Cyclodextrin-Based [c2]Daisy Chain Rotaxane Insulating Two Diarylacetylene Cores.

A [c2]daisy chain rotaxane with two diarylacetylene cores was efficiently synthesized in 53 % yield by capping a C2 -symmetric pseudo[2]rotaxane composed of two diarylacetylene-substituted permethylated α-cyclodextrins (PM α-CDs) with aniline stoppers. The maximum absorption wavelength of the [c2]daisy chain rotaxane remained almost unchanged in various solvents, unlike that of the stoppered monomer, indicating that the two independent diarylacetylene cores were insulated from the external environment by the PM α-CDs. Furthermore, the [c2]daisy chain rotaxane exhibited fluorescence emission derived from both diarylacetylene monomers and the excimer, which implies that the [c2]daisy chain structure can undergo contraction and extension. This is the first demonstration of a system in which excimer formation between two π-conjugated molecules within an isolated space can be controlled by the unique motion of a [c2]daisy chain rotaxane.

Effects of Candesartan Cilexetil Compared with Amlodipine on Serum Asymmetric Dimethylarginine Levels in the Chronic Stage of Cerebral Infarction: A Preliminary Study.

OBJECTIVE: Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor and a marker of vascular endothelial damage. Angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker (ARB) are reported to reduce the serum ADMA level. Our group administered either ARB or calcium antagonist to patients after cerebral infarction and discussed the ADMA changes observed. METHODS: Hypertensives in the chronic stage of cerebral infarction were enrolled. These subjects included patients of atherothrombotic cerebral infarction or lacunar infarction. The patients received candesartan cilexetil (candesartan group) or amlodipine (amlodipine group). The blood pressure and serum ADMA concentration were measured and compared before the treatment commenced and at 1-3 months after the treatment commenced. RESULTS: Seven subjects received candesartan and six received amlodipine. There was no difference between the groups in the change of blood pressure before and after the drug treatment. The ADMA level (nmol/mL) fell significantly from 0.57±0.10 (before administration) to 0.52±0.09 (after administration) in the candesartan group (P<0.05). The ADMA level did not change between before and after administration in the amlodipine group. CONCLUSION: Treatment with candesartan cilexetil reduced the level of ADMA in hypertensive patients in the chronic stage of cerebral infarction. Candesartan cilexetil may be useful in hypertensive patients at the chronic stage of cerebral infarction with expected anti-atherosclerotic effect.

A preliminary study of fluvoxamine maleate on depressive state and serum melatonin levels in patients after cerebral infarction.

OBJECTIVE: Antidepressants have been recommended for the treatment of post-stroke depression (PSD). The purpose of this study was to evaluate the effect of fluvoxamine maleate, a selective serotonin re-uptake inhibitor (SSRI), on depressive state, sleep disturbance, and serum melatonin levels in patients with depressive state after cerebral infarction. METHODS: Nineteen patients who were hospitalized for cerebral infarction and scored 40 points or higher on the Self Depression Scale (SDS) were enrolled in this study. Nine of the 19 patients received fluvoxamine as a treatment group and the other 10 patients were used as untreated controls. Before and after commencing the drug therapy, the patients were assessed by the SDS, Pittsburgh Sleep Quality Index (PSQI), Japan Stroke Scale for Depression (JSSD), and Japan Stroke Scale for Emotional Disturbance (JSSE), and their serum melatonin levels were measured. The control group underwent the same evaluations as the treatment group. RESULTS: The SDS score improved in the treatment group at 1 week after the start of drug treatment, and in the control group at 1 and 2 weeks into the observation period. In the treatment group, the JSSD and PSQI scores improved and serum melatonin levels increased. CONCLUSION: The administration of fluvoxamine to patients with depressive state after cerebral infarction alleviated both the depressive state and sleep disturbances. Increased melatonin levels by the administration of fluvoxamine may contribute to improvement in sleep disturbance, one of the major symptoms of depression.

Effects of eicosapentaenoic acid on asymmetric dimethylarginine in patients in the chronic phase of cerebral infarction: a preliminary study.

