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Biomedical subjects

J M Stewart

Publications and source records attributed to J M Stewart.

At least 73 records · Page 4Linked to original sources
PubMed1997

Potent, long-acting, orally-active bradykinin antagonists for a wide range of applications.

Actions of bradykinin (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg; BK) are mediated by constitutively expressed B2 receptors, that require the full BK peptide chain, and by B1 receptors, induced in inflammation, that use BK(1-8) as ligand. In addition to many physiological and pathophysiological functions, the growth factor activity of BK evidently allows it to act as an autocrine stimulant for small cell lung cancer. A new group of BK antagonists containing the novel amino acid a-(2-indanyl)glycine provides extremely potent broad-spectrum as well as selective antagonists for all these functions.

Bradykinin↗
PubMed1997

Oral activity of peptide bradykinin antagonists following intragastric administration in the rat.

This study has investigated the oral activity, following intragastric administration, of three potent and long-acting peptide-based bradykinin antagonists, HOE-140, B9430, and CP-0597, in the anesthetized rat, using bradykinin-induced hypotension. Two of the three bradykinin antagonists, B9430 and HOE-140, but not CP-0597, were found to be active following intragastric administration, producing dose-dependent (1, 3, and 10 mg/kg) and selective inhibition of bradykinin-induced hypotension. At a dose of 10 mg/kg, the inhibition of bradykinin-induced hypotension occurred within 15 min and lasted for at least 2 h, which was the duration of the experiment. HOE-140 and CP-0597, 10 micrograms/kg i.v., produced significant inhibition of bradykinin-induced responses that lasted for 60 min. B9430, 10 micrograms/kg i.v., produced a significantly greater inhibition than HOE-140 and CP-0597, this inhibition being significant for the duration of the experiment (2 h) compared with saline controls. Considering the close chemical structure of CP-0597 compared with HOE-140 and B9430, it is not clear as to why CP-0597 was inactive via the intragastric route. This is the first demonstration of the oral activity of peptide-based bradykinin antagonists following intragastric administration in the rat.

Administration, Oral↗
PubMed1997

Potent, long-acting bradykinin antagonists for a wide range of applications.

Actions of bradykinin (Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg; BK) are mediated by constitutively expressed B2 receptors (which require the full BK peptide chain) and by B1 receptors (which require BK (1-8) as ligand) that are induced in inflammation. BK has many functions in normal and pathological physiology, including initiation of most, if not all, inflammation. BK also evidently functions as an autocrine stimulant for growth of small cell lung cancer (SCLC). A new group of BK antagonists containing the novel amino acid alpha-(2-indanyl)glycine (Igl) provides both broad-spectrum and selective antagonists for all these functions. As examples, D-Arg-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic-Arg (B9430) is an extremely potent and long-acting antagonist of both B1 and B2 receptors, is stable against endogeneous kininase enzymes, and is active in various in vivo models, including by intragastric administration. Acylation of B9430 with dehydroquinuclidine-2-carboxylic acid (Dhq) gives B9562, a highly selective B2 antagonist. In contrast, Lys-Lys-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic (B9858) is a highly potent and selective B1 antagonist. The dimer of B9430 linked at the amino terminus with suberimide is a potent selectively cytotoxic agent for SCLC cells. Results with these peptides suggest that a new generation of antiinflammatory and anticancer drugs may be at hand.

Amino Acid Sequence↗
PubMed1996

Helix propensities of basic amino acids increase with the length of the side-chain.

Helix formation in a 17-residue alanine-lysine peptide and analogous peptides with specific lysine --> X substitutions, where X is 2,3-diamino-L-propionic acid, 2, 4-diamino-L-butyric acid or L-ornithine, have been examined using circular dichroism measurements. The dependence of helix content on X, its position in the sequence, and the number of lysine --> X substitutions are reasonably well described by using the Lifson-Roig theory modified to include N-capping, without explicitly considering charge-helix dipole interactions. The helix propensities for these basic amino acids increase with the length of the side-chain in the rank order 2,3-diamino-L-propionic acid < 2,4-diamino-L-butyric acid < ornithine < lysine. This parallels the increase in helix propensities with side-chain length of other polar and charged amino acids.

