Highly controlled living radical polymerization through dual activation of organobismuthines.
Explore the source record for details and available documents.
Journal Article↗
Biomedical subjects
Takeshi Fukuda
Publications and source records attributed to Takeshi Fukuda.
Potent and selective cathepsin K inhibitors.
A novel series of cathepsin K inhibitors derived from Novartis compound I is described. Optimization of the P1, P3, and P1' units led to the identification of 4-aminophenoxyacetic acid 24b with an IC(50) value of 4.8 nM, which possessed an excellent selectivity over other human cathepsins and good pharmacokinetic (PK) properties. Oral administration of compound 24b to ovariectomized (OVX) rats showed a trend toward an improvement of bone mineral density (BMD) in the femur bone.
Administration, Oral↗
Arylamine based cathepsin K inhibitors: investigating P3 heterocyclic substituents.
A modification of novel cathepsin K inhibitors I was carried out. The structural design was aimed at reducing the lipophilic character of compounds I for obtaining better pharmacokinetic profiles. This modification afforded several less lipophilic compounds with good inhibitory activities and pharmacokinetic profiles, although the enzyme selectivity over cathepsin S was left at issue.
Amines↗
Gefitinib prevents bleomycin-induced lung fibrosis in mice.
RATIONALE: Transforming growth factor-alpha and epidermal growth factor (EGF), the ligands for EGF receptor (EGFR), stimulate fibroblast proliferation and play an important role in the pathogenesis of pulmonary fibrosis. Therefore, inhibition of the EGFR signal by an EGFR tyrosine kinase inhibitor (EGFR-TKI) may prevent pulmonary fibrosis. However, there is a possibility that blocking the EGFR signal may inhibit epithelial cell repair, thereby exaggerating lung fibrosis. OBJECTIVE: To investigate the effect of EGFR-TK inhibition on lung fibrosis. METHODS: We looked at the effects of the EGFR-TKIs gefitinib (20, 90, 200 mg/kg) and AG1478 (12 mg/kg) on a bleomycin-induced lung fibrosis model in mice. MEASUREMENTS AND MAIN RESULTS: Gefitinib prevented lung fibrosis at all three doses. Furthermore, in those mice that did not receive bleomycin treatment, gefitinib at 200 mg/kg did not induce lung fibrosis. Immunohistochemistry revealed that phosphorylation of EGFR in lung mesenchymal cells induced by bleomycin was inhibited by gefitinib. AG1478 also attenuated the lung fibrosis. In vitro studies further demonstrated that the addition of gefitinib or AG1478 suppressed the EGFR ligand-induced proliferation of lung fibroblasts. CONCLUSIONS: These findings suggest that, in the preclinical setting, EGFR-TKIs may have a protective effect on lung fibrosis induced by bleomycin. Because these molecular targeted drugs may have differing effects depending on species and individuals, a cautious interpretation is warranted.
Animals↗
Cognitive impairment associated with intraoperative and postoperative hypoperfusion without neurologic deficits in a patient undergoing carotid endarterectomy.
BACKGROUND: Neuropsychological testing detects cognitive impairment in 20% to 30% of patients after carotid endarterectomy (CEA). CASE DESCRIPTION: A 51-year-old man with asymptomatic right cervical internal carotid artery (ICA) stenosis underwent a CEA. Intraoperative transcranial regional cerebral oxygen saturation monitoring revealed ischemia in the right cerebral hemisphere during ICA clamping and transient hyperemia subsequent to ICA declamping. The patient recovered without the appearance of new neurologic deficits. Brain single-photon emission computed tomography performed immediately after CEA showed a decrease in cerebral blood flow in the right cerebral hemisphere. Diffusion-weighted magnetic resonance imaging showed no new abnormal findings. Positron emission tomography performed 2 months after surgery revealed decreased cerebral metabolic rate of oxygen in the right cerebral hemisphere, and neuropsychological testing demonstrated a decline in performance IQ relative to preoperative levels. CONCLUSIONS: Intraoperative ischemia and postischemic delayed hypoperfusion in CEA can impair cognition even in the absence of development of postoperative neurologic deficit.
Brain↗
Stevens-Johnson syndrome associated with intravenous acetazolamide administration for evaluation of cerebrovascular reactivity. Case report.
A 62-year-old man with left middle cerebral artery stenosis manifesting as transient ischemic attack underwent evaluation of regional cerebrovascular reactivity to acetazolamide using single photon emission computed tomography. Three days after intravenous administration of acetazolamide, erythematous eruptions of various sizes appeared on his back and spread over almost his entire body. Subsequently, painful ulcerations developed on his lips, and oral and nasal mucosa, and the conjunctiva became hyperemic, indicating Stevens-Johnson syndrome. The results of the lymphocyte transformation test were positive to only acetazolamide. Stevens-Johnson syndrome, also known as erythema multiforme major, can be life-threatening, and may be induced by intravenous administration of acetazolamide.
Acetazolamide↗
Prospective survey on safety evaluation of injectable methylxanthines in Japan.
