Kentaro Tokuoka

Induction of Heme Oxygenase Protein Protects Neurons in Cortex and Striatum, But Not in Hippocampus, against Transient Forebrain Ischemia

To clarify whether heme oxygenase-1 (HO-1) protein plays a protective role against cerebral ischemia, we investigated the effects of an HO inhibitor (tin mesoporphyrin IX [SnMP] three doses of 30 μmol/kg, intraperitoneally) and an HO inducer (hemin, three doses of 30 μmol/kg, intraperitoneally) on the pathologic outcome and on the immunohistochemical reaction for HO-1 after 20-minute transient forebrain ischemia followed by 3-day reperfusion in rats. Hemin significantly increased viable neurons in the cortex (compared to the SnMP-treated group, P<.05) and striatum (compared to the saline-treated group at P<.01 and SnMP-treated group at P<.05), and intense HO-1 immunoreactivity was observed in cortex and striatum, whereas the administration of SnMP tended to decrease viable neurons in the parietal cortex. In contrast, neither hemin nor SnMP affected the pathologic outcome in the CA1 and CA3 hippocampi, in which HO-1 immunoreactivity was weak. These results suggest that induction of HO-1 protein may contribute to cellular defense against ischemic damage in brain regions where potential ability to synthesize HO-1 is retained in ischemia.

Influence of non-steroidal anti-inflammatory drugs on antiplatelet effect of aspirin

What is known and Objective:  It has been reported that ibuprofen interferes with the antiplatelet effect of low‐dose aspirin. This interaction is ascribed to steric hindrance at the active site of cyclooxygenase‐1 by ibuprofen, when aspirin is administered after ibuprofen. However, whether other non‐steroidal anti‐inflammatory drugs (NSAIDs) interact with aspirin similarly is not well defined. The aim of this study was to assess the influence of nine NSAIDs on the antiplatelet effect of aspirin.

Relationship between atherosclerotic risk factors and aortic plaques in patients with first-ever ischaemic stroke.

OBJECTIVE Aortic plaque is considered a risk factor of ischaemic stroke, and both ulceration and plaque thickness are considered important. However, the relative importance of aortic plaque and carotid plaque remains unclear. The purpose of this study is to clarify the relation between aortic and carotid plaque lesions and atherosclerotic risk factors in patients with acute ischaemic stroke. METHODS We enrolled 76 patients with first-ever ischaemic stroke, undergoing transoesophageal echocardiography, whose aetiology of ischaemic stroke was unknown. We divided the patients into two groups according to aortic plaque thickness, based on previous reports, i.e., a high-risk group (over 4mm) and a low-risk group (less than 4mm). We also examined several atherosclerotic risk factors. RESULTS Mean age, gender and hypertension was not significantly different between the low-risk and high-risk group. HDL-cholesterol (P<0.01), LDL/HDL ratio (P<0.05), non-HDL-cholesterol (P<0.05), HbA1c (P<0.05) and eGFR (P<0.01) were significantly different between the two groups. Max plaque thickness in the carotid artery was correlated with aortic plaque lesions. CONCLUSION Multiple atherosclerotic risk factors are associated with greater aortic plaque lesions. Aortic plaque is important not only as an embolic source, but also as one of the atherosclerotic markers.

Prediction of Antiplatelet Effects of Aspirin In Vivo Based on In Vitro Results

The aim of this study was to establish a method to predict the antiplatelet effects of aspirin in vivo based on in vitro results. Aspirin in 5 different concentrations was added to the platelet-rich plasma samples, and the rates of platelet aggregation induced by collagen were determined in vitro. In addition, platelet aggregation and plasma drug concentration values were determined in vivo before and after the administration of aspirin (162 mg). The 50% effective concentration (EC50) values obtained from the in vivo and in vitro experiments were shown to have relevance, because the EC50 ratio for each subject was the same (0.23 ± 0.03). The actual and predicted values for the rate of inhibition of platelet aggregation were well correlated (P < .0001, r = .95) when the predicted rate was determined using the present method. Our results suggest that the antiplatelet effects of aspirin can be predicted using blood samples obtained before its administration.

Theory-based analysis of clinical efficacy of triptans using receptor occupancy

BackgroundTriptans, serotonin 5-HT1B/1D receptor agonists, exert their action by targeting serotonin 5-HT1B/1D receptors, are used for treatment of migraine attack. Presently, 5 different triptans, namely sumatriptan, zolmitriptan, eletriptan, rizatriptan, and naratriptan, are marketed in Japan. In the present study, we retrospectively analyzed the relationships of clinical efficacy (headache relief) in Japanese and 5-HT1B/1D receptor occupancy (Φ1B and Φ1D). Receptor occupancies were calculated from both the pharmacokinetic and pharmacodynamic data of triptans.MethodsTo evaluate the total amount of exposure to drug, we calculated the area under the plasma concentration-time curve (AUCcp) and the areas under the time curves for Ф1B and Ф1D (AUCФ1B and AUCФ1D). Moreover, parameters expressing drug transfer and binding rates (Acp, AФ1B, AФ1D) were calculated.ResultsOur calculations showed that Фmax1B and Фmax1D were relatively high at 32.0-89.4% and 68.4-96.2%, respectively, suggesting that it is likely that a high occupancy is necessary to attain the clinical effect. In addition, the relationships between therapeutic effect and AUCcp, AUCΦ1B, AUCΦ1D, and Acp · AUCcp differed with each drug and administered form, whereas a significant relationship was found between the therapeutic effect and AΦ1B · AUCΦ1B or AΦ1D · AUCΦ1D that was not affected by the drug and the form of administration.ConclusionsThese results suggest that receptor occupancy can be used as a parameter for a common index to evaluate the therapeutic effect. We considered that the present findings provide useful information to support the proper use of triptans.

Case of neuromyelitis optica spectrum disorder with atopic factors

Neuromyelitis optica (NMO) is an inflammatory disease in which the primary lesions occur in the optic nerves and spinal cord. The presence of anti-aquaporin-4 antibody (anti-AQP-4 Ab) can differentiate NMO and multiple sclerosis (MS). Recently, NMO spectrum disorder (NMOSD), which does not meet the diagnostic criteria of NMO, was proposed as a new concept. We experienced a case of NMOSD with the elevation of immunoglobulin E (IgE) levels in the serum and cerebrospinal fluid (CSF), and discussed the involvement of atopic factors for pathology. A 69-year-old Japanese man, who had a history of hypertension and palmoplantar pustulosis, presented at a nearby hospital complaining of fever and respiratory symptoms in July 2009. He had no allergic and breeding history. He was diagnosed with myco-