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Biomedical subjects

D D Miller

Publications and source records attributed to D D Miller.

At least 163 records · Page 9Linked to original sources
PubMed1992

Prognostic significance of exercise thallium-201 testing in patients aged greater than or equal to 70 years with known or suspected coronary artery disease.

The prognostic value of exercise thallium-201 myocardial perfusion imaging has not been studied in an elderly (aged greater than or equal to 70 years) population. Retrospective analysis of 120 consecutive elderly patients undergoing Bruce protocol exercise stress with quantitative planar thallium-201 scintigraphy, followed clinically for a mean of 36 +/- 12 months after testing, revealed a 10% cardiac event rate (6 cardiac deaths from arrhythmia or congestive heart failure, and 5 fatal and 1 nonfatal myocardial infarction). There were no exercise stress-related complications. Survival without cardiac events was associated with greater exercise duration (5.6 +/- 2.4 vs 3.1 +/- 2.4 minutes; p less than 0.0007) and peak exercise heart rate (131 +/- 18 vs 120 +/- 19 beats/min; p less than 0.05). Univariate variables associated with higher cardiac event rates included: (1) peak exercise less than or equal to stage I (18 vs 6%; p = 0.04); (2) maximal ST-segment depression greater than or equal to 2 mm (27 vs 6%; p = 0.003); and (3) presence of a fixed or reversible thallium-201 perfusion defect (18 vs 2%; p = 0.004). Multivariate stepwise logistic regression analysis identified the combination of peak exercise less than or equal to stage I and any thallium-201 perfusion defect as the most powerful predictor of subsequent cardiac events (relative risk = 5.3 at 1 year). Thus, exercise thallium-201 scintigraphy in elderly patients is safe and provides important prognostic information.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

Effects of the stereochemical orientation of phenethylamines and imidazolines on alpha-adrenergic receptor-mediated DNA synthesis in primary cultured rat hepatocytes.

The hepatic alpha 1-adrenergic receptor mediates a variety of hepatic functions including respiration, glycogenolysis, gluconeogenesis, and growth. We have utilized a rat primary hepatocyte culture system to show that the alpha 1-adrenergic receptor can be activated in a stereoselective manner by a series of phenethylamines and catecholimidazolines resulting in the stimulation of DNA synthesis as determined by [3H]thymidine incorporation. The phenethylamines adhered to the Easson-Stedman hypothesis with a rank order of potency of (-)-(R)-norepinephrine (NE) greater than (+)-(S)-NE greater than the desoxy analog dopamine (DA) for the stimulation of DNA synthesis. However, the 2-substituted catecholimidazolines did not follow this trend and demonstrated an order of potency of the desoxy analog 3,4-dihydroxybenzyl imidazoline (DHT) greater than or equal to (-)-(R)-2-(3,4,alpha-trihydroxybenzyl)imidazoline (TBI) greater than (+)-(S)-TBI. 4-Substituted catecholimidazolines were less potent as inducers of DNA synthesis than the corresponding 2-substituted analogs with an order of potency of (+)-(R)-4-(3,4-dihydroxybenzyl)imidazoline (DBI) greater than (+,-)-(R,S)-DBI greater than (-)-(S)-DBI. When the beta-hydroxyl moiety of NE is replaced with an amino group as in 3,4-dihydroxyphenylethylenediamine, the isomers are less active than the beta-hydroxylated analogs and also demonstrate no stereoselectivity for the stimulation of DNA synthesis. These results demonstrate that the hepatic alpha 1-adrenergic receptor can recognize various isomeric forms of these compounds and that hepatocellular growth can be modulated in a stereoselective manner by phenethylamines and imidazolines.

Animals↗
PubMed1992

Resolution and adrenergic activities of the optical isomers of 4-[1-(1-naphthyl)ethyl]-1H-imidazole.

