Ann H. Hunt

Oral Delivery of Biologically Active Parathyroid Hormone

AbstractPurpose. Parathyroid hormone (PTH), the only drug known to stimulate bone formation, is a peptide therapeutic indicated in the treatment of osteoporosis. Unfortunately, PTH is only effective when dosed by injection because it has no oral bioavailability. Herein we report the oral absorption of PTH in rats and monkeys facilitated by the novel delivery agent, N-[8-(2-hydroxy-4-methoxy)bensoyl]amino caprylic acid (4-MOAC). Methods. 4-MOAC was selected from a group of 100 delivery agents based on in vitro chromotography studies and in vivo screening studies in rats. The PTH/4-MOAC combination was then tested in monkeys. The interaction of 4-MOAC and PTH was evaluated by nuclear magnetic resonance (NMR) spectroscopy. Results. Monkeys were administered an aqueous solution containing 4-MOAC and PTH and mean peak serum PTH concentrations of about 3000 pg/mL were obtained. The relative bioavailability of oral PTH was 2.1% relative to subcutaneous administration. The biological activity of the orally-delivered PTH was further evaluated in a rat model of osteoporosis. These studies showed that the bone formed following oral PTH/4-MOAC administration was comparable to that formed following PTH injections. The 4-MOAC mediated absorption of PTH is hypothesized to be the result of a noncovalent interaction between 4-MOAC and PTH. The preliminary evaluation of this interaction by NMR is described. Conclusions. 4-MOAC facilitates the absorption of PTH following oral administration to both rats and monkeys. The orally-absorbed PTH is biologically active as demonstrated in a rat model of osteoporosis.

A90720A, a serine protease inhibitor isolated from a terrestrial blue-green alga Microchaete loktakensis

Abstract The isolation and structure elucidation of A90720A, 1 , a cyclic depsipeptide from the terrestrial blue-green alga Microchaete loktakensis is described. 1 was isolated on the basis of its thrombin inhibitory activity and its structure was determined using spectral methods and amino acid analysis. The absolute configurations of the constituent amino acids were found to be as follows: the nucleus contains L -threonine, L -arginine, L -3-amino-6-hydroxy-2-piperidone (Ahp, i.e., glutamic acid-γ-car☐aldehyde), L -leucine, L -N-methyl-tyrosine and L -valine. The side chain off the L -threonine amino group contains D -leucine, followed by a 3-O-sulfated R -glycerate moiety.

Formation of multilayered vesicles from water/organic-solvent (W/O) emulsions: theory and practice

Multilayered liposome (MLV) formation from water/organic-solvent (W/O) emulsions was studied. A fundamental liposome population parameter, the Eratio, was defined and used to estimate the bilayer number and water spacing in MLV liposomes. MLVs prepared from W/O emulsions have optimum drug entrapment at an emulsion-lipid/emulsion-water ratio of ∼0.33. Drug entrapment is typically 50 to 65% under these optimal conditions.

Structures of A88696 C,D and F: Gastric ATP-ase inhibitors

Abstract The structures of A88696C ( 1 ), D ( 2 ) and F ( 3 ), isolated from Streptomyces sclerotialus , are described on the basis of spectroscopic analysis. 1 and 3 are spirotetronic acid-containing macrolides, and 2 is the β-dicarbonyl tautomer with a spiroepoxide at the α-site of the lactone ring.

3-oxa-5-carba analogues of β-lactam antibiotics

Abstract The syntheses of some 3-oxa-l-azabicyclo[4.2.0]octan-8-one carboxylic acid salts is described using Hg+2-assisted intramolecular cyclization of an allyl-azetidinone alcohol.

Isolation and characterization of 4-epi-vancosamine

Abstract Methanolysis of glycopeptides from the A82846 complex with 1.5 N HCl in methanol gives the 2,3,6-trideoxy amino sugar 4- epi -vancosamine, 1 ; this is the first isolation of 1 from a natural product. The structure elucidation is based on NMR studies of the N , O -dibenzoyl methyl glycoside anomers 2 and 3 .