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Biomedical subjects

D D Miller

Publications and source records attributed to D D Miller.

At least 19 recordsLinked to original sources
PubMed2006

Antagonism by imidazoline-type drugs of muscarinic and other receptors in the guinea-pig ileum.

1 Several imidazolines were examined for the antagonism of muscarinic (M3) and other receptors on the isolated ileum of guinea-pig. The effect of the muscarinic agonist, carbachol was competitively antagonized by oxymetazoline at 10(-5) m. A dissociation constant (KB) of 3.6 microm for the antagonist was calculated. At higher concentrations, 3 x 10(-5) and 10(-4) m, of the antagonist, the agonist dose-response curve was shifted to the right with a decrease in the maximum effect. Thus, a non-competitive block occurred at higher concentrations of oxymetazoline. Blockade of histamine H, and serotonin receptor-mediated responses by oxymetazoline were also of a non-competitive type. 2 Naphazoline at 10(-4) m shifted the dose-response curves of carbachol and serotonin to the right by two- and 15-fold, respectively. The maximum contraction of the agonist was not affected. Tolazoline also had a weak antihistaminic activity. At similar concentration; tetrahydrozoline clonidine and phentolamine at 10(-5) m produced two-, three- and four-fold shift of the carbachol dose-response curve without significant changes in the maxima. Neither methoxamine, p-amino-clonidine nor cimetidine blocked the responses of carbachol. 3 The isosteric nature of the alpha-adrenoceptor agonist, oxymetazoline and some imidazolines with carbachol, in part, explains its molecular competition at the muscarinic M3 receptor of the guinea-pig ileum. Surprisingly, contractile effects of carbachol (M3), histamine (H1) or serotonin (5HT3/5HT4) were not influenced by methoxamine, tetrahydrozoline, p-amino clonidine and cimetidine.

Animals↗
PubMed2004

Pharmacokinetics of S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro- 3-trifluoromethyl-phenyl)-propionamide in rats, a non-steroidal selective androgen receptor modulator.

1: S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide (also known as S-4) is a non-steroidal selective androgen receptor modulator demonstrating tissue-selective androgenic and anabolic effects. The purpose of the present study was to examine the systemic pharmacokinetics, elimination and oral bioavailability of S-4 in rats. 2: Thirty-five male Sprague-Dawley rats weighing approximately 250 g were randomly assigned to one of seven treatment groups. Intravenous doses of 0.5, 1, 10, and 30 mg kg(-1) were given via a jugular catheter. Oral doses of 1, 10 and 30 mg kg(-1) were administered via gavage. Plasma concentrations were determined using a validated high-performance liquid chromatography or by a high-performance liquid chromatography/mass spectrometry method. 3: Clearances ranged between 1.0 and 2.1 ml min(-1) kg(-1) and varied with dose. The volume of distribution was approximately 0.448 l kg(-1) in all treatment groups. Oral bioavailability was also dose dependent, with the lower doses showing complete oral bioavailability. The half-life of S-4 over the dose range tested was between 2.6 and 5.3 h. 4: It was demonstrated that S-4 is rapidly absorbed, slowly cleared, and has a moderate volume of distribution in rats. The pharmacokinetics and oral bioavailability of S-4 indicate that it is an excellent candidate for clinical development.

Acetamides↗
PubMed2004

Calcium, zinc, and iron bioavailabilities from a commercial human milk fortifier: a comparison study.

Adding human milk fortifiers (HMF) to human milk (HM) is one way of overcoming the nutrient deficits found in the latter. In this study, the bioavailabilities of calcium, zinc, and iron in S-26/SMA HMF added to HM were compared with those in HM fortified with various bovine milk proteins: alpha-lactalbumin, colostrum, caseinate, casein phosphopeptides, and whey protein concentrate. The bioavailability of each mineral was assessed using an in vitro digestion/Caco-2 cell culture model. Calcium and zinc uptake by the cells was traced with radioisotopes; iron uptake was assessed via cell ferritin levels. Samples were prepared on an equal protein content basis and with added calcium, but no zinc or iron was added. Results revealed that calcium uptake from HM + S-26/SMA was not different from any of the HM fortified with the bovine milk proteins, except for unfortified HM and HM + colostrum in which calcium uptake was significantly lower (-89 and -38%, respectively). Uptake of zinc and iron were significantly higher for HM + S-26/SMA than for the other HM + fortifiers.

