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Biomedical subjects

D A Baron

Publications and source records attributed to D A Baron.

At least 19 recordsLinked to original sources
PubMed1992

Enhancement of nasal delivery of a renin inhibitor in the rat using emulsion formulations.

Nasal absorption of O-(N-morpholino-carbonyl-3-L-phenylaspartyl-L-leucinamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane (I), a renin inhibitor, was evaluated in two rat nasal models, one involving surgery and the other requiring no surgical intervention. Oleic acid/monoolein emulsion formulations were tested along with a control PEG 400 solution. The percent absolute bioavailability of the compound was enhanced from 3-6% (PEG 400 solution) to 15-27% when the emulsion formulations were used. The different nasal model techniques (with and without surgery) did not produce any statistical difference in the absolute bioavailability values for I. Emulsion formulations did not produce appreciable damage as assessed morphologically. It is suggested that emulsion formulations containing membrane adjuvants such as oleic acid and monoolein can be used to enhanced the nasal delivery of low-bioavailable, lipid-soluble drugs.

Administration, Intranasal↗
PubMed1992

Anxiety disorders seen in primary care.

This paper presents a clinical overview of syndromal anxiety and its treatment as seen in a family practice setting, where many patients with anxiety disorders are first seen. Panic disorder, social phobia, agoraphobia, and generalized anxiety disorder are the ones most often seen by such physicians. Treatment options include psychotherapy, behavioral-cognitive therapy, and pharmacotherapy. The primary care physician may choose from the benzodiazepines or the heterocyclic antidepressants or both. The monoamine oxidase inhibitors have also proved very useful in the treatment of panic disorder and social phobia, but probably should be used only by physicians with experience with this type of medication.

Anxiety Disorders↗
PubMed1991

Differential effect of pH on thromboxane A2/prostaglandin H2 receptor agonist and antagonist binding in human platelets.

The effects of changes in pH on the binding of agonists and antagonists to the human platelet thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptor were determined. Competition binding studies were performed with the TXA2/PGH2 mimetic [1S-1 alpha,2 beta (5Z), 3 alpha(1E,3R*),4 alpha)]-7-[3-(3-hydroxy-4'-iodophenoxy)-1-buteny) 7-oxabicyclo-[2.2.1]-heptan-2-yl]-5-heptenoic acid ([125I]BOP). The pH optimum for binding of [125I] BOP to washed human platelets was broad with a range of pH 4-6 in contrast to that of the TXA2/PGH2 receptor antagonist 9,11-dimethyl-methano-11,12-methano-16-(3-iodo-4-hydroxyl)-13-aza-15 alpha,beta-omega-tetranorthromboxane A2 ([125I]PTA-OH) which was 7.4. Scatchard analysis of [125I]BOP binding in washed platelets at pH 7.4, 6.0, and 5.0 revealed an increase in affinity (Kd = 1.16 +/- 0.06, 0.64 +/- 0.09, and 0.48 +/- 0.05 nM, respectively) and an increase in the number of receptors (Bmax = 2807 +/- 415, 5397 +/- 636, and 7265 +/- 753 sites/platelet, respectively). The potency of I-BOP to induce shape change in washed platelets at pH 6.0 was also significantly increased from an EC50 value of 0.34 +/- 0.016 nM at pH 7.4 to 0.174 +/- 0.014 nM at pH 6.0 (n = 6, p less than 0.05). In contrast, the EC50 value for thrombin was unaffected by the change in pH. In competition binding studies with [125I]BOP, the affinity of the agonists U46619 and ONO11113 were increased at pH 6.0 compared to 7.4. In contrast, the affinity of the TXA2/PGH2 receptor antagonists I-PTA-OH, SQ29548, and L657925 were either decreased or unchanged at pH 6.0 compared to 7.4. Diethyl pyrocarbonate and N-bromosuccinimide, reagents used to modify histidine residues, reversed the increase in affinity of [125I]BOP at pH 6.0 to values equivalent to those at pH 7.4. In solubilized platelet membranes, the effects of NBS were blocked by coincubation with the TXA2/PGH2 mimetic U46619. The results suggest that agonist and antagonist binding characteristics are different for the TXA2/PGH2 receptor and that histidine residue(s) may play an important role in the binding of TXA2/PGH2 ligands to the receptor.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1991

Effects of the prostaglandin analogue misoprostol on inflammatory mediator release by human monocytes.