BACKGROUND: Eicosapentaenoic acid (EPA) possesses a variety of pharmacologic actions and demonstrates protective efficacy against stroke. Meanwhile, asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase inhibitor and is thereby considered one of the risk factors of cardiovascular disease. The effects of the EPA treatment on ADMA in patients in the chronic phase of cerebral infarction accompanied by dyslipidemia were investigated. METHODS: Study subjects were individuals with either atherothrombotic or lacunar cerebral infarction in the chronic phase accompanied by dyslipidemia, of which the onset was at least 4 weeks earlier. Lipid, fatty acid, and ADMA levels in the blood were measured at EPA 1800 mg per day and compared both before and after treatment. Twenty subjects were included in the study (average age, 71.9 ± 8.9 years). RESULTS: Of these 20 cases, eight were atherothrombotic and 12 were lacunar. Moreover, 17 cases were accompanied by hypertension and 10 cases were accompanied by diabetes mellitus. After EPA treatment (average duration of treatment, 143 ± 42 days), EPA increased from 65.1 ± 38.1 µg/mL to 201.1 ± 73.4 µg/mL (P < .01). Arachidonic acid (AA) decreased from 149.1 ± 34.8 µg/mL to 129.7 ± 22.3 µg/mL (P < .01), and the EPA/AA ratio increased from 0.45 ± 0.26 to 1.55 ± 0.46 (P < .01). ADMA decreased from 0.49 ± 0.07 nmol/mL before treatment to 0.46 ± 0.05 nmol/mL after treatment (P < .01). CONCLUSIONS: EPA treatment in patients in the chronic phase of cerebral infarction leads to a decrease in ADMA in the blood, suggesting that EPA improves vascular endothelial function and therefore supports the protective efficacy against cerebral infarction.

Carotid hemodynamic parameters are useful for discriminating between atherothrombotic infarction and lacunar infarction.

Using ultrasound, we investigated whether carotid parameters differed among subtypes of ischemic stroke and evaluated the usefulness of these parameters in discriminating among subtypes. Patients with ischemic stroke admitted to Nippon Medical School Hospital were consecutively recruited and grouped into 3 subtypes based on the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification: cardioembolism (group CE), large-artery atherosclerosis (group LAA), and small-vessel occlusion (group SVO). All subjects underwent carotid ultrasonography to determine maximum intima-media thickness (IMT), maximum systolic velocity (Vmax), minimum diastolic velocity (Vmin), mean velocity, and pulsatility index (PI). Carotid parameters that differed among subtypes were statistically identified. A total of 138 patients were enrolled. Intergroup comparisons revealed that the Vmin of the affected side was significantly lower in group LAA than in group SVO (mean±SD, 0.12±0.05 m/s vs 0.15±0.05 m/s; P=.02) and the Vmin of the mean of both sides was lower in group LAA than in group SVO (0.12±0.04 vs 0.16±0.05; P=.03). Multivariate analysis showed that the PI of the affected side was a useful adjunct to discriminate between groups SVO and LAA (odds ratio=2.94; P=.03, group SVO as control). Receiver operating characteristic curve analysis found that the Vmin of the affected side was the most useful parameter for discriminating between group SVO and group LAA. The PI and the Vmin of the affected side were found to differ among stroke subtypes, and thus these may be useful parameters for discriminating among ischemic stroke subtypes.

Correlation between insulin resistance and white matter lesions among non-diabetic patients with ischemic stroke.

OBJECTIVE: We investigated whether a correlation exists between insulin resistance and the severity of cerebral white matter lesions among non-diabetic patients with ischemic stroke. METHODS: The subjects were 105 consecutive patients without diabetes who were hospitalized due to non-cardioembolic stroke. The insulin resistance was evaluated by a homeostasis model assessment of insulin resistance (HOMA-IR). The degrees of periventricular hyperintensity (PVH) and deep and subcortical white matter hyperintensity (DSWMH) were evaluated by the brain MRI. The HOMA-IR values >or=2.5 were indicative of the insulin resistance. RESULTS: The presence of PVH and DSWMH were 86.7 and 83.8%, respectively. The ratio of insulin resistance increased with higher grades of PVH and DSWMH. The HOMA-IR level in grade 3 PVH was significantly higher than those in grades 0 and 1. The HOMA-IR level in grade 3 DSWMH was significantly higher than those in grades 0-2. Multiple linear regression analysis showed that HOMA-IR was significantly associated with PVH or DSWMH. CONCLUSION: It was found that insulin resistance correlated with white matter lesions among non-diabetic patients with non-cardiogenic ischemic stroke.