Amino Acids↗
PubMed1996

An NMR, CD, molecular dynamics, and fluorometric study of the conformation of the bradykinin antagonist B-9340 in water and in aqueous micellar solutions.

A detailed NMR, CD, fluorometry, and molecular modeling study of a novel bradykinin antagonist B-9340, containing a novel amino acid D-Igl (alpha-(2-indanyl)glycine) at position 7, was carried out. The sequence of B-9340 is D-Arg0-Arg1-Pro2-Hyp3-Gly4-Thi5-Ser6-D- Igl7-Oic8-Arg9, where Hyp is hydroxyproline, Thi is beta-(2-thienyl)alanine, and Oic is (3aS,7aS)-octahydroindole-2-carboxylic acid. The CD results exhibit a striking effect of SDS on the spectrum of the BK antagonist, indicating that interaction with the surfactant induces a folded peptide structure. The interaction of this antagonist with phosphatidylinositol was monitored by fluorometry, indicating that the interaction of the peptide with the lipid is cooperative, and gives a Hill coefficient of 2.3. The two-dimensional proton NMR measurements indicate that B-9340 has no stable secondary structure in water solution and contains about 10-15% cis peptide bonds arising from Pro2, Hyp3, and Oic8. In SDS micelles, NMR reveals the existence of two beta-turns based on a number of medium-range connectivities that were useful for molecular modeling. The actual molecular modeling and dynamic runs were performed on B-9340 in an environment consisting of a layer of octyl sulfate anions and water. Ther results indicate that the structure of B-9340 in a micellar environment is characterized by a nonideal betaII-turn comprising residues Pro2 to Thi5, a nonideal betaII'-turn comprising residues Ser6-Arg9, and broad folding in the middle part of the molecule. The structure is stabilized by several hydrogen bonds and by a salt bridge between the guanidine moiety of Arg1 and the carboxyl group of Arg9, whereas the middle part of the peptide is buried in the micelle. The structure is deposited as Brookhaven PDB file 1 BDK.

Amino Acid Sequence↗
PubMed1996

Highly selective bradykinin agonists and antagonists with replacement of proline residues by N-methyl-D- and L-phenylalanine.

For further studies on the structural and conformational requirements of positions 2,3, and 7 in the bradykinin sequence, we replaced the proline residues by the more hydrophobic and conformationally restricted N-methyl-L- and D-phenylalanine (NMF). The biological activities of the new analogs were evaluated on rat uterus, guinea pig ileum, and guinea pig lung strip. Receptor binding of the analogs was studied in membranes from rat uterus and guinea pig ileum. Influence of bradykinin analogs on the release of cytokines from mouse spleen cell cultures was also measured. Bradykinin analogs were synthesized by the solid phase method, using Boc strategy on PAM or Merrifield resins. The best results in the formation of the N-methylamide bond were obtained with the coupling reagent PyBrop. In position 7 the substitution of D-Phe by D-NMF, retaining the configuration of the amino acid, converts bradykinin antagonists into agonists. The bradykinin analogs with D-NMF at position 7 gave the highest known tissue selectivity for rat uterus among agonists. [L-NMF(2)]bradykinin has moderate agonist activity on rat uterus but antagonist activity on guinea pig lung strip. It represents a new antagonist for B(2) receptors without any replacement at position 7. The same analog completely inhibits bradykinin-evoked cytokine expression by mononuclear cells.

Amino Acid Sequence↗
PubMed1996

Familial cerebral cavernous angioma: a gene localized to a 15-cM interval on chromosome 7q.

Cerebral cavernous angiomas are collections of closely clustered vessels without intervening normal brain parenchyma, with microscopic evidence of hemorrhage, frequently multiple; they are best visualized with magnetic resonance imaging. Familial cerebral cavernous angioma occurs as an autosomal dominant disorder, although carriers of the gene are often asymptomatic. Recently, a gene responsible for familial cerebral cavernous angioma in a large Hispanic kindred was mapped to human chromosome 7q11-22, representing a large segment of DNA containing approximately 33 cM (about 33 million base pairs). This distance did not allow more restricted isolation of the region containing the familial cerebral cavernous angioma gene. In this report, we present a large white kindred with familial cerebral cavernous angioma and confirm the mapping to 7q11-22, including the genetic markers D7S558/D7S1789 and D7S804. Recombination between several markers in the region suggests that the candidate region is distal to D7S804. Combining our results with those previously published, we suggest that the gene is likely to reside within a 15-cM region bounded by markers D7S660 and D7S558/D7S1789. These results should assist the further refinement of the candidate region for familial cerebral cavernous angioma and facilitate the search for the gene.

