stress levels also had increased anxiety (mean, 28 points) and compromised sleep quality (mean, 7.03 points). In conclusion, a liver transplantation recipient who experiences bad sleep quality also has higher levels of anxiety and stress, suggesting a relationship between the sleep-wakefulness cycle and anxiety/stress. Planning strategies aimed at reducing such emotional shifts among recipients is of paramount importance. Therefore, new strategies focusing on improving the sleep pattern of patients are necessary because unhealthy sleep behavior may impair postoperative recovery.
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Ansiedade/etiologia , Distúrbios do Sono por Sonolência Excessiva/etiologia , Transplante de Fígado/psicologia , Complicações Pós-Operatórias/psicologia , Distúrbios do Início e da Manutenção do Sono/etiologia , Estresse Psicológico/etiologia , Adulto , Idoso , Ansiedade/diagnóstico , Ansiedade/psicologia , Estudos Transversais , Distúrbios do Sono por Sonolência Excessiva/diagnóstico , Distúrbios do Sono por Sonolência Excessiva/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Complicações Pós-Operatórias/diagnóstico , Estudos Prospectivos , Distúrbios do Início e da Manutenção do Sono/diagnóstico , Distúrbios do Início e da Manutenção do Sono/psicologia , Estresse Psicológico/diagnóstico , Estresse Psicológico/psicologiaRESUMO
The neuroprotective activity of the novel, selective glycine antagonist GV150526 was assessed in the middle artery occlusion (MCAo) model of focal ischemia. Postischemia administration of GV150526 (3 mg/kg i.v.) up to 6 h post-MCAo resulted in a significant reduction of the infarct volume measured histologically 24 h later. The neuronal protection by GV150526 was accompanied by functionally significant protection determined by somatosensory evoked potential (SEP) responses recorded from the primary somatosensory cortex of rats under urethane anesthesia. Experimental occlusion of the MCA 7 days prior to electrophysiological testing induced a clear reduction in the SEP amplitude. GV150526 (3mg/kg, i.v.) was able to protect SEP responses recorded from the hindpaw cortical field in two groups of animals treated either 1 (n = 9) or 6 h (n = 10) post-MCAo. SEP responses recorded from the forepaw cortical field, an area closer to the core of the ischemic damage, were significantly protected only in the group treated 1 h post-MCAo. Histological evaluation of the rat brain regions showed a correlated decrease in the ischemic area of GV150526-treated groups. The volumes of the ischemic brains of both GV150526 groups were statistically different from the MCAo group (P < 0.05). These findings demonstrate that GV150526 is able to prevent the ischemic damage assessed histologically and affect the functional correlates of the ischemia evaluated by the electrophysiological SEP measurements.
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Isquemia Encefálica/tratamento farmacológico , Infarto Cerebral/tratamento farmacológico , Potenciais Somatossensoriais Evocados/fisiologia , Glicinérgicos/farmacologia , Indóis/farmacologia , Animais , Arteriopatias Oclusivas/tratamento farmacológico , Arteriopatias Oclusivas/fisiopatologia , Isquemia Encefálica/fisiopatologia , Infarto Cerebral/fisiopatologia , Modelos Animais de Doenças , Maleato de Dizocilpina/farmacologia , Estimulação Elétrica , Antagonistas de Aminoácidos Excitatórios/farmacologia , Membro Anterior , Membro Posterior , Masculino , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Córtex Somatossensorial/irrigação sanguínea , Córtex Somatossensorial/patologia , Córtex Somatossensorial/fisiopatologiaRESUMO
AIMS: Lacidipine, a long acting 2, 4-dihydropyridine calcium channel antagonist is frequently administered with cholesterol lowering agents, particularly in elderly populations. The effects of lacidipine on the pharmacokinetics of simvastatin were investigated, since they share the CYP3A4 pathway for metabolism. METHODS: The study was an open, randomised, two-way crossover design, with at least 7 days washout. Eighteen healthy subjects received simvastatin, 40 mg once daily, alone and together with lacidipine, 4 mg once daily, for 8 days. The pharmacokinetics of simvastatin were studied on the eighth day. Analysis was made of total simvastatin acid concentrations (naive simvastatin acid plus that derived from alkaline hydrolysis of the lactone). RESULTS: Lacidipine increased the maximum concentration of simvastatin (Cmax) by approximately 70% (P=0.016) and the area under the plasma concentration-time curve AUC(0,24 h) by approximately 35% (P=0.001). The mean Cmax and AUC(0,24 h) of simvastatin (95% confidence interval) when given alone were 8.76 (6.72-11.41) ng ml(-1) and 60.36 (47.15-77.28) ng ml(-1) h. During treatment with lacidipine they were, respectively, 14.89 (10.77-20.58) ng ml(-1) and 80.96 (64.62-101.44) ng ml(-1) h. No significant differences were observed in either time to peak concentration (tmax was 1.0 h for simvastatin alone and 1.5 h for the combination) or in the half-life (t1/2,z was 8.5 h in both cases). The combination was safe and well tolerated. CONCLUSIONS: The observed increased exposure to simvastatin 40 mg following coadministration of lacidipine is unlikely to be of clinical relevance.