Cesium carbonate-catalyzed alpha-phenylchalcogenation of carbonyl compounds with diphenyl dichalcogenide.

It was found that cesium carbonate has a unique catalytic ability on the reaction of carbonyl compounds with diphenyl diselenide to give the corresponding alpha-phenylseleno carbonyl compounds in moderate to good yields. Similarly, the alpha-phenylthiolation of carbonyl compounds with diphenyl disulfide was promoted by the cesium carbonate catalyst.

Cerebral infarction in a patient with macrothrombocytopenia with leukocyte inclusions (MTCP, May-Hegglin anomaly/Sebastian syndrome).

We report on a 78-year-old woman patient with macrothrombocytopenia with leukocyte inclusions (MTCP, May-Hegglin anomaly/Sebastian syndrome), who had no history of hemorrhagic symptoms and had a platelet count of 10,000 or less, but had a cerebral infarction. The patient was found to have idiopathic thrombocytopenic purpura, hypertension, and atrial fibrillation 16 years ago, yet received no medication. She was found to have had a cerebral infarction with aphasia as the chief complaint and was admitted to our hospital. Thrombocytopenia was found in three family members. Blood examinations revealed normal bleeding time and platelet aggregation ability. The patient was found to have the triad of giant platelets, thrombocytopenia, and inclusion bodies in leukocytes. Genetic analysis showed a mutation of the MYH-9 gene in the patients second daughter. Consequently, this patient received a diagnosis of MTCP. There have only been a few reports of the onset of thrombosis in patients with MTCP and no reports of the onset of cerebral infarction. Our report is the first case of MTCP in a patient with cerebral infarction.

Effects of long-term administration of HMG-CoA reductase inhibitor, atorvastatin, on stroke events and local cerebral blood flow in stroke-prone spontaneously hypertensive rats.

The objective of this study was to determine whether the long-term administration of an HMG-CoA reductase inhibitor, atorvastatin, confers protective effects against stroke events in stroke-prone spontaneously hypertensive rats (SHRSPs). Atorvastatin (2 mg/kg, 20 mg/kg) or vehicle was orally administered to 8-week-old SHRSPs for 11 weeks. The survival ratio and stroke incidence were calculated, and plasma lipids and plasma levels of asymmetric dimethylarginine (ADMA), a circulating endogenous competitive inhibitor of NO synthase, were measured after sacrifice. The effect of atorvastatin on local cerebral blood flow (l-CBF) was also determined in 13-week-old SHRSPs after treatment with 20 mg/kg atorvastatin daily for 5 weeks. The survival ratios at 19 weeks of age were 15, 30, and 50% in the vehicle, low-dose (2 mg/kg), and high-dose groups (20 mg/kg), respectively. The survival ratio was significantly higher in the high-dose group than in the vehicle group. The incidence of stroke was significantly lower in the high-dose group than in the vehicle group. The levels of ADMA were 0.81+/-0.18 (mean+/-S.D.), 0.62+/-0.09, and 0.61+/-0.06 micromol/l in the vehicle, low-dose, and high-dose groups, respectively. Atorvastatin administration significantly reduced the ADMA levels without affecting the levels of plasma lipids. The level of l-CBF tended to be higher in the treated group, but not to a significant extent. Thus, atorvastatin was determined to confer a protective effect against hypertension-based stroke. The data suggest that the efficacy of the statin for stroke protection may be partially involved in the improvement of endothelial function via NO production and reduction of ADMA. Statins may confer useful protection against not only atherosclerosis-based stroke, but also hypertension-based stroke.

Effect of ischemic preconditioning on cerebral blood flow after subsequent lethal ischemia in gerbils.

Ischemic tolerance, the phenomenon where a sublethal ischemic preconditioning protects the brain against a subsequent lethal ischemia, has been widely studied. Studies have been done on cerebral blood flow levels prior to the lethal ischemia, but the hemodynamic pattern after global ischemia with ischemic preconditioning has not been reported. Sequential changes in regional cerebral blood flow (rCBF) in gerbil hippocampus after 5 min global ischemia with or without 2 min ischemic preconditioning were studied to determine if ischemic preconditioning affects rCBF. Four different treatments were given: (1) sham-operated, (2) 2 min ischemia, (3) non-preconditioned, and (4) preconditioned. Groups (1) and (2) (both groups n = 5) were given a 24-h recovery period and the rCBF was measured for baseline values. 24 h after sham-operation (3) and 2 min ischemia (4), gerbils were subjected to 5 min ischemia followed by 1 h, 6 h, 1-day or 7-day reperfusion periods (all groups n = 5). Although no regional difference was observed in the recovery pattern of rCBF, the values of rCBF were significantly higher in the preconditioned group throughout whole brain regions including hippocampus. These results indicate that ischemic preconditioning facilitated the recovery of rCBF after 5 min global ischemia. It needs further study to determine whether the protecting effects of preconditioning relate to the early recovery of rCBF or not. However, our results could be interpreted that the early recovery of rCBF may lead to benefits for cell survival in the CA1 neuron, probably facilitating other protecting mechanisms.