The effect of misoprostol (M) on IL-1 beta, TNF-alpha, and lipid mediator release (assessed by RIA) by adherent (assessed by electron microscopy) human monocytes were studied in vitro. Human monocytes stimulated with E. Coli-derived lipopolysaccharide showed an increase in both IL-1 beta and TNF-alpha release. Incubation of the monocytes with LPS and M (18 hrs.), resulted in a reduction of both IL-1 beta and TNF-alpha levels. Leukotriene B4 levels did not increase in response to LPS or M. LPS also caused an increase in thromboxane (TXB2). M decreased TXB2 levels. 6-keto PGF1 alpha (6KP). Incubation with LPS and M stimulated release. LPS caused an increase in PGE2 levels. M (100 microM) caused an increase in PGE2 levels, M (1 microM) had no effect on PGE2. These data suggest a possible immunomodulatory role for misoprostol in inflammatory diseases.

Escherichia coli↗
PubMed1991

Atrial natriuretic peptide inhibits oxidant-induced increases in endothelial permeability.

Chemically and enzymatically generated oxidants alter endothelial cell shape, increase macromolecular permeability across endothelial cell monolayers, and increase lung microvascular permeability. We examined the effect of ANP (atrial natriuretic peptide) on oxidant-induced injuries to bovine aortic endothelial cell monolayers and to isolated, perfused rabbit lungs. Treatment of cultured endothelial monolayers with glucose oxidase (1.4 U/ml) caused changes in cell shape characterized by a retraction of cells and the formation of numerous intercellular gaps. Glucose oxidase treatment also caused a reduction in F-actin stress fibers visualized by rhodamine-phalloidin fluorescence. Pretreatment (5 min) of the endothelial monolayers with ANP (10(-7) M) attenuated the oxidant-induced changes in cell shape and reduction in F-actin staining. In addition, ANP significantly (P less than 0.05) reduced increases in endothelial monolayer permeability to albumin resulting from glucose oxidase treatment. Oxidant-induced injury of isolated, perfused rabbit lungs produced pulmonary edema measured as an increase in lung weight. This increase in weight was significantly (P less than 0.05) inhibited by pretreatment of lungs with ANP (10(-7) M). Collectively, these results suggest that ANP may act to preserve endothelial barrier function and reduce edema formation caused by oxidant injury.

Animals↗
PubMed1991

Dementia in patients with the acquired immunodeficiency syndrome.

Central nervous system (CNS) manifestations are common in patients with the acquired immunodeficiency syndrome (AIDS). The most common CNS syndrome is a dementing illness referred to as the AIDS dementia complex, in which motor and cognitive changes may also be seen. Neurodiagnostic studies are fairly characteristic, though highly nonspecific. Dementia may precede overt manifestations of AIDS, and either an insidious or a fulminant course may be seen. Appropriate management of the patient with AIDS includes differentiating dementia from psychologic responses to the disease.

AIDS Dementia Complex↗
PubMed1991

Monochloramine, a neutrophil-derived oxidant, stimulates rat colonic secretion.