Animals↗
PubMed2001

Structural elements of the osteopontin SVVYGLR motif important for the interaction with alpha(4) integrins.

The osteopontin SVVYGLR motif binds the integrins alpha(4)beta(1) and alpha(9)beta(1). We show that alpha(4)beta(7) also interacts with this motif and that an SVVYGLR-OH peptide antagonises the alpha(4)beta(7) MAdCAM interaction. The important elements of this motif required to bind alpha(4)beta(1) and alpha(4)beta(7) were probed using a series of mutated peptides based around SVVYGLR. Leu167 is important for the interaction with alpha(4) integrins, as is the C-terminal carboxylic acid of Arg168 exposed by thrombin cleavage. The importance of the acidic group means that SVVYGLR has structural elements in common with other alpha(4) integrin-binding motifs and suggests why thrombin cleavage activates this motif.

Amino Acid Motifs↗
PubMed2001

Significance of hydrogen bonding at the S(1)' subsite of calpain I.

alpha-Ketohydroxamates were synthesized as bioisosteres of alpha-ketoamides. The alpha-ketohydroxamates were generally more potent than the corresponding alpha-ketoamides. The potency of the compounds suggests that hydrogen bonding and steric bulk of substituents on the nitrogen atom of the ketoamide moiety influence calpain inhibition.

Calpain↗
PubMed2001

Homology modeling using multiple molecular dynamics simulations and docking studies of the human androgen receptor ligand binding domain bound to testosterone and nonsteroidal ligands.

To facilitate the rational design of novel and more potent androgen receptor ligands, three-dimensional models for the human androgen receptor ligand binding domain bound to testosterone have been developed. These models of the androgen receptor were based on the crystal structure of the highly homologous human progesterone receptor ligand binding domain. The homology modeled androgen receptor was refined using unrestrained multiple molecular dynamics simulations in explicit solvent. Key H-bonding partners with the 17-hydroxy group and 3-keto group of testosterone are Asn705 and Thr877, and Gln711 and Arg752, respectively. These models show the presence of a unique unoccupied cavity within the androgen receptor binding pocket which may be valuable in the development of novel selective androgen receptor ligands. A qualitative analysis of amino acid mutations within the hAR binding pocket that affect ligand binding are consistent with these androgen receptor models. In addition to testosterone, the binding modes of several hydroxyflutamide-like nonsteroidal ligands for the androgen receptor are investigated using flexible docking with FlexX followed by refinement of the initial complexes with molecular dynamics simulations. These docking studies indicate that Asn705 is an important determinant in binding hydroxyflutamide and its derivatives by participating in H-bond interactions with the alpha-hydroxy moiety of these ligands. In addition, the nitro functionality mimics the 3-keto group of the natural ligand testosterone and is involved in H-bonding interactions with Gln711 and Arg752. From these docking studies, we suggest a mechanism for the enantioselective binding of chiral hydroxyflutamide derivatives and expand upon the previously reported structure-activity relationship for hydroxyflutamide and its derivatives.

Amino Acid Substitution↗
PubMed2001

Direct quantitative analysis of lysophosphatidic acid molecular species by stable isotope dilution electrospray ionization liquid chromatography-mass spectrometry.

In order to better understand the role of lysophosphatidic acid (LPA) in physiology and pathophysiology, it is necessary to accurately determine the molecular species and amounts of LPA in biological samples. We have developed a stable-isotope dilution, liquid chromatography-mass spectrometry assay for the direct quantitative analysis of 1-acyl-LPA. This method utilizes a deuterium-labeled internal standard, LPA (18:0-d(35)), and a single liquid-liquid extraction with acidic butanol that allows >95% recovery of LPA, followed by online normal-phase liquid chromatography-mass spectrometry. This protocol allows for the accurate, sensitive, and reproducible analysis of the individual 1-acyl-LPA species present in biological samples. The utility of the assay is demonstrated through the analysis of LPA species in plasma and serum from human volunteers. Total LPA in EDTA plasma was 0.61 +/- 0.14 microM in males and 0.74 +/- 0.17 microM in females, which increased to 0.91 +/- 0.23 and 0.99 +/- 0.38 microM after incubation for 24 h at 25 degrees C. Total LPA in serum was 0.85 +/- 0.22 microM in males and 1.57 +/- 0.56 microM in females, which increased to 4.78 +/- 0.89 and 5.57 +/- 0.73 microM after incubation for 24 h at 25 degrees C.