A facile method for the synthesis of thiocarbamates: palladium-catalyzed reaction of disulfide, amine, and carbon monoxide.

[reaction: see text] A new method for the synthesis of thiocarbamates has been developed. When dialkyl or diaryl disulfides were allowed to react with secondary amines and carbon monoxide in the presence of a catalytic amount of a palladium complex, the thiocarbamates were obtained in moderate to good yields. In contrast to that of secondary amines, in the reaction of a primary amine, no formation of thiocarbamate was confirmed, but urea was formed in good yield.

Effect of glycerol on ischemic cerebral edema assessed by magnetic resonance imaging.

The aim of this study is to assess the anticerebral edema effect of glycerol on a large cerebral infarction with magnetic resonance imaging (MRI). Glycerol, which is widely used as an osmotic agent against cerebral edema, could exacerbate brain tissue shift, since it has been suggested that glycerol might shrink a noninfarcted hemisphere and worsen the mass effect after a large hemispheric cerebral infarction. To investigate these issues, changes in a large hemispheric infarction with cerebral edema were studied using MRI before and after glycerol administration. Infarct volumes, normal brain tissue volumes and lateral ventricle volumes, in addition to signal intensities of T(2)-weighted images, were measured in six patients before and after administration of 300 ml of glycerol. Ventricle volumes were significantly increased (p=0.0015) and the T(2) signal intensity of the post-treatment ischemic region decreased after glycerol administration. In contrast, no significant differences in either cerebral volume or T(2) signal intensity were seen in the noninfarcted hemisphere before and after administration. Our data suggest that glycerol does not exacerbate the mass effect on a large hemispheric infarction.

Neuroprotective effect of NS-7, a novel Na+ and Ca2+ channel blocker, in a focal ischemic model in the rat.

NS-7 is a novel, voltage-dependent Na(+) and Ca(2+) channel blocker. This study evaluated the in vivo neuroprotective effect of NS-7 in a rat transient focal ischemic model when administered during occlusion. Left middle cerebral artery occlusion was induced in adult male Sprague-Dawley rats for 120 min using an intraluminal thread method. The rats received a single intravenous injection of NS-7 or saline (control group) just after the onset of ischemia, and at 30, 60 and 120 min after ischemia. Their brains were removed after 48 h reperfusion, sectioned, and stained with hematoxylin and eosin. Animals were evaluated by neurological examination at 120 min ischemia and 48 h reperfusion. Infarcted cortex and striatum were measured quantitatively and infarction volumes were calculated. Cortical infarction volumes were 128+/-74 (NS-7) and 214+/-64 mm(3) (control) immediately after the ischemia group, 155+/-48 (NS-7) and 225+/-12 mm(3) (control) after the 30 min group, 160+/-54 (NS-7) and 225+/-48 mm(3) (control) after the 60 min group, and 176+/-43 (NS-7) and 223+/-38 mm(3) (control) after the 120 min group. Cortices in NS-7-treated groups were significantly less infarcted than in control groups at all treatment times. There was no significant difference in the striatal infarction volume between the treatment and control groups. Neurological examination showed that hemiparesis and abnormal posture of the NS-7 groups were significantly more improved at 48 h reperfusion than those of the control groups without posture examination in the 120 min group. These observations suggest that NS-7 may be a new potential therapeutic agent for the acute phase of cerebral infarction.

Phenyl tributylstannyl selenide as a promising reagent for introduction [corrected] of the phenylseleno group.