Brain↗
PubMed1996

A benchmark concentration for carbon disulfide: analysis of the NIOSH carbon disulfide exposure database.

A statistical analysis of the NIOSH (National Institute for Occupational Safety and Health) carbon disulfide (CS2) exposure database was conducted for purposes of establishing a benchmark concentration (BMC) for CS2. The analysis addressed the effects of CS2 exposure on the peripheral nervous system and on ischemic heart disease risk factors. The BMC is based on models relating response to exposure determined from statistical analysis of the continuous exposure data for individuals recorded in the NIOSH database. The results demonstrate that changes in the responses associated with increases in CS2 exposure at levels represented in the NIOSH database are relatively small after adjustment for confounders. The only response variables that had statistically significant relationships with CS2 were the peroneal nerve MCV (motor conduction velocity) and the peroneal nerve amplitude ratio. Based on these results, BMCs of 16.2 and 18.5 ppm were derived for MCV and amplitude ratio, respectively.

Carbon Disulfide↗
PubMed1996

Comparative profile of novel potent bradykinin antagonists at human B1 and B2 receptors.

We have undertaken a comparative pharmacological profile of novel bradykinin antagonists on human B1 and B2 receptor binding and functional assays. We found that there was an excellent correlation between binding and functional data for the compounds at the B1 receptor. In general, although there was a good correlation between the binding and functional data at the B2 receptor there was a greater degree of scatter in the correlation, particularly with compounds that possessed both B1 and B2 binding and antagonist activity. Of the compounds that were highly selective for the B2 receptor, CP-0597 had high binding activity but showed an unexpectedly low functional potency in the human ileum. The reason for this discrepancy is unclear. In general we found that binding activity with both the B1 and B2 antagonist compounds correlated well with their functional activity.

Adult↗
PubMed1996

A new generation of bradykinin antagonists.

Bradykinin B2 receptors are constitutively expressed, and require the entire peptide chain of bradykinin for recognition. Expression of B1 receptors is induced in inflammation; they recognize BK-(1-8). Heretofore blockade of all the actions of bradykinin required two different antagonists, one for each class of receptors. The new antagonists described here are full chain antagonists having high potency on B2 receptors, but they are also very potent antagonists for B1 receptors. They are highly resistant to kininases and show very long action in vivo. These antagonists contain the novel amino acid alpha-(2-indanyl)glycine (IgI) at positions 5 and 7. The peptide DArg-Arg-Pro-Hyp-Gly-Igl-Ser-DIgl-Oic-Arg (designated B9430) shows all these desirable characteristics. It represents a new class of bradykinin antagonist peptides.

Amino Acid Sequence↗
PubMed1996

Use of Dental Coping Beliefs Scale to measure cognitive changes following oral hygiene interventions.

This study employed a recently developed questionnaire, the Dental Coping Beliefs Scale (DCBS), to evaluate the effect of oral hygiene interventions on dental beliefs. The DCBS was administered to 100 subjects. Compared to an untreated control group, there was an increase in the ability to improve oral health through self-effort for the three experimental interventions: Attention (Al), Education (El) and Cognitive Behavioral (CBI). When the Dental Coping Beliefs Scale was divided into scales of Internal Locus of Control, External Locus of Control, Self-Efficacy, and Oral Health Beliefs, additional changes were evident. For the CBI Group, all four scales changed significantly between baseline measurement and post-intervention toward beliefs favoring control and prevention of dental disease using brushing and flossing. For the A and E groups, three scales paralleled the results of the CBI: Internal Locus of Control and Self-Efficacy increased and External Locus of Control decreased after the intervention. However, unlike the CBI, Oral Health Beliefs did not significantly change. Overall, for all experimental groups, there was a shift from external locus of control beliefs to internal beliefs. The untreated Control Group showed no changes across the five weeks. This study was supported by a VA Medical Research Service Merit Review Award.

Adaptation, Psychological↗