Synthesis and analgesic and anti-inflammatory activities of 1,2-benzothiazine derivatives

Three 1,2-benzothiazine derivatives were synthesized, and their analgesic/anti-inflammatory efficacy and their effects on gastric irritation were evaluated. Among the three compounds, 39 exhibited the most potent analgesic action, but the effect was weaker than that of piroxicam. Nonetheless, the compound showed 4 times more potent analgesic action with less gastric damage than did ibuprofen. These compounds did not show anti-inflammatory effect at an oral dose of 5 mg/kg.     

Metabolism-based anticancer drug design

Many conventional anticancer drugs display relatively poor selectivity for neoplastic cells, in particular for solid tumors. Furthermore, expression or development of drug resistance, increased glutathione transferases as well as enhanced DNA repair decrease the efficacy of these drugs. Research efforts continue to overcome these problems by understanding these mechanisms and by developing more effective anticancer drugs. Cyclophosphamide is one of the most widely used alkylating anticancer agents. Because of its unique activation mechanism, numerous bioreversible prodrugs of phosphoramide mustard, the active species of cyclophosphamide, have been investigated in an attempt to improve the therapeutic index. Solid tumors are particularly resistant to radiation and chemotherapy. There has been considerable interest in designing drugs selective for hypoxic environments prevalent in solid tumors. Much of the work had been centered on nitroheterocyclics that utilize nitroreductase enzyme systems for their activation. In this article, recent developments of anticancer prodrug design are described with a particular emphasis on exploitation of selective metabolic processes for their activation.     

Inducible nitric oxide synthase inhibitors fromMelia azedarach var.Japonica

In bioassay-guided search for inducible nitric oxide synthase (iNOS) inhibitory compounds from higher plants of South Korea, two beta-carboline alkaloids, 4-methoxy-1-vinyl-beta-carboline (1) and 4,8-dimethoxy-l-vinyl-beta-carboline (2) have been isolated from the cortex of Melia azedarach var. japonica. The structures of these compounds were elucidated on the basis of spectroscopic data. Compounds 1 and 2 showed marked inhibitory activity of iNOS on LPS- and interferon-gamma-stimulated RAW 264.7 cells.     

Two new lignans fromLindera obtusiloba blume

Two new furanolignans (3, 5), together with three known lignans (1, 2, 4), were isolated from the stem of Lindera obtusiloba (Lauraceae). The structures of the compounds were determined as actifolin (1), pluviatilol (2), 5,6-dihydroxymatairesinol (3), (+)-syringaresinol (4), and (+)-9'-O-trans-feruloyl-5,5'-dimethoxylariciresinol (5) on the basis of physicochemical and spectroscopic evidences. Compounds 1, 2, 3, and 5 showed cytotoxicity against a small panel of human tumor cell lines with ED50 values of 3.40 to approximately 19.27 microg/ml.     

Primary intramedullary spinal cord primitive neuroectodermal tumor with intracranial seeding in an infant

Primary spinal cord primitive neuroectodermal tumor (PNET) is a rare entity. In all, 13 cases have been reported in the literature, including 3 with intracranial seeding. A 3-month-old girl with involvement of the spinal cord below the mid-thoracic level is described. The brain MRI revealed findings indicative of seeding along the intracranial subarachnoid space. Biopsy, duraplasty and removal of laminotomy flap were done. In spite of a good response to the first cycle of postoperative 8-drugs-in-a-day chemotherapy, further treatment was refused. She died 21 days after the onset of leg weakness, which reveals the rapid progression of untreated cases. To our knowledge, this is the first case of spinal cord PNET with parenchymal involvement that has been described in an infant.     

Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: PHYSIOLOGICAL ACTIONS OF ANGIOTENSIN II MEDIATED BY AT1 AND AT2 RECEPTORS IN THE BRAIN

• 1 Autoradiographic binding studies have shown that the AT₁ receptor is the predominant angiotensin II (AngII) receptor subtype in the central nervous system (CNS). Major sites of AT₁ receptors are the lamina terminalis, hypothalamic paraventricular nucleus, the lateral parabrachial nucleus, rostral and caudal ventrolateral medulla, nucleus of the solitary tract and the intermediolateral cell column of the thoraco-lumbar spinal cord.
• 2 While there are differences between species, AT₂ receptors are found mainly in the cerebellum, inferior olive and locus coeruleus of the rat.
• 3 Circulating AngII acts on AT₁ receptors in the subfornical organ and organum vasculosum of the lamina terminalis (OVLT) to stimulate neurons that may have a role in initiating water drinking.
• 4 Centrally administered AngII may act on AT₁ receptors in the median preoptic nucleus and elsewhere to induce drinking, sodium appetite, a sympathetic vasoconstrictor response and vasopressin secretion.
• 5 Recent evidence shows that centrally administered AT₁ antagonists inhibit dipsogenic, natriuretic, pressor and vasopressin secretory responses to intracerebroventricular infusion of hypertonic saline. This suggests that an angiotensinergic neural pathway has a role in osmoregulatory responses.
• 6 Central angiotensinergic pathways which include neural inputs to the rostral ventrolateral medulla may use AT₁ receptors and play a role in the function of sympathetic pathways maintaining arterial pressure.