Recently we synthesized a naphthalene analog of medetomidine, 4-[1-(1-naphthyl)ethyl]-1H-imidazole hydrochloride (1), and found it to be highly potent in adrenergic systems. The separation of optical isomers of this naphthalene analog was achieved by using the isomers of tartaric acid. The optical purities of the isomers were determined by HPLC using a chiral column. Using X-ray analysis the (+)-isomer was determined to have the S absolute configuration. It has been reported that the (+)-isomer of medetomidine (2) is the most potent enantiomer on alpha 2-adrenergic receptors. There were both qualitative and quantitative differences in biological activities of the optical isomers of 1 in alpha 1- and alpha 2-adrenergic receptor systems of guinea pig ileum and human platelets. (+)-(S)-1, but not (-)-(R)-1 was a selective agonist of alpha 2-mediated responses in ileum whereas (-)-(R)-1 was more potent than (+)-(S)-1 as an inhibitor of alpha 2-mediated platelet aggregation.

Adrenergic alpha-Agonists↗
PubMed1992

Determination of perioperative cardiac risk by adenosine thallium-201 myocardial imaging.

To determine the predictive value of adenosine thallium-201 myocardial imaging for perioperative cardiac events, 60 consecutive patients referred for preoperative cardiac evaluation were studied before vascular (n = 25), orthopedic (n = 14), or general (n = 21) surgery. Tomographic (n = 52) and planar (n = 8) thallium-201 imaging was performed after adenosine infusion at a rate of 140 micrograms/kg/min for 6 minutes. Two blinded expert observers graded results of adenosine thallium-201 studies as normal (33%), fixed defect only (2%), reversible defect only (48%), and combined (fixed and reversible) defects (17%). After 6 +/- 3 months of follow-up, 81% proceeded to surgery and 43% underwent preoperative coronary angiography. Clinical variables that correlated with perioperative cardiac events were a history of diabetes mellitus (p = 0.05), left bundle branch block (p = 0.02), and left ventricular hypertrophy (p = 0.06) on the resting ECG. This clinically "high-risk" group had an event rate of 22% as compared with no cardiac events in patients in the "low-risk" group without these clinical characteristics (p = 0.005). Stepwise logistic regression analysis revealed that the presence of a combined (fixed and reversible) adenosine thallium-201 defect (p = 0.0007), three-vessel coronary artery disease (p = 0.001), and left bundle branch block (p = 0.02) was predictive of subsequent cardiac events with relative risk ratios of 4.9, 2.9, and 2.2, respectively. Therefore the presence of an adenosine thallium-201 perfusion defect is correlated with and predictive of an increased risk of perioperative cardiac events in patients referred for preoperative risk evaluation.

Adenosine↗
PubMed1992

Prognostic value of dipyridamole thallium-201 imaging in elderly patients.

The prognostic value of intravenous dipyridamole myocardial perfusion imaging has not been studied in a large series of elderly patients. Patients greater than or equal to 70 years of age with known or suspected coronary artery disease were evaluated to determine the predictive value of intravenous dipyridamole thallium-201 imaging for subsequent cardiac death or nonfatal myocardial infarction. Of the 348 patients, 207 were symptomatic and 141 were asymptomatic; 52% of the asymptomatic group had documented coronary artery disease. During 23 +/- 15 months of follow-up, there were 52 cardiac deaths, 24 nonfatal myocardial infarctions and 42 revascularization procedures (percutaneous transluminal coronary angioplasty in 20; coronary artery bypass surgery in 22). Clinical univariate predictors of a cardiac event included previous myocardial infarction, congestive heart failure symptoms, hypercholesterolemia and diabetes (all p less than 0.05). The presence of a fixed, reversible or combined thallium-201 defect was significantly associated with the occurrence of cardiac death or myocardial infarction during follow-up (p less than 0.05). Cardiac death or nonfatal myocardial infarction occurred in only 7 (5%) of 150 patients with a normal dipyridamole thallium-201 study (p less than 0.001). Stepwise logistic regression analysis of clinical and radionuclide variables revealed that an abnormal (reversible or fixed) dipyridamole thallium-201 study was the single best predictor of cardiac events (relative risk 7.2, p less than 0.001). As has been demonstrated in younger patients, previous myocardial infarction (relative risk 1.8, p less than 0.001) and symptoms of congestive heart failure at presentation (relative risk 1.6, p = 0.02) were also significant independent clinical predictors of cardiac death or myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1992

Calcium carbonate depresses iron bioavailability in rats more than calcium sulfate or sodium carbonate.

