In vivo evaluation of a new polyurethane-coated catgut suture.

Plain catgut sutures were coated with different polyester-based polyurethanes. The sutures were implanted subcutaneously in rats and tested for tensile strength loss and tissue reactions. A polyurethane coating based on an oxalic acid polyester was hydrolysed too fast to protect the catgut against proteolysis. However, a 2-0 plain catgut having a 50 micron polyurethane coating based on glutaric acid polyester maintained its original tensile strength for 8 days. The tensile strength then decreased as for plain catgut. Histological examination of the surrounding tissues showed that the strong inflammatory reaction observed in the first three days with non-coated catguts is decreased, but occurs again later, although to a lesser extent.

In vitro and in vivo biological activities of SR140333, a novel potent non-peptide tachykinin NK1 receptor antagonist.

(S)1-(2-[3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenylacetyl)pip eridin-3- yl]ethyl)-4-phenyl-1-azoniabicyclo[2.2.2]octane chloride (SR140333) is a new non-peptide antagonist of tachykinin NK1 receptors. SR140333 potently, selectively and competitively inhibited substance P binding to NK1 receptors from various animal species, including humans. In vitro, it was a potent antagonist in functional assays for NK1 receptors such as [Sar9,Met(O2)11]substance P-induced endothelium-dependent relaxation of rabbit pulmonary artery and contraction of guinea-pig ileum. Up to 1 microM, it had no effect in bioassays for NK2 ([beta Ala8]neurokinin A-induced contraction of endothelium-deprived rabbit pulmonary artery) and NK3 ([MePhe7]neurokinin B-induced contraction of rat portal vein) receptors. The antagonism exerted by SR140333 toward NK1 receptors was apparently non-competitive, with pD2' values (antagonism potency evaluated by the negative logarithm of the molar concentration of antagonist that produces a 50% reduction of the maximal response to the agonist) between 9.65 and 10.16 in the different assays. SR140333 also blocked in vitro [Sar9,Met(O2)11]substance P-induced release of acetylcholine from rat striatum. In vivo, SR140333 exerted highly potent antagonism toward [Sar9,Met(O2)11]substance P-induced hypotension in dogs (ED50 = 3 micrograms/kg i.v.), bronchoconstriction in guinea-pig (ED50 = 42 micrograms/kg i.v.) and plasma extravasation in rats (ED50 = 7 micrograms/kg i.v.). Finally, it also blocked the activation of rat thalamic neurons after nociceptive stimulation (ED50 = 0.2 micrograms/kg i.v.).

SR 142801, the first potent non-peptide antagonist of the tachykinin NK3 receptor.

SR 142801 is the first potent and selective non-peptide antagonist of the tachykinin NK3 receptor. It inhibited [MePhe7]NKB binding to its receptor from various species, including humans. SR 142801 was a competitive antagonist of [MePhe7]NKB-mediated contractions of guinea-pig ileum and inhibited the acetylcholine release following the activation of the guinea-pig ileum tachykinin NK3 receptor. In vivo, SR 142801 potently inhibited the turning behaviour induced by intrastriatal injection of senktide in gerbils, and appears as a powerful tool for investigation of the physiological and pathological role of NKB and its NK3 receptor.

Novel solid-phase synthesis of thiol-terminated-poly(alpha-amino acid)-drug conjugate.

A new method using a controlled pore glass solid support for the preparation of a thiol-terminated-polymerdrug, notably poly-L-glutamate-daunomycin having a terminal thiol group, is described. The method consists of first polymerizing an ester-protected glutamic acid onto an amino-disulfide functionalized controlled pore glass support. The ester protecting group is then removed, freeing the gamma-carboxyl groups of the grafted polymer which then allows it to react with daunomycin. Finally, the disulfide bond linking the conjugated polymer-drug to the solid support is broken by thiolysis, thus releasing the desired product. The final product consists of only polymer-drug conjugates with terminal thiol groups (global yield 26%). This novel method is much simpler and more elegant than more conventional preparation methods requiring solution phase techniques.

Acute histopathological response to a new biodegradable polypeptidic polymer for implantable drug delivery system.

This article deals with the in vivo evaluation of a new class of synthetic polypeptides, the poly[(tert-butyloxycarbonylmethyl) glutamates], POMEG, as an injectable or implantable drug delivery system. Three different polymers, varying in their degree of esterification, were extruded either with or without progesterone, and finally implanted in rats up to 14 days. Histologic evaluation of the implant sites show evidence of the good biocompatibility of these polymers. In addition, the description of their in vivo behavior, based on microscopic observation of the implanted POMEG rods, enables one to appreciate their potential as a drug delivery system for short- or long-term therapy.