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Di-Hidropiridinas/farmacologia , Hipolipemiantes/sangue , Sinvastatina/sangue , Adulto , Bloqueadores dos Canais de Cálcio/efeitos adversos , Bloqueadores dos Canais de Cálcio/farmacologia , Estudos Cross-Over , Di-Hidropiridinas/efeitos adversos , Interações Medicamentosas , Feminino , Humanos , Hipolipemiantes/efeitos adversos , Masculino , Sinvastatina/efeitos adversosRESUMO
OBJECTIVE: To investigate the potential for systemic pharmacodynamic and pharmacokinetic interactions between inhaled salmeterol and fluticasone propionate when repeat doses of the two drugs are given in combination to healthy subjects. METHODS: Twenty-eight healthy subjects received salmeterol 100 microg, salmeterol 100 microg/fluticasone propionate 500 microg and fluticasone propionate 500 microg via a Diskus dry powder inhaler twice daily for 11 days according to a randomised, double-blind, placebo-controlled, crossover design. Subjects in the placebo group also received a single dose of salmeterol 100 microg on the morning of day 10. On day 10, the systemic effects of salmeterol [on pulse rate, blood pressure, corrected QT (QTc) interval and serum potassium and glucose levels] and fluticasone propionate (on 24-h urinary cortisol and morning plasma cortisol levels) were assessed. Maximal number and affinity of lymphocyte beta2-adrenoceptors and beta2-adrenoceptor polymorphism at loci 16 and 27 were also determined. Plasma pharmacokinetics of salmeterol and fluticasone propionate were determined after the morning dose on day 10. Dosing continued on the evening of day 10 and on day 11, and on day 12 the effect of repeat-dose treatment with salmeterol and salmeterol/fluticasone propionate on the systemic effects of cumulative doses of inhaled salbutamol (up to a total dosage of 3,200 microg) was evaluated. RESULTS: All treatments were safe and well tolerated. With the exception of a higher pulse rate after repeat administration of salmeterol [66.2 beats per minute (bpm) versus 63.6 bpm], there were no significant differences between the single-dose and repeat-dose salmeterol groups. The systemic pharmacodynamic effects of inhaled salmeterol were not affected by the co-administration of fluticasone propionate. Eleven days of treatment with salmeterol induced tachyphylaxis to the systemic effects of cumulative doses of salbutamol; however, co-administration of fluticasone propionate did not affect the response to salbutamol. Fluticasone propionate reduced 24-h urinary cortisol excretion (22.4 microg compared with 48.6 microg with placebo), but this was unaffected by the co-administration of salmeterol. Morning plasma cortisol levels were not reduced compared with placebo. There was no significant treatment effect on lymphocyte beta2-adrenoceptors and no correlation of beta2-adrenoceptor polymorphism at loci 16 and 27 with the development of tachyphylaxis. Salmeterol plasma concentrations were measurable only during the first half-hour after dosing. Co-administration of fluticasone propionate did not affect the peak plasma concentration (Cmax) of salmeterol. For fluticasone propionate, there were no statistically significant differences between salmeterol/fluticasone propionate and fluticasone propionate with respect to Cmax, plasma concentration at the end of the dosing interval (Ct), terminal elimination half-life (t1/2) or time to Cmax (tmax). The area under the concentration-time curve within a dosing interval (AUCt) for fluticasone propionate after inhalation of salmeterol/fluticasone propionate was statistically significantly higher (about 8%) than after inhalation of fluticasone propionate alone (P=0.0135). However, the 90% confidence intervals (CIs) for the AUCt and Cmax ratios for the two treatments were within the accepted limits for bioequivalence (1.03, 1.13 and 0.97, 1.12, respectively). CONCLUSION: These results in healthy subjects indicate that there is no systemic pharmacodynamic or pharmacokinetic interaction between inhaled salmeterol and fluticasone propionate when given in combination.
