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Biomedical subjects

D D Miller

Publications and source records attributed to D D Miller.

At least 199 records · Page 11Linked to original sources
PubMed1990

Septic pulmonary arteriovenous fistula. An unusual conduit for systemic embolization in right-sided valvular endocarditis.

Right-sided valvular (tricuspid, pulmonic) endocarditis is frequently complicated by septic pulmonary embolization. Systemic embolization may also rarely occur due to associated left-sided endocarditis or right-to-left shunting in patients with septal defects. This report documents the occurrence of systemic embolization causing a cerebrovascular accident in an intravenous drug abuser with recurrent tricuspid valve endocarditis due to an isolated peripheral septic pulmonary arteriovenous fistula. Noninvasive diagnosis of the fistula by cardiac auscultation, contrast echocardiography, and nuclear magnetic resonance imaging was confirmed by selective pulmonary angiography. Subselective balloon embolization of the pulmonary arteries feeding this fistula was accomplished.

Adult↗
PubMed1990

Stereostructure activity relationships of catecholamines on human platelet function.

The concentration-dependent effects of clonidine, isomers of epinephrine, norepinephrine (NE), isoproterenol, cobefrin and alpha-methyldopamine, and related desoxy analogs (epinine, dopamine, N-isopropyldopamine) were examined on human platelets. The rank order of aggregatory potency (pD2 values) was R(-)-epinephrine (6.3) greater than R(-)-NE (5.9) greater than (+/-)-erythro-cobefrin (5.3) greater than S(+)-epinephrine (4.7) = S(+)-NE (4.7) = clonidine (4.7) = dopamine (4.6) greater than epinine (4.4) greater than S(+)-alpha-methyldopamine (4.3) = R(-)-alpha-methyldopamine (4.3) greater than (+/-)-threo-cobefrin (3.7). The isoproterenol isomers and N-isopropyl-dopamine were inactive as agonists. In 9 of 16 platelet-rich plasma preparations, R(-)-epinephrine, R(-)-NE, and (+/-)erythro-cobefrin were agonists and the remaining analogs blocked R(-)-NE-induced aggregation with a rank order of inhibitory potencies (pKB values) of clonidine (6.2) greater than S(+)-alpha-methyldopamine (5.0) greater than dopamine (4.6) = R(-)-alpha-methyldopamine (4.4) greater than or equal to S(+)-NE (4.3) greater than N-isopropyldopamine (4.1) greater than S(+)-isoproterenol (3.7) = R(-)-isoproterenol (3.5). Each compound was also able to reverse prostaglandin E1 (PGE1) (0.1 microM)-induced blockade of the maximal aggregation response to ADP. At high concentrations, R(-)-isoproterenol was more potent than either the S(+)-isomer or desoxy analog, N-isopropyldopamine, in the reversal of PGE1 inhibition of ADP aggregation. Phentolamine blocked these alpha 2-adrenoceptor-mediated actions against PGE1 on ADP aggregation. The rank order of potency for the reversal of PGE1-mediated inhibition of ADP aggregation by these catecholamines was similar to that observed for platelet aggregation. Our results indicate that (i) the stereochemical requirements for the interaction of catecholamines with platelet alpha 2-adrenoceptors are in agreement with the Easson-Stedman hypothesis and other alpha-adrenoceptor tissues; (ii) catecholamines lacking a benzylic hydroxyl group in the R-configuration and/or possessing an N-isopropyl group were alpha 2-adrenoceptor antagonists; (iii) clonidine gave quantitatively different responses compared with catecholamines for interaction with alpha 2-adrenoceptors; and (iv) inhibition of platelet adenylate cyclase is correlated to the inhibition of epinephrine-induced aggregation response for this series of compounds.

Adenosine Diphosphate↗
PubMed1990

Pharmacokinetic protocol for predicting plasma haloperidol concentrations.

