Synthesis of thiazolotriazine derivatives and their antinociceptive effects in mice.

Ans raci A series of 2-(4-arylpiperazin-1-yl-methyl)-4-methyl-1-oxo-5,6,8,8a-tetrahydro -thiazolo[3,4-d] [1,2,4]triazines was prepared and tested for antinociceptive activity. The compounds were prepared by the Mannich reaction from the corresponding 2-unsubstituted thiazolotriazines. When administered intraperitoneally most were found to have potent analgesic activity in the mouse during tests of phenylbenzoquinone-induced abdominal constriction; ED50 values (doses resulting in half the maximum effect) ranged from 10 to 87 mg kg(-1). Derivatives with a 3-chloro- or 4-fluorophenylpiperazinylmethyl side-chain in the 2-position of the bicyclic system were, when administered intraperitoneally at doses greater than 25 mg kg(-1), also effective in the hot-plate test without associated sedative effects. The compounds have a large therapeutic index; intraperitoneal LD50 values (doses which result in the death of half the animals) were > 700 mg kg(-1). Naloxone attenuated the analgesic activity of the 3-chloro derivative, suggesting the participation of micro-receptors in the antinociceptive effects of this drug. In addition, a nonopioid mechanism, probably related to enhancement of the release of 5-hydroxytryptamine and noradrenaline, or inhibition of the neuronal re-uptake of these compounds, has been evinced to explain the analgesic properties of the 3-chloro or 4-fluoro derivatives. These results provide evidence for the involvement of noradrenergic and 5-hydroxytryptaminergic pathways in the analgesic activity of 3 and 4. Because of their potential effectiveness, the 3-chloro- or 4-fluorophenylpiperazinylmethyl derivatives might be suitable for treatment of a wide variety of painful conditions and could be attractive reserve agents for patients dissatisfied with opioids.

A preliminary study of the adsorption and release of preservatives by contact lenses and collagen shields.

PURPOSE: We evaluated the adsorption and release of preservatives and a beta-blocking agent (metipranolol) by three different contact lens materials and two collagen shields. METHODS: We recorded the ultraviolet absorption spectra of these materials before, during, and after extended exposure to pharmaceutical preparations of artificial tears, beta-blocking eye drops, and a contact lens cleaning solution. The presence of preservatives and active ingredients was demonstrated by thin layer chromatography. RESULTS: Significant differences were observed depending on the nature of the absorbant materials and the preservatives. Soft lenses showed the greatest affinity for benzalkonium chloride and metipranolol but also readily released them. CONCLUSIONS: This preliminary study points out that rinsing with a sodium chloride isotonic solution without preservatives has an important place in daily contact lens care.

[Adapto-electroretinographic study of regeneration of the visual pigments in the fauve de Bourgogne and albino rabbit after photobleaching with monochromatic light]. / Etude adapto-électrorétinographique de la régénération des pigments visuels chez les lapins fauve de Bourgogne et albinos après éblouissement en lumière monochromatique.

Kinetics of rod pigment regeneration were studied in vivo in Fauve de Bourgogne and Albino rabbits by adapto-electroretinography (AERG). Electroretinography in the rabbit using polychromatic flashes affords the means to dissociate the response of the cones (a-wave, b1-wave: photopic function), from that of the rods (b2-wave scotopic function). After photobeachting, electroretinograms were recorded at two minutes' intervals during dark adaptation of one hour duration. Variations of b2/b1 with time of dark adaptation provide an adapto-electroretinogram giving relative measurements of rod pigment concentration at various stages of regeneration. In the present study, photobleaching was provoked by monochromatic light (at 405, 436 and 546 nm) actinometrically controlled. Studies were conducted in two Fauve de Bourgogne and two Albino rabbits. The effect of four doses, varying from 4.10(17) photon.cm-2 to 1.10(19) photon.cm-2, was measured at each wavelength on the AERG in the four rabbits. First order kinetics for rod pigment regeneration were observed, mainly at 546 nm and at high dose levels: overall regeneration rate is apparently controlled by the isomerization step. For Fauve de Bourgogne and Albino rabbits, the regeneration rate depends on the bleaching wavelength and on the dose. At high dose levels and for long wavelengths, delayed recoveries are observed in the Fauve de Bourgogne animals. However, durations of delays are shorter with monochromatic light experiments than with polychromatic light bleaching, at the same dose. Differences of ocular media transmission may be responsible for a faster regeneration process at shorter than at longer wavelengths.