Neutrophil-derived oxidants may be involved in inflammatory bowel disease. Stable oxidants formed by halogenation of primary amines (e.g., monochloramine, NH2Cl) are extremely potent and may be of major importance in the pathophysiological response in inflammatory bowel disease. We tested the effects of NH2Cl relative to other oxidants on muscle-stripped rat colon under short-circuit conditions. Serosal addition of the oxidants evoked a concentration-dependent increase in short-circuit current (Isc). The EC50 values were 3.2 microM for NH2Cl, 6.5 microM for HOCl and 6.5 microM for H2O2. Responses to NH2Cl and H2O2 were abolished by removal of Cl- or Ca++. Unidirectional 36Cl- flux measurements showed that both oxidants (50 microM) evoked significant decreases in net chloride absorption. Tetrodotoxin (0.5 microM) and atropine (0.5 microM) partially inhibited the initial phase of the response to 50 microM NH2Cl; tetrodotoxin completely inhibited and atropine partially inhibited the response to 50 microM H2O2. Piroxicam (5 microM) inhibited the increase in Isc to 50 microM NH2Cl and H2O2 by 20-45% and 90%, respectively. Serosal prostaglandin E2 levels were significantly increased after the addition of 50 microM NH2Cl and H2O2. The morphological response to NH2Cl consisted of changes in mucosal depth and crypt architecture. In conclusion, at concentrations found in inflamed tissue, both NH2Cl and H2O2 increase Isc probably by stimulating release of arachidonate metabolites and neurotransmitter(s). NH2Cl also may act directly on the epithelial cell to stimulate Isc and evoke Cl- secretion.

Animals↗
PubMed1990

Extrusion of colonic epithelial cells in vitro.

Rat colonic mucosae fixed in situ in Ussing chambers provided a model of the extrusion of absorptive enterocytes and less commonly of goblet and enteroendocrine cells. The cells were lost at extrusion zones midway between crypt mouths. Even in mucosae in which the number of extruding cells was large, epithelial continuity was maintained as evaluated morphologically and electrophysiologically. Beneath points of remaining contact between desquamating cells and the epithelial sheet, microfilaments of the terminal web formed band-like structures linking adjacent junctional complexes. Freeze-fracture replicas disclosed extensive macular regions of tight junction strands in the plasma membranes of desquamating cells. Tight junctions between newly neighboring cells were often irregular and often occurred beneath the terminal web region. Dithiothreitol enhanced cell loss and increased basal epithelial conductance, but histological continuity was maintained and the mucosae continued to respond typically to bradykinin. These observations suggest that during the loss of senescent enterocytes, tight junctions are maintained; old junctional elements are lost, and tight junctions are formed between remaining adjacent cells. This model offers a means to study the synthesis and turnover of tight junctions and the maintenance of the colonic epithelial barrier.

Animals↗
PubMed1990

Effects of prostaglandin E1 on platelet attenuation of oxidant-induced edema in isolated rabbit lungs.

Numerous studies suggest that platelets may contribute to preservation of normal endothelial cell permeability in models of lung injury. We have previously shown that washed human platelets prevent xanthine oxidase-induced edema in the isolated perfused lung and that protective mechanisms depend on the platelet glutathione redox cycle. It is uncertain, however, whether platelets preserve endothelial function by reducing toxic oxygen metabolites or by aggregating and releasing endothelial cell supportive factors-an activity that may require the glutathione redox cycle. In this study, we present data demonstrating that platelet prevention of oxidant lung injury occurs independent of platelet aggregation and release. Isolated rabbit lungs perfused with a cell-free medium were instilled with purine (2 mmol/L) and xanthine oxidase (0.003 U/ml) to generate oxidant lung edema. The infusion of washed human platelets (1 x 10(10) cells) prevented lung edema formation as measured by lung weight gain, wet-to-dry lung weight ratios, and lung histology. Incubation of platelets with prostaglandin E1 (PGE1), a potent inhibitor of platelet aggregation and release, did not inhibit platelet attenuation of lung edema. Additionally, with the instillation of PGE1 into the perfusate to further inhibit platelet aggregation, no prevention of lung protection by PGE1-treated platelets was seen when these results were compared with those from studies in which lungs were infused with xanthine oxidase and PGE1. Aggregometry studies documented that the inhibitory effect of PGE1 on platelet aggregation persisted for up to 60 minutes, which was the duration of the isolated lung protocol. We conclude that platelet aggregation and release of platelet factors is not required for platelet attenuation of oxidant lung edema.

Alprostadil↗
PubMed1989

Atrial and brain natriuretic peptides share binding sites in the kidney and heart.