The accurate prediction of steady-state plasma haloperidol concentrations was successfully accomplished by obtaining two blood samples following a 20 mg test dose (kinetic method). Prediction of steady-state concentrations on the basis of a mg/kg/day dosage (dose method), although equally precise, generated significantly less information concerning the variance between observed and predicted haloperidol plasma concentrations. Both predictive methods were less precise when the daily doses exceeded 0.47 mg/kg/day. Fifty percent (6/12 patients) of the haloperidol plasma concentrations were underpredicted if this threshold was exceeded. This finding may suggest the possibility of dose-dependent pharmacokinetics with haloperidol in some patients.

Dose-Response Relationship, Drug↗
PubMed1989

Nifedipine, but not propranolol, improves left ventricular systolic and diastolic function in patients with hypertension.

The effects of nifedipine and propranolol on cardiac function both at rest and at peak exercise were compared in 22 hypertensive patients whose diastolic blood pressures remained in excess of 95 mm Hg despite diuretic therapy. In this double-blind, placebo-controlled study, left ventricular systolic and diastolic function at rest and at peak exercise during bicycle ergometry was assessed by first-pass radionuclide angiography using the Baird Scinticor before and after treatment with either nifedipine or propranolol. Both agents effectively reduced blood pressure in the supine and upright positions and at peak exercise. Nifedipine was associated with a significant increase in cardiac output and stroke volume at rest and at peak exercise, while propranolol decreased cardiac output at rest and at peak exercise. Systemic vascular resistance decreased with nifedipine treatment at rest and at peak exercise, but increased significantly with propranolol. Nifedipine increased ejection fraction in patients at rest and also increased maximal oxygen consumption at peak exercise, while propranolol decreased maximal oxygen consumption at peak exercise. At rest and at peak exercise, nifedipine increased peak filling rate, but time to peak filling rate was not affected by either drug. The fraction of total diastolic filling at the midpoint of diastole was significantly increased by nifedipine therapy at rest but was not affected by propranolol therapy. Nifedipine significantly decreased atrial filling volume while propranolol had no effect. Propranolol therapy did not result in any improvement in left ventricular function. In contrast, nifedipine improved left ventricular systolic and diastolic function at rest and peak exercise. Future selection of an antihypertensive agent should include consideration of the impact of therapy on left ventricular function.

Adult↗
PubMed1989

Pharmacologic implications of alpha-adrenoreceptor interactive parameters for epinephrine enantiomers in the rat vas deferens.

After alkylation of a fraction of the total alpha-adrenoreceptors by phenoxybenzamine in rat vas deferens, the dissociation constants of (-)- and (+)-epinephrine in functional studies were 7 X 10(-7) M and 2 X 10(-5) M, respectively. In the adrenoreceptor-containing tissue fraction, when 3H-labeled WB4101 was used as the interacting ligand, for each enantiomer two affinity sites were found. Only the low-affinity dissociation constant for each isomer correlates with the constant obtained from the functional studies. If the change in Gibb's free energy, delta G degrees, is calculated from the low-affinity binding constants, the values -8.1 and -6.2 kcal/mol for (-)- and (+)-isomer, respectively, are obtained. The small difference in the value between isomers is consistent with the view that the benzylic hydroxyl group of the (-)-isomer forms a hydrogen bond with the receptor. The interaction of epinephrine with this receptor appears to be driven largely by the entropy of the drug-receptor interaction with only a small nonstereoselective contribution from the enthalpy of interaction.

Animals↗
PubMed1989

MRI detection of myocardial perfusion changes by gadolinium-DTPA infusion during dipyridamole hyperemia.

To detect abnormal regional myocardial coronary flow reserve, serial spin-echo MR tomograms of four control dogs and six with a partial balloon occlusion of the left anterior descending (LAD) coronary artery were acquired before and after dipyridamole infusion and during the paramagnetic effect of a bolus plus infusion of gadolinium-DTPA. Microsphere myocardial blood flow was measured for correlation with serial regional changes in MR signal intensity. Significant difference in gadolinium-enhanced MR signal intensity existed between the hypoperfused LAD and the hyperemic left circumflex perfusion beds (46 +/- 22% vs 78 +/- 29% above baseline, respectively; P less than 0.05). The percentage changes in gadolinium-enhanced MR signal and microsphere myocardial blood flow were significantly correlated (r2 = 0.93).