Calcium carbonate supplements depress iron bioavailability when consumed with meals. Our objective was to determine whether this effect is due to the calcium, the carbonate or a combination of the two. A rat hemoglobin repletion assay and an in vitro digestion procedure were used to assess the effects of four salts (calcium carbonate, calcium sulfate, sodium carbonate and sodium sulfate) on iron bioavailability. The salts were added to purified rat diets (for the hemoglobin repletion study) or to iron-fortified infant formula (for the in vitro study) at three different levels. Calcium carbonate had the greatest depressive effect on iron bioavailability, depressing hemoglobin iron gain in a dose-related manner. Calcium sulfate and sodium carbonate also depressed hemoglobin iron gain but to a lesser extent and only in rats fed diets containing the highest level of these two salts. Sodium sulfate did not affect hemoglobin iron gain. Significant interactions between cation, anion and salt concentration were found, suggesting that both the cation and the anion in calcium carbonate contribute to the iron absorption-depressing action of this salt. Results from the in vitro experiments were similar to the in vivo results.

Absorption↗
PubMed1992

Imaging of vascular injury with 99mTc-labeled monoclonal antiplatelet antibody S12. Preliminary experience in human percutaneous transluminal angioplasty.

BACKGROUND: To evaluate the in vivo safety, biodistribution, and diagnostic accuracy of a monoclonal Fab' antibody (S12) that is specific for the platelet membrane glycoprotein (GMP-140) expressed during platelet activation at vascular injury sites, 11 peripheral percutaneous transluminal angioplasty (PTA) patients (age, 61 +/- 8 years) with severe vascular disease had serial 99mTcS12 radionuclide imaging at 5 and 90 minutes, 4-6 hours, and 20-24 hours after a total of 23 angiographically successful PTA procedures. No acute allergic reactions or hematologic toxicity occurred. METHODS AND RESULTS: The average PTA percent angiographic diameter stenosis (DS) at all 23 sites decreased from 85 +/- 12% to 12 +/- 11%, with a mean before-to-after-PTA change of 73 +/- 14% (p less than 0.01). The mean radionuclide image-derived ratio of 99mTc S12 activity in PTA versus contralateral non-PTA arterial segments for all angioplasty sites was 1.6 +/- 0.5. Vascular 99mTc S12 antibody activity was qualitatively evident in the majority (78%) of PTA sites at 4-6 hours after injection. 99mTc S12 target-to-background (muscle) ratio equaled 2.3 +/- 0.6 at PTA sites. Nine PTA sites (39%) had residual 99mTc S12 activity at 24 hours after injection (mean PTA site-to-contralateral artery ratio, 1.5 +/- 0.4). The mean vascular 99mTc S12 activity ratios in 10 procedurally complicated (defined as extensive dilation [greater than 2 cm] or grade I or greater arterial dissection) and 13 uncomplicated PTA segments were 1.9 +/- 0.5 versus 1.2 +/- 0.1, respectively (p less than 0.01). The associated before-to-after-PTA angiographic improvement was significantly less in procedurally complicated PTA sites (66 +/- 12% versus 80 +/- 12% DS; p less than 0.01). CONCLUSIONS: 99mTc S12 activity is significantly increased at angiographically patent PTA sites that are procedurally complicated and are associated with less significant before-to-after-PTA angiographic improvement. 99mTc S12 monoclonal Fab' antibody imaging permits noninvasive identification of local vascular platelet activation resulting from angioplasty balloon injury in humans.

Angioplasty, Balloon↗
PubMed1992

alpha-Amino-3-hydroxy-5-methylisoxazole-4-propionate/kainate receptor antagonists in the nucleus accumbens and ventral pallidum decrease the hypermotility response to psychostimulant drugs.