BACKGROUND: Injectable methylxanthines are useful drugs in the treatment of asthma. The Asthma Prevention and Management Guidelines (JGL) that are followed in Japan recommend the use of sustained-release theophylline to control the disease and use of injectable methylxanthines to alleviate symptoms. In contrast, the guidelines followed in the west do not promote theophylline use due to safety concerns, and the use of injectable methylxanthines in particular are not recommended. We thus conducted a study on adult patients with bronchial asthma or chronic obstructive pulmonary disease treated with theophylline and injectable methylxanthines in Japan in order to assess the safety of these drugs. METHODS: 876 patients were surveyed at 55 medical institutions by the Committee on the Safety of Sustained-Release Theophylline and Injectable Methylxanthines (CST) of the Committee for Asthma Prevention and Management Guidelines of the Japanese Society of Allergology (JSA). 682 of the patients were evaluated for safety. RESULTS: Adverse reactions including facial flushing, palpitations, headache, tinnitus, diaphoresis, nausea, vomiting and tachycardia were reported by only 2 (0.29%) of the 682 patients, but none of these were serious. CONCLUSIONS: The results confirm that injectable methylxanthines are safe, when used in accordance with the JGL.
Adolescent↗
A prospective survey on safety of sustained-release theophylline in treatment of asthma and COPD.
BACKGROUND: Theophylline is a useful drug for the treatment of asthma. The Asthma Prevention and Management Guidelines (JGL) recommend use of sustained-release theophylline products as controllers and of injectable aminophylline products as relievers. The Global Initiative for Asthma: Global Strategy for Asthma Management and Prevention, the NHLB/WHP Workshop Report 1995 (GINA, 1995) and guidelines in Western countries recommend sustained-release theophylline, but not as positively as in the JGL. The aim of this survey was to determine the occurrence of serious adverse reactions. METHODS: The survey was conducted in 66 institutions staffed by physicians certified by the Japanese Society of Allergology (JSA). The target diseases were asthma and COPD including chronic bronchitis and pulmonary emphysema, which are indications for use of sustained-release theophylline products in Japan. RESULTS: 3,921 patients were included in the safety evaluation. No serious adverse reactions were observed among the patients in this survey, although 54 patients (1.38%) exhibited non-serious adverse reactions. The incidence of adverse reactions was found to be high in patients who had begun use of sustained-release theophylline products at the time of registration in this survey, and in patients who were concomitantly taking macrolide antibiotics. CONCLUSIONS: The present survey demonstrates that sustained-release theophylline is safe, as long as used appropriately, although adverse reactions tend to develop early after initiation of administration.
Adolescent↗
4-Aminophenoxyacetic acids as a novel class of reversible cathepsin K inhibitors.
We have designed and synthesized a novel series of 3-biphenylamino acid amides as cathepsin K inhibitors based on compound I. In these inhibitors, we have discovered 4-aminophenoxyacetic acids 43 and 47 with good IC(50) values, although lipophilic groups are favorable for the hydrophobic S1' pocket.
Cathepsin K↗
Quantitative assessment of cerebral hemodynamics using perfusion-weighted MRI in patients with major cerebral artery occlusive disease: comparison with positron emission tomography.
BACKGROUND AND PURPOSE: Cerebrovascular reactivity (CVR) to acetazolamide is a key parameter in determining the severity of hemodynamic impairment in patients with major cerebral artery occlusive disease. Perfusion-weighted MRI (PW MRI) can measure the cerebral blood volume (CBV) as an indicator of hemodynamic impairment. CBV measured by PW MRI was compared with CVR measured by positron emission tomography (PET). METHODS: Twelve normal subjects and 17 patients with major cerebral artery occlusive disease underwent PW MRI and PET. The images were coregistered with 3-dimensional spoiled gradient-recalled acquisition images. Quantitative PW MRI-CBV maps were generated using the indicator dilution method with arterial input function. One large cortical region of interest for each unilateral middle cerebral artery territory was determined on each image. PET-CVR was calculated by measuring cerebral blood flow before and after acetazolamide challenge. RESULTS: A significant negative correlation was observed between PW MRI-CBV and PET-CVR (r=-0.713; P<0.0001). PW MRI-CBV higher than the mean +2 SD obtained in normal subjects (15.2 mL/100 g) was defined as elevated and PET-CVR lower than the mean -2 SD obtained in normal subjects (15.1%) was defined as reduced. Assuming the PET-CVR as the true determinant of hemodynamic impairment, PW MRI-CBV provided 80.0% sensitivity and 91.7% specificity, with 80.0% positive predictive value for detecting patients with reduced CVR. CONCLUSIONS: The PW MRI-CBV method can simply and accurately identify patients with hemodynamic impairment without exposure to ionizing radiation.
Adult↗
Transient crossed cerebellar diaschisis secondary to cerebral hyperperfusion following carotid endarterectomy.
We report a case of transient crossed cerebellar diaschisis secondary to cerebral hyperperfusion following carotid endarterectomy. The appearance of crossed cerebellar diaschisis under the presence of cerebral hyperperfusion may suggest the development of hyperperfusion syndrome.