Animals↗
PubMed1989

Acute hemodynamic changes during intravenous dipyridamole thallium imaging early after infarction.

In order to determine the safety and hemodynamic effects of intravenous dipyridamole infusion for thallium-201 scinitigraphy in patients with acute ischemic syndromes, 10 patients with recent uncomplicated myocardial infarction (7 +/- 2 days pre-test) had central pressures and cardiac output values measured serially in a coronary care unit during and after the administration of dipyridamole (0.56 mg/kg over 4 minutes) and following aminophylline reversal (50 to 150 mg intravenously) of dipyridamole effect. Cardiac medications were not discontinued. Double product did not change significantly (8522 +/- 1811 versus 9044 +/- 1701; p = NS). Serious ischemic events did not occur, although 20% of patients had noncardiac side effects and 30% developed greater than or equal to 1 mm ST segment depression with associated angina in one-third of these cases. The peripheral blood pressure and heart rate response did not predict the occurrence of myocardial ischemia. Dipyridamole significantly reduced systemic vascular resistance (1218 +/- 302 to 739 +/- 166 dyne/sec-1/cm-5; p less than 0.05) and increased cardiac index (3.1 +/- 0.7 to 4.7 +/- 1.0 L/min/m2; p less than 0.05) within approximately 10 minutes, in association with a significant increase in pulmonary capillary wedge pressure (13 +/- 5 to 17 +/- 6 mm Hg; p less than 0.05). Three patients developed silent new "V" waves in their pulmonary capillary wedge pressure tracing, associated with anterior thallium redistribution. All three patients with newly elevated wedge pressures (greater than 15 mm Hg) had both thallium-201 redistribution and multivessel coronary disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminophylline↗
PubMed1989

Effect of the inhibition of dopamine uptake on the dopamine- and dimethyldopamine-induced-inhibition of the potassium-evoked release of [3H]acetylcholine from striatal slices.

1. Dimethyldopamine was eight times more potent than dopamine in activating the D2 receptor that inhibits the potassium-evoked release of [3H]acetylcholine from striatal slices. 2. Cocaine and mazindol produced an eight-fold shift in the concentration-response curve for dopamine, but not for dimethyldopamine. 3. The IC50 of dimethyldopamine for the inhibition of [3H]dopamine uptake was thirty times greater than that for dopamine. 4. Dopamine may be less potent than dimethyldopamine at the D2 receptor because dopamine has a higher affinity for the dopamine uptake system, resulting in its rapid removal from the vicinity of the receptor.

Acetylcholine↗
PubMed1989

Calcium in the diet: food sources, recommended intakes, and nutritional bioavailability.

Calcium nutritional status among some groups in the United States is suboptimal when judged by calcium intakes and the high prevalence of osteoporosis. Unfortunately, however, it is not clear that increases in calcium intake will have a significant impact on osteoporosis or other chronic diseases that have been linked to calcium nutriture. There is still considerable controversy surrounding the issue of calcium RDAs. The body's ability to adapt to varying levels of calcium intakes, the lack of sensitive indicators of calcium status, and the complexity and slow progression of chronic diseases such as osteoporosis make it very difficult to establish the role of diet in this regard. Great progress has been made in the study of calcium absorption. Much is known about the mechanisms involved in calcium absorption and its regulation. Thus, a rapidly advancing field and further developments will be invaluable to our understanding of the role of diet in calcium nutrition. Calcium bioavailability is affected by diet composition and the chemical form of calcium in foods. The calcium in dairy products is readily absorbed in the intestine. Lactose enhances calcium absorption efficiency under some conditions. Components of plants such as fiber, phytate, and oxalic acid may depress calcium absorption. High intakes of protein increase urinary losses of calcium but this effect may be partially offset by the phosphate association with most high-protein foods. Calcium absorption from salts used in supplement tablets is generally good. Absorption from salts such as calcium carbonate which require acid for dissolution may be poor in persons with achlorhydria unless the tablets are consumed with a meal. The practical significance of factors that may alter calcium bioavailability in normal mixed diets is difficult to assess. It may be a significant factor when calcium intakes are marginal or when absorption by the active transport, vitamin D-dependent process is impaired or not fully developed, i.e., it may be significant when vitamin D status is poor, in the elderly, and in young infants.