The purpose of this study was to determine the role of alpha-amino-3-hydroxy- 5-methylisoxazole-4-propionate (AMPA)/kainate excitatory amino acid receptors in the nucleus accumbens and the ventral pallidum in the hypermotility responses to amphetamine, caffeine and scopolamine. To accomplish this, we determined the effects of intracranial injections of 6,7-dinitroquinoxaline-2,3-dione (DNQX) and gamma-D-glutamylaminomethyl-sulfonate (GAMS), which inhibit the responses to AMPA, quisqualate and kainate in electrophysiological and behavioral studies. The bilateral administration of either DNQX (1 micrograms/0.5 microliters) or GAMS (5 micrograms/0.5 microliters) into the nucleus accumbens inhibited the locomotor stimulation produced by amphetamine (0.5 mg/kg s.c.) but not by caffeine (20 mg/kg s.c.) or scopolamine (0.5 mg/kg s.c.). However, the bilateral administration of either of the two antagonists into the ventral pallidum inhibited the response to all three stimulants. The administration of 6-amino-7-fluroquinoxaline-2,3-dione, a chemical analog of DNQX that does not bind to AMPA receptors, into either the nucleus accumbens or the ventral pallidum did not inhibit the locomotor stimulation produced by amphetamine. Neither DNQX nor GAMS injected into either the nucleus accumbens or the ventral pallidum produced significant changes in the locomotor activity of animals not injected with the stimulants. These results suggest that activation of AMPA/kainate receptors in the nucleus accumbens is important in the stimulation of locomotion produced by amphetamine, whereas activation of these receptors in the ventral pallidum is involved in the hypermotility response to all three central nervous system stimulants.

Animals↗
PubMed1991

Diversity of the pharmacological actions of some tolazoline analogues in human platelets and rat aorta.

Tolazoline and two 4'-substituted benzyl analogues, 2-(4'-aminobenzyl) imidazoline (ABI) and 2-(4'-isothiocyanatobenzyl)imidazoline (IBI) were synthesized and evaluated for adrenoceptor activity in human platelets (alpha 2) and rat aorta (alpha 1), respectively. IBI was prepared as an affinity label for alpha-adrenoceptors and compared with chloroethylclonidine. Tolazoline, IBI, ABI and chloroethylclonidine inhibited the primary and secondary waves of epinephrine-induced human platelet aggregation. In aspirin treated platelets, primary wave aggregatory responses to epinephrine were blocked in a competitive manner by tolazoline, ABI. IBI and chloroethylclonidine giving pA2 values of 6.33, 6.12, 4.71 and 5.70, respectively. Only IBI blocked the aggregation responses to ADP (secondary wave only) arachidonic acid and U46619 (a thromboxane A2 agonist). Arachidonic acid-induced serotonin release and malondialdehyde formation and thrombin-induced release of [3H]arachidonic acid from membrane phospholipids were also blocked by IBI. These data indicate that IBI blocks arachidonic acid release, prostaglandin biosynthesis and the action of thromboxane A2. One hour exposure of aspirin treated platelets with IBI abolished inhibitory effects against epinephrine induced aggregation. In contrast to human platelets, both ABI and IBI produced contractions of rat aorta; however, only the responses to ABI were blocked in a competitive manner by the alpha-antagonists, phentolamine, prazosin, and SKF 104078. Moreover, idazoxan blocked the stimulatory actions of IBI, cirazoline and phenylephrine on rat aorta.(ABSTRACT TRUNCATED AT 250 WORDS)

Affinity Labels↗
PubMed1991

Pharmacologic antagonism of thromboxane A2 receptors by trimetoquinol analogs in vitro and in vivo.

Although (-)-(S)-trimetoquinol [1-(3,4,5-trimethoxy-benzyl)- 6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline; TMQ] is recognized as a potent bronchodilator, (+)-(R)-TMQ is a selective antagonist of human platelet aggregation and serotonin secretion induced by thromboxane A2 (TXA2) agonists. To confirm the pharmacological actions of TMQ analogs, the interaction of the drugs with TXA2 receptors was examined in human platelets and in a mouse sudden death model. The inhibitory potencies of TMQ analogs (pIC50 values) for displacement of [3H]SQ 29,548 binding to platelets showed excellent correlation with the respective pIC50 (-log IC50) values for U46619-induced aggregation (r = 0.99, P less than 0.01) and serotonin secretion (r = 0.99, P less than 0.01) in human platelet-rich plasma and for whole blood aggregation (r = 0.99, P less than 0.01). In each system, the rank order of inhibitory potencies was rac-iodoTMQ greater than or equal to (+)-(R)-TMQ greater than rac-TMQ much greater than (-)-(S)-TMQ. Antithrombotic effects of TMQ analogs were evaluated in a mouse sudden death model. In vivo antithrombotic potencies of these compounds were consistent with the in vitro potencies as TXA2 receptor antagonists in platelet systems. Administration of rac-iodoTMQ, (+)-(R)-TMQ and rac-TMQ 15 min before the injection of U46619 (800 micrograms/kg, iv) protected mice against U46619-induced sudden death. On the other hand, (-)-(S)-TMQ did not protect animals against death. Protection of U46619-induced cardiopulmonary thrombosis by TMQ analogs was seen at doses of 3-100 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

