SUMMARYPurpose: To assess the pharmacology of perampanel and its antiseizure activity in preclinical models. Perampanel [2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl) benzonitrile] is a novel, orally active, prospective antiepileptic agent currently in development for refractory partial-onset seizures. ]Perampanel binding to rat forebrain membranes was not significantly displaced by glutamate or AMPA but was displaced by the noncompetitive AMPA receptor antagonists CP465022 (K i 11.2 ± 0.8 nM) and GYKI52466 (K i 12.4 ± 1 lM). In mice, perampanel showed protective effects against audiogenic, MES-induced, and PTZ-induced seizures (ED 50 s 0.47, 1.6, and 0.94 mg/kg, respectively). Perampanel also inhibited 6 Hz electroshock-induced seizures when administered alone or in combination with other antiepileptic drugs (AEDs). In amygdala-kindled rats, perampanel significantly increased afterdischarge threshold (p < 0.05 vs. vehicle), and significantly reduced motor seizure duration, afterdischarge duration, and seizure severity recorded at 50% higher intensity than afterdischarge threshold current (p < 0.05 for all measures vs. vehicle). Perampanel caused dosedependent motor impairment in both mice (TD 50 1.8 mg/ kg) and rats (TD 50 9.14 mg/kg), as determined by rotarod tests. In mice, the protective index (TD 50 in rotarod test/ ED 50 in seizure test) was 1.1, 3.8, and 1.9 for MES-induced, audiogenic, and PTZ-induced seizures, respectively. In rat, dog, and monkey, perampanel had a half-life of 1.67, 5.34, and 7.55 h and bioavailability of 46.1%, 53.5%, and 74.5%, respectively. Significance: These data suggest that perampanel is an orally active, noncompetitive, selective AMPA receptor antagonist with potential as a broad spectrum antiepileptic agent.

Reaction cross sections (sigma(R)) for 19C, 20C and the drip-line nucleus 22C on a liquid hydrogen target have been measured at around 40A MeV by a transmission method. A large enhancement of sigma(R) for 22C compared to those for neighboring C isotopes was observed. Using a finite-range Glauber calculation under an optical-limit approximation the rms matter radius of 22C was deduced to be 5.4+/-0.9 fm. It does not follow the systematic behavior of radii in carbon isotopes with N < or = 14, suggesting a neutron halo. It was found by an analysis based on a few-body Glauber calculation that the two-valence neutrons in 22C preferentially occupy the 1s(1/2) orbital.

We examined the presence ofcathepsins B, H, and L in bronchoalveolar epithelial cells, induding alveolar maaophages, and in bronchoalveolar lavage fluid (BALF), using immunocytochemistry and immunoblotting. By light and dcctron microscopy, immunoreactivity for cathepsins B, H, and L was detected in lysosomes ofciliated and non-ciliated epitheial cells ofbronchi and bronchioles, and in maaophages. Immunodeposits for cathepsin H only were demonstrated in lamellar bodies of Type II alveolar epitheial cells, suggesting the cosecretion ofsurfactants and cathepsin H from the cells into the alveolar space. By immunoblotting,

One and two-neutron removal-reactions from 19 C and 20 C have been studied using a liquid-hydrogen target at 40 A MeV. A small cross section has been observed in the one-neutron removal reaction from 20 C. The observed inclusive removal cross sections are compared with theoretical removal cross sections calculated by using shell model spectroscopic factors and Glauber-model single-particle cross-sections. The observed momentum distributions are also compared with those calculated by using continuum-discretized coupled-channel methods. Good consistency between theory and experiment is shown in the one-neutron removal reaction from 19 C. However, our theoretical calculation fails to reproduce the neutron removal reactions from 20 C, which suggests that further improvements of the theoretical descriptions are necessary.

The chemical specificity and structural requirements of short-chain fatty acids (SCFAs) in stimulating pancreatic endocrine responses was investigated in conscious sheep. Normal SCFAs with one to eight carbons were injected intravenously at seven doses of 39-2,500 mumol/kg body wt. The isomers or derivatives of SCFAs were administered at 625 mumol/kg body wt. Analysis of dose-response curves showed that n-butyric acid (4 carbons in the molecule) was most effective for both insulin and glucagon secretion among the normal SCFAs tested. In addition, one carboxylic group was absolutely required, since hormone secretion was significantly reduced or abolished with compounds in which the carboxylic element was replaced by other groups and with dicarboxylic acids. The form of the hydrocarbon chain (branched, cyclic, or benzoic ring) also affected hormone secretory activity. Most of the compounds that replaced hydrogen in the hydrocarbon chain by other groups at various positions reduced or abolished the hormone secretory effect obtained by n-butyric acid. In conclusion, a monocarboxylic acid with several numbers of hydrocarbons was required for insulin or glucagon secretion. These results suggest that the pancreatic endocrine system can recognize the chemical structure of SCFAs in detail and induce hormone secretion in sheep.