Analysis of Variance↗
PubMed2001

Comparison of the effects of risperidone and haloperidol on regional cerebral blood flow in schizophrenia.

BACKGROUND: Atypical antipsychotics, such as risperidone, have been shown to be more effective for the treatment of the symptoms of schizophrenia and have a greater beneficial effect on neurocognition compared to the conventional antipsychotics. The present study used [(15)O]H(2)O positron emission tomography imaging of regional cerebral blood flow to examine and compare the effects of haloperidol and risperidone on brain function. METHODS: Thirty-two subjects with schizophrenia participated in the study. Each subject was scanned in a medication-free state, and after being on a stable clinically assigned dose of either risperidone or haloperidol for 3 weeks. The off-medication scan was subtracted from the on-medication scan, using a within-subjects design. A randomization analysis was used to determine differences between the effects of haloperidol and risperidone on regional cerebral blood flow. RESULTS: Haloperidol was associated with a significantly greater increase in regional cerebral blood flow in the left putamen and posterior cingulate, and a significantly greater decrease in regional cerebral blood flow in frontal regions compared to risperidone. Risperidone was associated with a significantly greater decrease in regional cerebral blood flow in the cerebellum bilaterally compared to haloperidol. CONCLUSIONS: The results show that risperidone and haloperidol have significantly different effects on brain function, which may be related to their differences in efficacy and side effects. Further work is required to more precisely determine the mechanisms by which different antipsychotic medications exert their therapeutic effects on the clinical symptoms and cognition in schizophrenia. These findings emphasize the importance of controlling for both medication status and the individual antipsychotic in neuroimaging studies.

Adult↗
PubMed2001

Sphingosylphosphocholine is a naturally occurring lipid mediator in blood plasma: a possible role in regulating cardiac function via sphingolipid receptors.

Blood plasma and serum contain factors that activate inwardly rectifying GIRK1/GIRK4 K+ channels in atrial myocytes via one or more non-atropine-sensitive receptors coupled to pertussis-toxin-sensitive G-proteins. This channel is also the target of muscarinic M(2) receptors activated by the physiological release of acetylcholine from parasympathetic nerve endings. By using a combination of HPLC and TLC techniques with matrix-assisted laser desorption ionization-time-of-flight MS, we purified and identified sphingosine 1-phosphate (SPP) and sphingosylphosphocholine (SPC) as the plasma and serum factors responsible for activating the inwardly rectifying K+ channel (I(K)). With the use of MS the concentration of SPC was estimated at 50 nM in plasma and 130 nM in serum; those concentrations exceeded the 1.5 nM EC(50) measured in guinea-pig atrial myocytes. With the use of reverse-transcriptase-mediated PCR and/or Western blot analysis, we detected Edg1, Edg3, Edg5 and Edg8 as well as OGR1 sphingolipid receptor transcripts and/or proteins. In perfused guinea-pig hearts, SPC exerted a negative chronotropic effect with a threshold concentration of 1 microM. SPC was completely removed after perfusion through the coronary circulation at a concentration of 10 microM. On the basis of their constitutive presence in plasma, the expression of specific receptors, and a mechanism of ligand inactivation, we propose that SPP and SPC might have a physiologically relevant role in the regulation of the heart.

Animals↗
PubMed2001

Similarity of ventricular function in patients alive 5 years after randomization to surgery or angioplasty in the BARI trial.

BACKGROUND: Left ventricular ejection fraction (LVEF) is a recognized determinant of survival in patients with coronary artery disease. In major trials comparing surgical and percutaneous revascularization approaches, the long-term effect of the coronary revascularization strategy on LVEF has not been reported. METHODS AND RESULTS: In the NHLBI-sponsored Bypass and Angioplasty Revascularization Investigation (BARI) randomized trial comparing angioplasty and bypass surgery as initial treatment strategies, 1220 (75%) of the 1617 surviving randomized patients had their EF measured by radionuclide ventriculography 5 years after study entry. For the total study group, the 5-year EF in the CABG group (n=623) was 55.8+/-12.3, compared with 55.7+/-12.7 in PTCA group (n=597, P:=0.82). There was no significant difference in measured EF between the CABG group and the PTCA group within multiple subgroups determined by the presence or absence of diabetes, 3-vessel disease, complete revascularization, or prior myocardial infarction. In a multiple linear regression model developed to predict 5-year EF, treatment assignment to PTCA or CABG was not significant (P:=0.95). If an EF of 0 was imputed for patients who were dead and missing EF data, however, there was a higher EF in the CABG group (P:=0.0018) among diabetic patients only. CONCLUSIONS: In the BARI randomized trial, initial treatment assignment to angioplasty was not associated with any difference in long-term ventricular function compared with initial treatment assignment to surgery. These results apply, however, only to patients who were alive at 5 years.