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

Simultaneous cardiac mechanics and phosphorus-31 NMR spectroscopy during global myocardial ischemia and reperfusion in the intact dog.

To investigate the high-energy phosphate metabolic correlates of left ventricular (LV) dysfunction during the onset and recovery from severe, global myocardial ischemia in vivo, seven preinstrumented closed-chest dogs had ECG-gated phosphorus-31 (31P) NMR-spectroscopy (NMR-S) studies performed and LV micromanometer and sonomicrometer data measured before, during, and every 5 min following severe occlusive global myocardial ischemia. Ischemic LV + dP/dtmax fell from 2396 +/- 576 mm Hg/s at baseline to 2185 +/- 478 mm Hg/s (p less than 0.05) and did not normalize until after 30 min of reperfusion. LV ejection fraction (EF) decreased significantly (0.32 +/- 0.07 EF units to 0.12 +/- 0.13 EF units; p less than 0.05) and did not recover by 30 min of reperfusion (0.27 +/- 0.09 units; P less than 0.05 vs baseline). Simultaneous 31P NMR-S studies demonstrated excellent beta-ATP signal-to-noise (10 +/- 4:1). Myocardial acidosis occurred during global ischemia (delta pH = -0.22 +/- 0.23 units; p less than 0.05), with recovery at 30 min of reperfusion. Inorganic phosphate/phosphocreatine ratio (Pi/PCr) increased significantly during ischemia (0.46 +/- 0.07 to 0.61 +/- 0.07; P less than 0.05), with delayed normalization of this ratio at 30 min of reperfusion. beta-ATP peak area did not change during ischemia. Pi/PCr and LV contractility (+dP/dtmax) were significantly correlated at baseline (r = -0.70) and during global ischemia (r = -0.78; p less than 0.01), but not during recovery (r = 0.006; p = NS). Therefore, the simultaneous evaluation of high-fidelity hemodynamic data and topical 31P NMR-S can be performed in the intact state.

Adenosine Triphosphate↗
PubMed1991

Molecular aspects of the receptor activation by imidazolines: an overview.

Based on the pharmacological activity of chiral imidazolines the steric requirements for the activation of the alpha-adrenoceptor are provided. Importantly, the sequence of interaction of the critical groups of the asymmetric carbon of imidazolines and catecholamines with the alpha-adrenoceptor is postulated. Thus, initial determinants of molecular efficacy are hypothesized. The effect of aromatic fluoro-substitution and introduction of a double bond in the imidazoline moiety on the pharmacologic activity is discussed. The unique mechanism of non-adrenergic vascular activity of isothiocyanato-tolazoline is presented.

Animals↗
PubMed1991

Structure-activity studies of new imidazolines on adrenoceptors of rat aorta and human platelets.