We examined the distribution of binding sites for atrial natriuretic peptide (ANP) and the recently discovered brain natriuretic peptide (BNP) in rat kidney and heart by receptor autoradiography. In frozen kidney sections, both 125I-ANP and 125I-BNP exhibited localized binding to cortical glomeruli. The binding of each radiolabeled peptide was abolished by inclusion of either excess (1 microM) unlabeled ANP or excess unlabeled BNP, suggesting that ANP and BNP share cortical glomerular binding sites. In frozen cardiac sections, ANP and BNP binding sites were localized to the endothelium of the endomural channels and endocardium. As was the case for kidney, binding of each peptide at these sites was abolished by the presence of excess unlabeled ANP or BNP, suggesting that these natriuretic peptides share binding sites in the heart as well. To explore further the possibility that ANP and BNP utilize the same receptor(s), we performed competitive binding experiments using cultured pulmonary artery endothelial (CPAE) cells. ANP and BNP competitively displaced one another with equivalent IC50 values from CPAE cell binding sites. Furthermore, both ANP and BNP elevated the levels of cGMP, a putative second messenger for ANP, in these cells. These data are consistent with the observation that BNP, like ANP, causes a natriuresis and diuresis in rats, and suggest that BNP may possess other biological activities known for ANP.

Animals↗
PubMed1989

Atrial natriuretic peptide binding sites in the mammalian heart: localization to endomural vessels.

The distribution of binding sites for atrial natriuretic peptide in cardiac ventricles of several mammalian species, including rat and human, was determined by in vitro autoradiography. The results revealed a unique anatomic localization of atrial natriuretic peptide binding sites to endomural vessels (Thebesian vessels), which communicate directly with the ventricular chambers. Digital image analysis indicated that these vascular channels possessed binding site densities comparable to those of the renal glomeruli, a major target site for circulating atrial natriuretic peptide. In contrast, no specific labeling of branches of the coronary arteries and veins was detected. The discrete localization of atrial natriuretic peptide binding sites to this "primitive" cardiac circulatory system allows speculation as to the role of this hormone in the regulation of endocardial circulation during cardiac development, normal ventricular function, and in coronary insufficiency.

Adult↗
PubMed1989

Enhanced activity of the cardiac endocrine system during right ventricular hypertrophy.

In a model of pulmonary hypertension induced by a single injection of monocrotaline (MCT), we observed a time-dependent right ventricular hypertrophy, which became apparent in treated rats 21 days after administration of MCT and progressed through day 45. Associated with this right ventricular hypertrophy were time-dependent increases in ventricular levels of immunoreactive atrial natriuretic peptide (iANP). Forty-five days after MCT treatment, treated rats exhibited a 72-fold increase in right ventricular iANP levels and a 7-fold increase in left ventricular iANP levels. Hybridization analysis of total RNA extracted from cardiac tissue indicated that both atrial and ventricular ANP mRNA levels were elevated in treated rats. These data suggest that during pulmonary hypertension and cardiac hypertrophy the endocrine activity of the heart expands to include ventricular tissue. ANP binding site autoradiography revealed decreased binding site density in the kidney and hearts of treated rats at 49 days, consistent with the occurrence of desensitization/down-regulation. Enhanced ventricular ANP production may serve as a compensatory response to sustained elevation of pulmonary arterial pressure or may function as an autocrine/paracrine system regulating cardiac function. In either case, the effects of augmented ANP production may be subject to modulation by the status of ANP receptors in target organs and cells.

Animals↗
PubMed1989

Atriopeptin inhibition of thrombin-mediated changes in the morphology and permeability of endothelial monolayers.

To determine the role of endothelial atriopeptin (AP) receptors, we examined the effect of AP-III on the morphology and macromolecular permeability of monolayer cultures of bovine aortic endothelial cells. AP-III alone (10(-9)-10(-6) M) had no observable effect on the morphology of the monolayers or their permeability to 125I-labeled albumin. However, incubation of the endothelial monolayers with AP-III (10(-8)-10(-6) M) antagonized thrombin-induced (1 unit/ml) cell-shape change and the formation of intercellular gaps. AP-III also opposed the effect of thrombin on the distribution of actin filaments in the endothelial cytoskeleton. Further, thrombin caused a 2-fold increase in monolayer permeability to 125I-labeled albumin, which was abolished by 10(-8)-10(-6) M AP-III pretreatment. Taken together with the findings that AP-III exhibited specific and saturable binding in these cells, these data suggest that AP regulates endothelial permeability through a receptor-mediated process.