Angioplasty↗
PubMed2001

Comparison of relative coronary Doppler flow velocity reserve to stress myocardial perfusion imaging in patients with coronary artery disease.

To compare relative coronary artery vasodilator reserve (rCVR = CVRtarget/CVRreference) to myocardial perfusion stress imaging, 48 patients with coronary artery stenoses (61% +/- 16%; mean, +/- SD; range, 30%-91%) had measurements of target and reference vessel CVR (Doppler-tipped guidewire). rCVR was computed and compared to stress 201thallium or (99m)technetium-sestamibi myocardial tomography. Compared to 24 patients with negative stress imaging studies, 24 patients with positive stress studies had angiographically more severe stenoses (74% +/- 13% vs. 44% +/- 24%; P = 0.0005) with lower CVR(target) (1.68 +/- 0.55 vs. 2.46 +/- 0.74; P = 0.002) and lower rCVR (0.72 +/- 0.22 vs. 1.0 +/- 0.26; P < 0.003). Based on receiver-operator characteristic (ROC) cut points (CVR > 1.9; rCVR > 0.75), compared to CVR, rCVR had similar agreement (Kappa 0.54 vs. 0.50), sensitivity (63% vs. 71%), specificity (88% vs. 83%), and positive predictive value (83% vs. 81%) with myocardial perfusion tomography. A concordant CVRtarget/rCVR only slightly increased sensitivity, specificity, and positive predictive values (77%, 90%, and 87%, respectively). Although rCVR, like CVR, correlates with stress myocardial perfusion imaging results, rCVR did not have significant incremental prognostic value over CVR alone for myocardial perfusion imaging. However, rCVR does provide additional information regarding the status of the microcirculation in patients with coronary artery disease and complements the CVR for lesion assessment.

Adult↗
PubMed2001

Iron loading and large doses of intravenous ascorbic acid promote lipid peroxidation in whole serum in guinea pigs.

Large doses of ascorbic acid may mobilise Fe from Fe-binding proteins in vivo which in turn could catalyse lipid peroxidation, a process associated with degenerative diseases. This hypothesis was tested in vitro in the serum of Fe-loaded animals. Eighteen male guinea pigs weighing about 500 g on arrival were allocated to two groups of nine. Fe loading was induced in one group by two intraperitoneal injections of 200 mg iron dextran given on days 1 and 5. Blood (6 ml) was drawn from all animals on day 12 by cardiac puncture. Serum and LDL were separated. Serum was tested for loosely-bound Fe (bleomycin assay) and lipid peroxidation (thiobarbituric acid reactive substances (TBARS) assay) and LDL for susceptibility to in vitro oxidation (TBARS and conjugated diene assays). On day 12, another intraperitoneal injection of 200 mg iron dextran was given to the animals in the Fe-loaded group. On day 19, all animals were given 75 mg ascorbic acid by intraperitoneal injection. Blood (6 ml) was drawn 4 h later by cardiac puncture. Serum and LDL assays were repeated. Ascorbic acid increased loosely-bound Fe and in vitro oxidation in the serum from animals of the Fe-loaded group but not in the serum from animals of the control group. Susceptibility of LDL to in vitro oxidation increased after the ascorbic acid injection in the control group but there was no further increase in the Fe-loaded group. These data suggest that large doses of ascorbic acid promote Fe mobilisation and in vitro oxidation in the serum of Fe-loaded animals.

Animals↗
PubMed2001

When symptoms persist: clozapine augmentation strategies.