Potencies of new aromatic substituted fluoro or iodo analogues of catecholimidazolines on functional responses in rat aorta (alpha 1) and platelets (alpha 2) were quantified. (1) When compared either on the basis of EC50 or the dissociation constant (KA), 5-fluorocatecholimidazoline was as potent as the reference alpha 1-adrenoceptor agonist, phenylephrine in the vascular tissue. The maximum contraction of aorta produced by the fluoro analogue was, however, 17% higher than that of phenylephrine. The time required for 1/2 relaxation of the tissue after 5-fluoro hydroxy imidazoline was at least twice as long as that of the phenylephrine. The catechol moiety as well as fluorine substitution at the critical 5-position of the aromatic ring is essential for higher alpha 1 adrenoceptor-mediated potency. (2) As compared to the fluoro analogues, the adrenoceptor-mediated potencies of iodo-analogues were relatively weak on vascular tissue. Naphazoline and its analogues were partial agonists on vascular tissue with dissociation constants which ranged from 110 to 2600 nmol/l. (3) Imidazole analogues were generally less potent agonist than the imidazolines by one order of magnitude. (4) The vacular effects of all agonists were competitively blocked by prazosin with KB values which ranged from 0.04 to 0.48 nmol/l. Since the variation in KB values were within normal limits, the action of new imidazolines on rat aorta appears to be mediated mainly by the activation of the alpha 1-adrenoceptor. Prazosin 10 nmol/l abolished the vascular response of some partial agonists. This indicates a slightly different mode of interaction of agonists with the transduction process. (5) Carbon 4-substituted imidazolines produced little or no alpha 1 adrenoceptor-mediated intrinsic activity, but competitive receptor blocking potency was comparable to that of phentolamine. (6) Medetomidine was a partial agonist on the rat aorta with a KA of 260 nmol/l. When investigated as a blocker, the KB of medetomidine against phenylephrine was approximately 5600 nmol/l. The variation in the latter value was high. (7) In acetylsalicylic acid-treated human platelets, the alpha 2-adrenoceptor-mediated aggregatory effect of all fluoro analogues was weak. Iodo or naphazoline analogues did not initiate platelet aggregation but blocked the aggregation induced by epinephrine. The affinity of naphazoline for the alpha 2-adrenoceptor was 1100 nmol/l. The IC50 of medetomidine for platelet anti-aggregatory effect was 3300 nmol/l, which compares favorably with other imidazoline type of blockers of platelet aggregation. (8) Sympathomimetic vasoconstrictor actions and platelet aggregation effects of these compounds can be dissociated.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Collagen stability and collagenolytic activity in the normal and aneurysmal human abdominal aorta.

Two issues were addressed in this study. The first was whether a bona fide collagenase exists within the wall of the aorta. The second was whether the activity of this putative collagenase is greater in aneurysmal tissue. No collagenase could be extracted from the wall of the aorta under nondenaturing conditions. However, hydroxyproline was liberated from tissue samples allowed to autolyze at neutral pH under reaction conditions favoring the activity of collagenase. Such an activity was probably enzymic as it occurred in a time- and temperature-dependent fashion and was suppressed by chelators. In normal and stenotic tissue, activity was increased by adding aminophenylmercuric acetate, an activator of latent collagenase. Examination of the blanks revealed that the collagen of aneurysmal aorta was more soluble than normal. Furthermore, its digestion kinetics differed in a way that suggested that aneurysmal aorta possessed a labile component that was absent from normal tissue. Although the activity of the putative aortic collagenase was higher than normal in the aneurysmal tissue, our assays do not distinguish between changes in the amount or activity of the enzyme and alterations in the collagen.

Adult↗
PubMed1991

Pharmacological properties of novel bicyclic isoquinoline analogs in isolated guinea pig atria, trachea and in human platelets: relationship to trimetoquinol.

1. Antiplatelet and beta-adrenoceptor activities of a set of secondary and tertiary N-methyl substituted amine analogs of trimetoquinol (TMQ, I and II, respectively) and 5,8-ethano-l-(p-methoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquin oline (bicyclic isoquinoline compounds III and IV, respectively) were examined. 2. Compounds III and IV induced relaxations of guinea pig trachea which were blocked by propranolol whereas neither compound acted as an agonist nor antagonist of beta-adrenoceptors (chronotropy) in guinea pig atria. TMQ analogs (I and II) were agonists in both beta-adrenoceptor systems. 3. When tested in human platelets, compounds III and IV, like the TMQ analogs, blocked several inducers of the prostaglandin-dependent and -independent pathways, and the alpha 2-adrenoceptor-mediated pathway of platelet activation. 4. The bicyclic isoquinoline analogs (III and IV) possessed more selective beta 2-adrenoceptor stimulatory activity and equal or greater inhibitory activity against inducers of the prostaglandin-independent pathways of platelet function than the corresponding TMQ analogs (I and II). 5. These chemically novel lipophilic bicyclic compounds provide a new lead to the development of agents useful for the treatment of asthma and thrombotic disorders.

Adrenergic beta-Agonists↗