A new synthetic method of organoselenium compounds has been developed. When phenyl tributylstannyl selenide (PhSeSnBu(3)) was allowed to react with acyl or aroyl chlorides in the presence of a catalytic amount of a palladium complex such as Pd(PPh(3))(4), Se-phenyl selenol esters were obtained in moderate to good yields. Similarly, the palladium complex catalyzed the reaction of PhSeSnBu(3) with alpha-halo carbonyl compounds to afford the corresponding alpha-phenyseleno carbonyl compounds in moderate yields.

One-pot synthetic method of unsymmetrical diorganyl selenides: reaction of diphenyl diselenide with alkyl halides in the presence of lanthanum metal.

A convenient synthetic method of unsymmetrical selenides has been developed. When diphenyl diselenide was allowed to react with two equimolar amounts of primary alkyl iodides and bromides in the presence of an equimolar amount of lanthanum metal, alkyl phenyl selenides were formed in moderate to good yields. For the reaction of primary alkyl chlorides and secondary alkyl iodides, the yields of the selenides were low; however, the yields were dramatically improved by the addition of TMEDA or HMPA. A reaction pathway involving the generation of a lanthanum phenylselenolate intermediate was suggested.

Reaction of carbonyl compounds with trialkylsilyl phenylselenide and tributylstannyl hydride under radical conditions.

A novel method for the hydrosilylation of carbonyl compounds has been developed. When carbonyl compounds were allowed to react with trimethylsilyl phenylselenide and tributylstannyl hydride in the presence of a catalytic amount of AIBN as the radical initiator, hydrosilylation of the carbonyl compounds efficiently proceeded to give the corresponding silyl ethers in moderate to good yields. In the absence of carbonyl compounds, the triethylsilyl hydride was obtained by the reaction of PhSeSiEt(3) with Bu(3)SnH. Although the tributylgermyl phenylselenide instead of PhSeSiMe(3) was treated with tributylstannyl hydride in the presence of a benzaldehyde under radical conditions, hydrogermylated product was not obtained and tributylgermyl hydride was mainly formed.

Tributylstannyl radical-catalyzed reaction of 1,2,3-selenadiazoles with olefins or dienes.

It was found that the reaction of 1,2,3-selenadiazoles derived from cyclic ketones with olefins or dienes was markedly promoted by a catalytic amount of tributylstannyl radical, which was generated in situ from tributylstannyl hydride or allyltributylstannane and AIBN, to give the corresponding dihydroselenophenes in moderate to good yields. In contrast, when 1,2,3-selenadiazoles prepared from linear and aromatic ketones were used as substrates, the same reaction did not take place, and alkynes were formed as the sole product.

Reduction of organic halides with lanthanum metal: a novel generation method of alkyl radicals.

Results of the reaction of alkyl halides with lanthanum metal have been shown. The reduction of alkyl iodide with 1/3 equiv of lanthanum metal efficiently proceeded to give the corresponding reductive dimerized products along with the formation of reduction and dehydroiodination products. In the case of alkyl bromides and chlorides, the reaction did not proceed under the same reaction conditions as that of alkyl iodides; however, the reaction was dramatically promoted by the addition of a catalytic amount of iodine. A reaction pathway including alkyl radicals was suggested.

Alkane Oxidation with Molecular Oxygen Using a New Efficient Catalytic System: N-Hydroxyphthalimide (NHPI) Combined with Co(acac)(n)() (n = 2 or 3).

A novel class of catalysts for alkane oxidation with molecular oxygen was examined. N-Hydroxyphthalimide (NHPI) combined with Co(acac)(n)() (n = 2 or 3) was found to be an efficient catalytic system for the aerobic oxidation of cycloalkanes and alkylbenzenes under mild conditions. Cycloalkanes were successfully oxidized with molecular oxygen in the presence of a catalytic amount of NHPI and Co(acac)(2) in acetic acid at 100 degrees C to give the corresponding cycloalkanones and dicarboxylic acids. Alkylbenzenes were also oxidized with dioxygen using this catalytic system. For example, toluene was converted into benzoic acid in excellent yield under these conditions. Ethyl- and butylbenzenes were selectively oxidized at their alpha-positions to form the corresponding ketones, acetophenone, and 1-phenyl-1-butanone, respectively, in good yields. A key intermediate in this oxidation is believed to be the phthalimide N-oxyl radical generated from NHPI and molecular oxygen using a Co(II) species. The isotope effect (k(H)/k(D)) in the oxidation of ethylbenzene and ethylbenzene-d(10) with dioxygen using NHPI/Co(acac)(2) was 3.8.