Aged↗
FcepsilonRI-mediated amphiregulin production by human mast cells increases mucin gene expression in epithelial cells.
BACKGROUND: Topical application of a glucocorticoid is now widely recognized as the first-line therapy for bronchial asthma. However, glucocorticoid treatment is largely ineffective in relation to overproduction of sputum and lung tissue remodeling. OBJECTIVE: The purpose of the current study was to identify human mast cell (MC) products that are related to goblet cell hyperplasia. METHODS: The FcepsilonRI-mediated gene expression profile of MCs was examined by using high-density oligonucleotide probe arrays and RT-PCR. Secretion of a protein, amphiregulin, by the MCs was measured by ELISA. Upregulation of mucin genes in NCI-H292 cells by amphiregulin was evaluated by real-time RT-PCR. The expression levels of amphiregulin on histological sections obtained from 40 subjects with asthma and 6 healthy control subjects were estimated by immunohistochemical staining, and the correlation with the number of goblet cells was studied. RESULTS: Amphiregulin was secreted by human MCs after aggregation of FcepsilonRI, and its expression was not inhibited by a glucocorticoid (dexamethasone). Amphiregulin upregulated mucin gene expression in airway epithelial cells. Upregulation of amphiregulin expression was observed in MCs of patients with asthma, but not normal control subjects. Furthermore, upregulation of amphiregulin in MCs significantly correlated with the extent of goblet cell hyperplasia in the mucosa of patients with bronchial asthma. CONCLUSION: These results suggest that after exposure to antigens, human MCs may induce sputum production via release of amphiregulin. Therefore, amphiregulin may be a new target molecule for treatment of overproduction of sputum in bronchial asthma.
Amphiregulin↗
Effects of the free radical scavenger, edaravone, on the development of postoperative cognitive impairment in patients undergoing carotid endarterectomy.
BACKGROUND: Some patients undergoing carotid endarterectomy (CEA) experience postoperative cognitive impairment. The purpose of the present case cohort study with historical control was to determine whether pretreatment with a novel free radical scavenger, edaravone, could prevent development of cognitive impairment after CEA. METHODS: Fifty-five patients with ipsilateral internal carotid artery (ICA) stenosis (> or =70%) underwent CEA with administration of edaravone before ICA clamping. Neuropsychological testing was performed preoperatively and at the first postoperative month. Cerebral blood flow was also measured using single-photon emission computed tomography before and immediately after CEA and on the third postoperative day. RESULTS: Postoperative cognitive impairment was observed in only 1 (2%) patient, who exhibited postoperative cerebral hyperperfusion (cerebral blood flow increase > or =100% compared with preoperative values). Incidence of postoperative cognitive impairment in the control group (92 CEA patients without administration of edaravone) was significantly higher (12%) (P = .0298, control vs treatment group). Logistic regression analysis demonstrated that postoperative cerebral hyperperfusion and absence of pretreatment with edaravone were significant independent predictors of postoperative cognitive impairment. CONCLUSION: Pretreatment with edaravone can prevent development of cognitive impairment after CEA.
Aged↗
Self-regulated structures in nanocomposites by directed nanoparticle assembly.
Adding surface-modified silica nanoparticles (NPs) to polymer blend films, we demonstrate that directed interfacial segregation of NPs stabilize either three-dimensional (3D) interpenetrating or 2D discrete structures at high and low volume fractions of NPs, respectively. A simple interfacial energy argument provides a general guideline for predicting whether the NPs are directed to the interface between phases or into one phase. The final morphology and domain size can be predicted from the volume fraction of NPs, film thickness, and NP size.
Journal Article↗
Definition, diagnosis, disease types, and classification of asthma.
Explore the source record for details and available documents.
Adult↗
Pharmacologic control of asthma.
Explore the source record for details and available documents.
Adult↗
Neural damage caused by cerebral hyperperfusion after arterial bypass surgery in a patient with moyamoya disease: case report.
OBJECTIVE AND IMPORTANCE: The prognosis of cerebral hyperperfusion syndrome after vascular reconstructive surgery, including extracranial-intracranial arterial bypass, is not poor unless intracerebral hemorrhage develops secondary to hyperperfusion. CLINICAL PRESENTATION: A 48-year-old man with symptomatic moyamoya disease with misery perfusion in the right cerebral hemisphere underwent double right superficial temporal artery-to-middle cerebral artery bypasses. The postoperative course was uneventful until the patient developed headache and agitated delirium on the 4th postoperative day. INTERVENTION: Perfusion computed tomographic imaging demonstrated hyperperfusion in the right temporal lobe. The symptoms resolved by institution of intensive blood pressure control. Positron emission tomography performed 2 months after surgery demonstrated a postoperative reduction of the cerebral metabolic rate of oxygen in the right temporal lobe, where brain atrophy was observed on magnetic resonance images 3 months postoperatively. Neuropsychological testing performed 3 months postoperatively showed worsening digit span, which adversely affected the patient's quality of life. CONCLUSION: The current case suggests that cerebral hyperperfusion after vascular reconstructive surgery can cause irreversible neural damage, which results in cognitive impairment.
Brain Injuries↗