The vanishing point of the mismatch negativity at sleep onset.

OBJECTIVE: To determine when the mismatch negativity (MMN) disappears at sleep onset, event-related potentials (ERPs) were recorded continuously from wakefulness to sleep. METHODS: Ten healthy young students were told to fall asleep ignoring the tones presented through a loudspeaker above their head. Standard (1000 Hz, P=0.90), high deviant (1200 Hz, P=0.05), and low deviant (1050 Hz, P=0.05) tones were presented in a quasirandom order with a fixed stimulus onset asynchrony of 500 ms. ERP waveforms were obtained separately for 5 successive stages characterized by typical electroencephalographic (EEG) patterns of the sleep onset period. The EEG staging was made manually with very short (5 s) scoring epochs. RESULTS: The MMN appeared in wakefulness and in the early phase of stage 1 sleep (EEG stage II) but disappeared when low-voltage theta waves emerged after alpha flattening (EEG stage III). Instead, P240 and N360 developed particularly for high deviant tones. CONCLUSIONS: Concurrently with the disappearance of alpha waves, the automatic change detection system in wakefulness seems to stop operating and a different sleep-specific system becomes dominant.

Effect of tranilast oily gel on carrageenin-induced granulation in rats.

Tranilast (TL) oily gels consisting of hydrogenated soybean phospholipid and fatty-acid ester were prepared, and the inhibitory effect of the gels on the growth of granulation tissue were evaluated in a carrageenin-induced rat granulation model. By the application of 0.1 and 0.2% TL oily gel, the weight of granulation tissue was significantly reduced to 64 and 55%, respectively, of control value. Furthermore, these gels reduced their respective hydroxyproline content to 64 and 51% of the control. On the other hand, the inhibitory effect of 10% TL ointments, which are clinically used for the treatment of keloids and hypertrophic scars as hospital preparations, was much lower than that of the oily gels. In addition, the application of 0.1 and 0.2% oily gel led to high concentration (0.1% gel, 168+/-18 microg/g; 0.2% gel, 221+/-16 microg/g) of TL in the dermis as compared with the 10% TL ointments. These results suggest that TL oily gels may be a useful topical formulation for the treatment of keloids and hypertrophic scars.

Effect of UV-absorbing agents on photodegradation of tranilast in oily gels.

Tranilast (TL) oily gels containing UV-absorbing agents (UV absorber) were prepared, and the effect of the agents against photodegradation of TL was investigated. When 0.1% TL oily gel without UV absorber was exposed to light, TL was photochemically decomposed to the extent of 74.1% of its initial content at the end of the first hour. Although there were differences in the preventive effect on photodegradation of TL depending on the UV absorbers employed, 2-(2-benzotriazolyl)-p-cresol (BTPC) was the most effective absorber. The addition of UV absorbers to the oily gel did not affect the release of TL from the gel, the skin permeation, or the skin concentration of TL following topical application. UV absorbers added to TL oily gel penetrated into skin; however, their concentration in skin was similar to that following application of commercial sunscreen. These results suggest that the addition of UV absorbers to the oily gel of TL may be useful in preventing photodegradation of TL in the gel.

Effects of inhaled KAA-276, a selective histamine H1 receptor antagonist, on antigen- and histamine-induced bronchoconstriction in animals.

The antiasthmatic profile of KAA-276 (1-[1-(4-fluorophenylmethyl)-1H-benzimidazole-2-yl]-5-[2-[4-(2- carboxethyl) phenyl]ethyl]-1,5-diazacyclooctane sulfate, CAS 167264-26-8), a newly synthesized histamine H1 receptor antagonist, given by inhalation as an aerosol was investigated and compared with the profiles obtained using other routes of administration. When given by inhalation, or by intravenous or oral routes, KAA-276 inhibited antigen-induced bronchoconstriction in rats with ID50 (a dose to inhibit the antigen-induced response by 50%) values of 0.054%, 1 mg/kg, and 51.2 mg/kg, respectively. KAA-276 prevented the histamine-induced wheal reaction in rats dose-dependently with ID50 values of 0.22% by inhalation, 0.18 mg/kg by the intravenous route, and 2.3 mg/kg by the oral route. To judge from these results, inhaled KAA-276, unlike intravenous or oral KAA-276, had no inhibitory effect on the histamine-induced wheal reaction at a dose (0.054%) that is effective against the antigen-induced airway asthmatic response. Inhaled KAA-276 suppressed antigen-induced bronchoconstriction in actively sensitized guinea pigs, and histamine-induced bronchoconstriction in monkeys. These results suggest that inhalation of KAA-276 would benefit patients with bronchial asthma without inducing unwanted systemic effects.

Pharmacological characterization of a novel long-acting histamine H1 receptor antagonist, KAA-276.

The pharmacological profile of a newly synthesized histamine H1 receptor antagonist, KAA-276 (1-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-yl]-5-12-[4-( 2-carboxyethyl)-phenyl]ethyl]-1,5-diazacyclooctane sulfate), was characterized. In a H1 receptor binding assay in vitro, KAA-276 inhibited [3H]mepyramine binding to guinea pig cerebellar membrane preparations with an IC50 of 0.66 nM. The inhibitory potency of KAA-276 was greater than that of terfenadine, but similar to that of astemizole and ketotifen. KAA-276 antagonized the histamine-induced constriction of ileum and trachea isolated from guinea pigs in a dose-dependent manner with a concomitant reduction in the maximum response. Furthermore, the inhibitory effect of KAA-276 on histamine induced contraction was potentiated depending on the duration of preincubation time and revealed an irreversible property. KAA-276 given orally, intraduodenally, and by inhalation significantly inhibited histamine-induced bronchoconstriction dose-dependently in guinea pigs. Inhalation of KAA-276 exhibited inhibitory activity with a rapid onset and long duration, while intraduodenal administration resulted in action with a slow onset. Therefore, KAA-276, an irreversible and selective histamine H1 receptor antagonist, was shown to be a useful drug for therapeutic strategies against bronchial asthma when administered by the aerosol route.

Highly selective inhibitors of thromboxane synthetase. 1. Imidazole derivatives.

The structure--activity relationships of imidazole derivatives as inhibitors of thromboxane (TX) synthetase were investigated. Introduction of various substituents (e.g., one or two methyl groups, a halogen atom, a methylidene group, unsaturated bonds, or a phenylene group) into the alpha position or other positions in the carboxy-bearing side chain of 1-(7-carboxyheptyl)imidazole (15) was found to increase the inhibitory potency. The length of the side chains with the phenylene group was optimum for the inhibitory potency on TX synthetase in the region of 8.5-9.0 A. Among the tested imidazole derivatives, 1-(7-carboxy-7-methyl-2-octynyl)imidazole (47), 4-[3-(1-imidazolyl)-propyl]benzoic acid (50), and (E)-4-(1-imidazolylmethyl)cinnamic acid (54) and its alpha-methyl analogue (57) showed the highest potency with an IC50 in the range of 10(-8) to 10(-9) M. Inhibition by these derivatives was highly selective for the TX synthetase, since other enzymes such as fatty acid cyclo-oxygenase and prostacyclin synthetase were not affected.