Recent data and clinical experience confirm that, in spite of superior efficacy for treatment-refractory schizophrenia, a substantial proportion of patients receiving clozapine will continue to experience disabling symptoms. Optimizing clozapine monotherapy is the first step in the management of "clozapine nonresponders." Described here is a synthesis of the available literature on the range and efficacy of clozapine augmentation strategies that may be used when monotherapy fails. Treatment options include adjunctive antipsychotic medications, mood stabilizers, selective serotonin reuptake inhibitors, glycinergic agents, and electroconvulsive therapy. The evidence favoring one augmentation strategy over another is lacking; overall, adjunctive therapy is associated with only modest clinical improvement. Moreover, case series and open-labeled clinical trials dominate the extant literature, and there is a dearth of double-blind trials comparing these augmentation agents. Current systematic efforts to enhance the treatment of these patients with adjunctive therapies are worthy of being studied in carefully conducted clinical trials.

Antipsychotic Agents↗
PubMed2001

Impact of a compliance program for billing on internal medicine faculty's documentation practices and productivity.

PURPOSE: Academic health centers and faculty practice plans have implemented programs to comply with Office of Inspector General (OIG) billing regulations. This study measured the impact of such a program on physicians' billing practices, faculty productivity, and operating revenues. METHOD: A prospective two-year study of departmental billing activities was carried out in 1997-98 and 1998-99 in the department of internal medicine at the Saint Louis University School of Medicine and its faculty practice plan. Compliance with inpatient evaluation and management (E/M) coding and Health Care Financing Administration (HCFA) billing was evaluated by an independent staff of experts. Beginning in 1998-99, the department provided detailed monthly reports of and education in billing and compliance performance to divisional managers and individual faculty. RESULTS: Inpatient admission profiles, practice patterns, and payer mixes of the faculty practice plan and department did not differ during the study. The gross collection rates for the practice and the department rose by 7.3% and 9.5%, respectively, and all divisions increased in their gross collection rates in 1998-99. All but one division increased E/M services in 1998-99 (range -4% to +151%). All divisions decreased their rates of unbillable E/M services in 1998-99. The two divisions with the highest unbillable rates in 1997-98 (gastroenterology and cardiology) significantly reduced their unbillable service rates in 1998-99 (-7.74% and -7.17%, respectively). Medical oncology and geriatrics recorded the greatest reductions in 1998-99 (-63% and -52%, respectively). All but two divisions increased the percentages of complex inpatient E/M services in 1998-99 (average = +27.4%), with commensurate reductions in less complex visits (p < 0.05), and there was an inverse correlation (R = -0.85; p < 0.01) between the relative increases in the division's inpatient encounters and the service complexity charged. A modest inverse correlation (R = -0.50; p < 0.05) existed between the reduction of relative percentages in divisions' unbillable rates (averaging -34%) and the increase in their gross collection rates (averaging + 31%). CONCLUSION: Implementation of a billing compliance program at the departmental level enhances physician productivity and billing compliance for inpatient E/M services, potentially increasing departmental revenues while reducing the institutional risk of an OIG audit.

Academic Medical Centers↗
PubMed2001

Biochemical activities of trimetoquinol analogs at human beta(1)- and beta(3)-adrenergic receptors.

The biochemical activities of trimetoquinol (TMQ) analogs were evaluated at the human beta(1)- and beta(3)-adrenergic receptor (AR) subtypes expressed in Chinese hamster ovary cells. In radioligand binding assays, the 1-benzyl iodine-substituted analogs exhibited higher binding affinities at both beta(1)- and beta(3)-AR subtype as compared to TMQ. In cAMP accumulation assays, these analogs exhibited high potencies at both beta(1)- and beta(3)-AR. The 3',5'-diiodo-4'-amino analog of TMQ was the most potent beta(3)-AR agonist, 17-fold more potent at the beta(3)-AR versus the beta(1)-AR. Masking of the 6,7-dihydroxy group of the catechol ring of 3',5'-diiodo-4'-acetamido analog of TMQ, a potent beta(1)- and beta(3)-AR agonist, abolished activity at both beta-AR subtypes. Furthermore, substitution of a strong electron withdrawing group such as the trifluoromethyl moiety at the 1-benzyl ring of TMQ dramatically decreased potency at beta(1)- and beta(3)-AR compared to TMQ. Replacement of the 1-benzyl ring of TMQ with a naphthalene ring did not alter affinity but reduced potency of resulting 1-naphthylmethyl and 2-naphthylmethyl analogs at beta(1)- and beta(3)-AR compared to TMQ. Our results define the structural and electronic properties of substituents on TMQ necessary for potent activation of beta(1)- and beta(3)-AR and suggest that further modifications of the 1-benzyl iodine-substituted analogs may yield potent beta(3)-AR agonists.

Adrenergic beta-Agonists↗