Biomedical Polypeptides — A Wellspring of Pharmaceuticals

Samanen, James

doi:10.1007/978-1-4757-0405-1_12

Cited by 11 publications

(11 citation statements)

References 226 publications

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“…Cross-linked casein microspheres have attracted attention recently as carriers for cytotoxic drugs (Chen et a1 1987;Jayakrishnan et a1 1993;Knepp et a1 1993). It is also reported that removal of the free amino groups in the protein reduces its proteolytic susceptibility (Samanen 1985). Aldehyde cross-linking of casein would result in the removal of most of the free amino groups in the protein and this is expected to impart stability to the microspheres in the gastrointestinal tract, as we have demonstrated in this work.…”

Section: Resultssupporting

confidence: 52%

Glutaraldehyde Cross-linked Bovine Casein Microspheres as a Matrix for the Controlled Release of Theophylline: In-vitro Studies

Latha

Jayakrishnan

1994

Journal of Pharmacy and Pharmacology

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A controlled release dosage form of theophylline in the form of microspheres using the milk protein casein as the matrix is described. Glutaraldehyde cross-linking of an aqueous alkaline solution of the protein containing the drug, dispersed in a mixture of dichloromethane/hexane having ca. 1% of an aliphatic polyurethane as the suspension stabilizer, led to the formation of the drug-loaded microspheres. Drug incorporation efficiency of around 80% could be achieved by the technique. Release profiles of the drug were examined in simulated gastric and intestinal fluids at 37 degrees C. It was observed that the release was diffusion-controlled and followed the Higuchi model. Release characteristics were influenced by the cross-linking density, particle size and the extent of loading. Data obtained indicate that the natural milk protein casein could be used as a matrix for sustained release oral dosage forms.

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Section: Resultssupporting

confidence: 52%

Glutaraldehyde Cross-linked Bovine Casein Microspheres as a Matrix for the Controlled Release of Theophylline: In-vitro Studies

Latha

Jayakrishnan

1994

Journal of Pharmacy and Pharmacology

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“…The low potency and short duration that has been observed with Ac-RGDS-NH2 diminish the therapeutic value of the native peptide fragment. These are common liabilities with native peptides, however, that have often been overcome through structure-activity studies leading to analogs with dramatically improved activity (26). We anticipate that the application of rational drug design principles to the RG D S pharmacophore will yield potent RGDS-like antithrombotic agents with wide-spread utility.…”

Section: Discussionmentioning

confidence: 99%

Demonstration of Ac-Arg-Gly-Asp-Ser-NH2 as an Antiaggregatory Agent in the Dog by Intracoronary Administration

Shebuski¹,

Berry²,

Bennett³

et al. 1989

Thromb Haemost

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SummaryThis study compared the anti-platelet effect of Ac-RGDS-NH2 which is a peptide fragment from fibrinogen to Ac-RGES-NH2 in which the aspartic acid (D) of Ac-RGDS-NH2 has been replaced by glutamic acid (E). When Ac-RGDS-NH2 was infused intracoronary at concentrations of 100–400 mM, acute platelet dependent thrombus formation in the dog coronary artery was inhibited. However, infusion of Ac-RGES-NH2 intracoronary at similar concentrations to Ac-RGDS-NH2 failed to inhibit platelet dependent thrombus formation in the dog. Ac-RGDS-NH2 and Ac-RGES-NH2 were also tested for their ability to inhibit collagen-induced platelet aggregation in vitro. Ac-RGDS-NH2 elicited concentration-dependent inhibition of collagen-induced aggregation with no effect of Ac-RGES-NHz otr collagen-induced platelet aggregation. Thus, Ac-RGDS-NH2 is an effective antiplatelet agent after intracoronary administration in the dog and also inhibits collagen-induced platelet aggregation in vitro. Ac-RGDS-NH2 is a specific inhibitor of platelet aggregation as replacement of the aspartic acid in Ac-RGDS-NH2 with glutamic acid results in complete loss of biological activity.

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“…Differences in development of peptide drugs and nonpeptide drugs Many drug discovery efforts today begin with a receptor that has been identified through the study of a pathological process using the tools of molecular biology. The endogenous ligand for these new therapeutic targets are quite often peptides or proteins (Samanen 1985), hence the ever increasing concern about peptidergic drugs and the attendant issue of oral bioavailability of peptidergic molecules.…”

Section: Introduction: Peptide Drugs Vs Nonpeptide Drugsmentioning

confidence: 99%

Chemical Approaches to Improve the Oral Bioavailability of Peptidergic Molecules

Samanen

Wilson

Smith

et al. 1996

Journal of Pharmacy and Pharmacology

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This review discusses both tools and strategies that may be employed as approaches towards the pursuit of orally active compounds from peptidergic molecules. Besides providing a review of these subjects, this paper provides an example of how these were utilized in a research programme at SmithKline Beecham involving the development of orally active GPIIb/IIIa antagonists. The tools for studying oral drug absorption in-vitro include variants of the Ussing chamber which utilize either intestinal tissues or cultured epithelial cells that permit the measurement of intestinal permeability. Example absorption studies that are described are mannitol, cephalexin, the growth hormone-releasing peptide SK&F 110679 and two GPIIb/IIIa antagonist peptides SK&F 106760 and SK&F 107260. With the exception of cephalexin, these compounds cross the intestine by passive paracellular diffusion. Cephalexin, on the other hand, crosses the intestine via the oligopeptide transporter. Structure-transport studies are reviewed for this transporter. The tools for studying oral drug absorption in-vivo involve animals bearing in-dwelling intestinal or portal vein catheters. A study of the segmental absorption of SK&F 106760 is provided. The review concludes with two chemical strategies that may be taken towards the enhancement of oral bioavailability of peptidergic molecules. The first strategy involves the chemical modification of peptides which enhance intestinal permeability, specifically the modification of amide bonds. The second strategy involves the design of compounds bearing nonpeptide templates, which are more amenable to the discovery of compounds with oral activity, from peptide pharmacophore models. An example is given regarding the discovery of SB 208651, a potent orally active GPIIb/IIIa antagonist, designed from the peptides SK&F 106760 and SK&F 107260.

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Biomedical Polypeptides — A Wellspring of Pharmaceuticals

Cited by 11 publications

References 226 publications

Glutaraldehyde Cross-linked Bovine Casein Microspheres as a Matrix for the Controlled Release of Theophylline: In-vitro Studies

Glutaraldehyde Cross-linked Bovine Casein Microspheres as a Matrix for the Controlled Release of Theophylline: In-vitro Studies

Demonstration of Ac-Arg-Gly-Asp-Ser-NH2 as an Antiaggregatory Agent in the Dog by Intracoronary Administration

Chemical Approaches to Improve the Oral Bioavailability of Peptidergic Molecules

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