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Corticosteroides/farmacologia , Albuterol/análogos & derivados , Albuterol/farmacologia , Androstadienos/farmacologia , Broncodilatadores/farmacologia , Receptores Adrenérgicos beta/efeitos dos fármacos , Administração por Inalação , Corticosteroides/farmacocinética , Adulto , Albuterol/farmacocinética , Análise de Variância , Androstadienos/farmacocinética , Área Sob a Curva , Pressão Sanguínea/efeitos dos fármacos , Broncodilatadores/farmacocinética , Estudos Cross-Over , Método Duplo-Cego , Interações Medicamentosas , Feminino , Fluticasona , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Receptores Adrenérgicos beta/genética , Xinafoato de SalmeterolRESUMO
In the rat, normal blood flow can be restored in the territory of the occluded artery after an arterial occlusion. This event has been attributed to changes in the collateral vessels supplying the territory of the occluded artery. Since only a limited amount of data is available about the plasticity of the microvascular system after a cortical ischemic lesion, in the present study we have evaluated whether the restoration of blood flow to normal levels in the territory of the middle cerebral artery after permanent ischemia is due only to flow through preexisting collateral vessels or also to the development of new microvessels. Middle cerebral artery occlusion was performed in 45 rats. After 24 h of ischemia, magnetic resonance imaging was used to select 16 rats with cortical lesions of similar size and location. After 2 weeks, vascular corrosion casts were obtained from 8 rats by injection of low-viscosity resin and observed by scanning electron microscopy. A correlative light and electron microscopy study was performed using the remaining 8 rats. Two different patterns of vascular modifications were found, one dorsal and one ventral to the lesion. The dorsal portion of the lesion was vascularized by collateral arteries originating from the anterior or posterior cerebral arteries. Collateral trunks showed a meandering course, mainly in the occipital pole. In the ventral portion of the lesion a complex microvascular system was found characterized by an intense vascular proliferation. The arterioles showed a parallel, candelabrum-like pattern with dichotomic branching. Contraction rings were frequently seen. The capillaries showed a sinusoid-like structure, with a large lumen and a continuous endothelium with many micropinocytotic vesicles. A peripheral ring-shaped venous sinus was composed of a network of flat vessels. These results give the first comprehensive description of the microvascular modifications in a focal model of infarct and suggest that the restoration of blood flow to normal levels described in the territory of the middle cerebral artery after permanent ischemia may be due not only to flow through collateral vessels but also to the development of a new vascular system originating mainly from branches of the middle cerebral artery before the occlusion point.
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Isquemia Encefálica/patologia , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/patologia , Animais , Córtex Cerebral/ultraestrutura , Masculino , Microcirculação/patologia , Microscopia Eletrônica de Varredura , Ratos , Ratos Sprague-DawleyRESUMO
Induction of NADPH-diaphorase (NDP) following ischemic infarction was studied by means of histochemistry in the rat cerebral cortex 1,2,7, and 14 days after distal occlusion of the right middle cerebral artery (MCA). The fine structure of cells in the penumbra region of the necrotic center was also investigated. MCA distal occlusion resulted in ischemic lesion of the frontoparietal cortex of variable extent; NDP induction was detected in neurons, astrocytes, macrophages, and endothelial cells, with regional specificity and a temporal gradient. One, two, and seven days after MCA occlusion, weak NDP positivity was consistently induced in some pyramidal neurons in cortical areas neighboring the necrotic area; NDP induction was also seen in pyramidal neurons of the ipsilateral anterior cingulate and infralimbic cortices and in the tenia tecta. In addition, numerous NDP-positive pyramidal neurons were detected in the contralateral frontoparietal cortex after relatively large ischemic lesions. Two weeks after MCA occlusion, NDP induction in neurons was only evident in the deep cortical layers near the lesion. NDP histochemistry combined with glial fibrillary acidic protein immunofluorescence, performed 7 days after MCA occlusion, indicated that the astrocytes at the periphery of the necrotic area were hypertrophic and some of them were also NDP-positive. One and two days after MCA occlusion, numerous macrophages displaying NDP positivity of variable intensity were seen at the periphery of the necrotic area and in the external capsule of the ischemic cerebral hemisphere. Many endothelial cells in the cortex and subcortical white matter were consistently NDP-positive in all rats. Electron microscopic studies indicated that the area adjacent to the necrotic center was composed of fibrous astrocytes, with the morphological characteristics of proliferation, and numerous lysosome-filled macrophages. Altogether the present results suggest that focal cerebral ischemia may induce in different cell types nitric oxide synthase, which is equivalent to NDP in fixed tissue. The induction of nitric oxide synthase may be related to (1) blood-flow regulation at relatively early postischemic stages, which may decline when collateral circulation is established, and/or (2) cytotoxic or neuroprotective mechanisms.