     

Suprathreshold Auditory Cortex Activation Visualized by Intrinsic Signal Optical Imaging

The suprathreshold tonotopic organization of rat and guineapig auditory cortex was investigated using intrinsic signaloptical imaging through a thinned skull. Optical imaging revealedthat suprathreshold pure sine wave tone stimulation (25–40dB) evoked activity over large cortical areas that were tonotopicallyorganized. Three-dimensional surface plots of the activatedareas revealed "patchy" auditory-evoked activity consistingof numerous local peaks and valleys building to a maximum. Subsequentdetailed electrophysiological mapping in the same subjects confirmedthe localization of auditory-evoked activity based on opticalimaging, including responses to a test frequency at corticalloci more than 2 octaves away from the threshold-defined isofrequencycontour. The success of this technique in visualizing auditorycortex functional organization at suprathreshold stimulus levelswill allow for future investigations of auditory cortex frequencyrepresentation. including representational plasticity inducedby a variety of experimental manipulations.     

Actigraphically recorded motor activity and immobility across sleep cycles and stages in healthy male subjects

The aim of this study was to compare the extent to which activity and immobility measures are related to sleep stages and sleep cycles in order to improve the informative value of actigraphic assessment of sleep. We therefore performed simultaneous ambulatory polysomnography and wrist-activity monitoring (AM) in 14 healthy male subjects without sleep complaints. In this context, a simple method for transforming raw motor activity data into a time-series reflecting onset and duration of activity and immobility clusters is introduced. Our results demonstrate that nocturnal AM measures were significantly affected by sleep stage. Low activity levels and particularly prolonged episodes of uninterrupted immobility were associated with increasing sleep depth. On the other hand, high activity levels and prolonged episodes of activity were related to intermittent wakefulness during sleep. Our results suggest that measures reflecting the occurrence and duration of activity and immobility clusters provide a better approach in studying the relationship between activity/immobility and sleep stages. Except for the duration of uninterrupted immobility episodes, which showed a significant decrease in the fourth cycle, none of the AM measures showed a significant cycle-to-cycle variation. Consequently, mean nocturnal motor activity measures provide an accurate reflection of the total sleep period. However, none of the AM-derived measures seems useful in evaluating the cycle structure during sleep.     

Mucoepidermoid odontogenic cyst

This unusual cystic lesion was previously described as a lesion that has features of both botryoid odontogenic cyst and mucoepidermoid tumor and later was named as glandular odontogenic cyst. An additional case is reported and its clinicopathologic features described. The name "mucoepidermoid odontogenic cyst" is proposed.     

Planum temporale and Heschl gyrus volume reduction in schizophrenia: a magnetic resonance imaging study of first-episode patients

BACKGROUND: Magnetic resonance imaging studies in schizophrenia have revealed abnormalities in temporal lobe structures, including the superior temporal gyrus. More specifically, abnormalities have been reported in the posterior superior temporal gyrus, which includes the Heschl gyrus and planum temporale, the latter being an important substrate for language. However, the specificity of the Heschl gyrus and planum temporale structural abnormalities to schizophrenia vs affective psychosis, and the possible confounding roles of chronic morbidity and neuroleptic treatment, remain unclear. METHODS: Magnetic resonance images were acquired using a 1.5-T magnet from 20 first-episode (at first hospitalization) patients with schizophrenia (mean age, 27.3 years), 24 first-episode patients with manic psychosis (mean age, 23.6 years), and 22 controls (mean age, 24.5 years). There was no significant difference in age for the 3 groups. All brain images were uniformly aligned and then reformatted and resampled to yield isotropic voxels. RESULTS: Gray matter volume of the left planum temporale differed among the 3 groups. The patients with schizophrenia had significantly smaller left planum temporale volume than controls (20.0%) and patients with mania (20.0%). Heschl gyrus gray matter volume (left and right) was also reduced in patients with schizophrenia compared with controls (13.1%) and patients with bipolar mania (16.8%). CONCLUSIONS: Compared with controls and patients with bipolar manic psychosis, patients with first-episode schizophrenia showed left planum temporale gray matter volume reduction and bilateral Heschl gyrus gray matter volume reduction. These findings are similar to those reported in patients with chronic schizophrenia and suggest that such abnormalities are present at first episode and are specific to schizophrenia.