Actins↗
PubMed1988

Subcellular localization of a thromboxane A2/prostaglandin H2 receptor antagonist binding site in human platelets.

The subcellular localization of a binding site for the competitive thromboxane A2/prostaglandin H2 (TXA2/PGH2) antagonist, 9,11-dimethylmethano-11,12-methano-16-(3-iodo-4- hydroxyphenyl)-13,14-dihydro-13-aza-15 alpha beta-omega-tetranor TXA2 ([125I]-PTA-OH), was determined. Subcellular fractions of platelets were prepared by glycerol lysis or nitrogen cavitation, and were characterized by the use of enzymatic markers specific for plasma membranes, endoplasmic reticulum (dense tubular system), mitochondria, granules, and cytosolic constituents. The Kd and density of binding sites in the subcellular fractions were determined by Scatchard analysis of equilibrium binding data. The Kd and Bmax for [125I]-PTA-OH determined in the lysates were 49 +/- 11 nM and 4.1 +/- 1.7 pmol/mg protein respectively (N = 6). The Kd values were not significantly different in any of the fractions assayed. The binding sites were coenriched (4.5 +/- 0.66 fold) with the enzymatic markers for plasma membranes (3.7 +/- 0.5 fold) and dense tubular system (2.4 +/- 0.4 fold). The binding sites were not coenriched with markers for cytoplasmic constituents, mitochondria, or granules. The ability of the TXA2/PGH2 mimetic U46619 to compete with [125I]-PTA-OH for the binding site was also determined for the various subcellular fractions. The IC50 for U46619 was 5.4 +/- 1.2 microM in the lysate, and was not significantly different in the subcellular fractions. These data suggest that the binding site is the TXA2/PGH2 receptor described previously. These data are consistent with the notion that the putative TXA2/PGH2 receptor is localized in the plasma membranes and/or the dense tubular system.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1988

The amobarbital interview in a general hospital setting, friend or foe: a case report.

The amobarbital interview has been in use for over 50 years. Its clinical indications have been primarily as an aid in determining a diagnosis and in conducting psychotherapy. This article presents an overview of the procedure along with a brief historic perspective. A case is presented which highlights its potential clinical utility and shortcomings.

Adult↗
PubMed1988

Intestinal anaphylaxis: rapid changes in mucosal ion transport and morphology.

Anaphylactic reactions can be elicited by beta-lactoglobulin (beta LG) in the isolated colonic and ileal mucosae of guinea pigs fed cow milk. We have shown that these tissues respond to antigen challenge with a rapid rise in short-circuit current (SCC) due to net chloride secretion in the colon and less well-characterized ion movements in the ileum. Here, tissues were characterized morphologically at or near the peak of the SCC response 2 min after antigen addition. These sensitized preparations, or naive tissues passively sensitized with immune sera and challenged with beta LG, showed numerous structural alterations that correlated significantly with the change in SCC. In the ileum, these changes included compound exocytosis of mucous granules from goblet cells of crypts but not of villi and a decrease in the intercellular space of the crypts. In contrast, colonic goblet cells of both crypts and luminal surface showed no evidence of secretion, but crypt architecture was reproducibly and characteristically altered. Thus antigen challenge of intestinal mucosa results in temporally related but diverse changes in morphology and ion transport.

Anaphylaxis↗
PubMed1987

Death notification.

Death notification--informing the deceased's family of an unexpected death--is a singularly stressful task common to medical personnel, clergy, and police. We surveyed by questionnaire a group of 50 Los Angeles Police Department homicide detectives, 21 of whom were subsequently interviewed by telephone. The detectives stated that their initial apprehension stemmed from feeling unprepared. Identification with victims' families was common and compounded the stress. One prevalent worry concerned the possible reactions of the family upon hearing the news, especially the risk of a violent attack on the police officer. Several coping styles were recognized. Our findings suggest that the repetitive performance of this continuously stressful task may be a prominent and underappreciated contribution to occupational burnout.

Death↗