Enoxaparin was well tolerated when administered subcutaneously or intravenously, and there appears to be no need to modify the currently recommended dose for obese volunteers.

No abstract

Conformational restrictions in the form of [i, i + 4] lactam bridges were sequentially incorporated into the shortest fragment of hPTH with recognized efficacy in the OVX rat model of osteoporosis, hPTH-(1-31)NH 2 (1). Cyclo(Lys 18 -Asp 22 )[Ala 1 ,Nle 8 ,Lys 18 ,Asp 22 ,Leu 27 ]hPTH(1-31)NH 2 (2) is a potent agonist of the PTH/PTHrP receptor located on the surface of ROS 17/2.8 cells as measured by its ability to stimulate adenylyl cyclase activity (EC 50 ) 0.29 nM). A second analogue, which constrains the entire C-terminal receptor binding domain, bicyclo(Lys 18 -Asp 22 ,Lys 26 -Asp 30 )[Ala 1 ,Nle 8 ,Lys 18 ,Asp 22 ,Leu 27 ] hPTH(1-31)NH 2 ( 6), is also shown to be a potent agonist (EC 50 ) 0.13 nM), thus providing further evidence for an extended helix as the relevant bioactive conformation in this region of the hormone. Adjacent lactam bridges were incorporated into the analogue bicyclo(Lys 13 -Asp 17 ,Lys 18 -Asp 22 )[Ala 1 ,Nle 8 ,Lys 18 ,Asp 17,22 ,Leu 27 ]hPTH(1-31)NH 2 (7) to evaluate the receptor's tolerance to conformational restriction in the midregion of the peptide. In fact, peptide 7 is also a highly potent agonist (EC 50 ) 0.43 nM) in the cAMP-based assay, which suggests that at least one bioactive form of the hormone requires a helical conformation extending from residue 13 to residue 22. Incorporation of all three lactam bridges afforded the most conformationally constrained PTH peptide agonist yet reported, tricyclo(Lys 13 -Asp 17 ,Lys 18 -Asp 22 ,Lys 26 -Asp 30 )[Ala 1 ,Nle 8 ,Lys 18 ,Asp 17,22 ,Leu 27 ]hPTH(1-31)NH 2 (9). Peptide 9 (EC 50 ) 0.14 nM) forces residues 13-30 into an extended helical conformation and is a more potent PTH receptor agonist than the parent linear hPTH(1-31)NH 2 (1, EC 50 ) 4.7 nM). Comparative circular dichroism studies indicate that peptide 9 is highly helical even in the absence of TFE, indicating that residues 1-12 are also likely to be helical in the bioactive conformation. Taken together, these results provide strong structural evidence that hPTH binds to its receptor in an extended helical conformation.

No abstract

Abstract. RHC 3024 has been investigated for its antiallergic activity in three in vitro models of anaphylaxis. We have also compared its activity profile in these models with that of disodium cromoglycate (DSCG) and other antiallergic agents. As an inhibitor of antigen-induced release of histamine from rat mast cells RHC 3024 was 4 times more potent than DSCG. In the same model the activity profile of RHC 3024 was identical to that of DSCG in the following respects: loss of inhibitory activity with increasing preincubation time, reversibility of the inhibition, tachyphylaxis and cross-tachyphylaxis to each other and inability to inhibit histamine release stimulated by Ca++ ionophore, dextran/phosphatidyl serine and compound 48/80. Both drugs had no effect in the other two models, IgG|-mediated histamine release from guinea pig lung and anti-IgE-induced histamine release from human basophils. We conclude: (1) RHC 3024 is a potent inhibitor of mediator release with a me chanism of action similar to that of DSCG, M&B 22,948, PRD-92-Ea and AH-7725 and (2) the in vitro activity profiles of proxicromil, doxantrazole, ICI 74,917 and WY-16,922 are different from DSCG and RHC 3024.