Animals↗
PubMed1989

Synthesis and D2 dopaminergic activity of pyrrolidinium, tetrahydrothiophenium, and tetrahydrothiophene analogues of sulpiride.

All of the existing dopamine receptor models recognize the amine nitrogen of agonist and antagonist drugs as playing a crucial role in receptor interactions. However, there has been some controversy as to which molecular form of the amine, charged or uncharged, is most important in these interactions. We have synthesized and examined the biological activity of permanently charged and permanently uncharged analogues of the dopaminergic antagonist, sulpiride. Sulpiride and the permanently charged pyrrolidinium (6,7) and tetrahydrothiophenium (9) analogues were able to antagonize the inhibitory effect of apomorphine on the K+-induced release of [3H]acetylcholine from striatal slices. In contrast, the permanently uncharged tetrahydrothiophene analogue 8 was inactive at concentrations up to 100 microM. Additionally, both sulpiride and the tetrahydrothiophenium analogue were able to displace [3H]spiperone from D2 binding sites, while the tetrahydrothiophene analogue was unable to produce any significant displacement. These results are consistent with our previous observations on permanently charged chlorpromazine analogues and provide further evidence that dopaminergic antagonists bind in their charged molecular forms to anionic sites on the D2 receptor.

Acetylcholine↗
PubMed1989

A comparison of intrinsic and extrinsic tracer methods for estimating calcium bioavailability to rats from dairy foods.

Dairy products doubly labeled with 45Ca and 47Ca were used to evaluate an extrinsic labeling procedure for calcium bioavailability determination. Nonfat milk, yogurt, and fresh cheese curd were prepared from caprine milk that was intrinsically labeled with 45Ca. The products were then labeled extrinsically with 47Ca and administered to rats by gavage. The 47Ca to 45Ca ratio in bone and teeth averaged about 1.00 with either milk, yogurt, or CaCl2, but the ratio was about 1.04 when dosed with cheese curd. Ca absorption, determined by whole-body counting of 47Ca, was lower (P less than 0.05) in cheese curd (59%) than in either milk (69%), yogurt (72%), or CaCl2 (72%). Expressed as percent of dose, the absorption of 47Ca was highly correlated with bone 47Ca (r = 0.973) and with bone 45Ca (r = 0.946). Correlation between tibia 47Ca and tibia 45Ca was r = 0.923. For the dairy products tested, our results indicated that extrinsic 47Ca was absorbed similarly to intrinsic 45Ca. Moreover, the percent of radioactive dose retained in bone appears to be a valid indicator of relative bioavailability of food Ca.

Animals↗
PubMed1989

Paradoxical effects of isothiocyanate analog of tolazoline on rat aorta and human platelets.

The isothiocyanate analog (IBI) of tolazoline produced contraction of the rat aortic strip, with an ED50 value of 1.63 x 10(-5) M. The maximum contraction of the analog was nearly equal to that of tolazoline or phenylephrine. At 27 degrees C the tissue reactivity of phenylephrine and IBI was similar. When compared at equiactive concentrations, the total duration of contraction of IBI was three times longer than that of tolazoline. Thus, the longer duration of action of IBI may be attributed to the S=C=N group substitution of the molecule. IBI at 10(-6) M shifted the dose-response curve of phenylephrine to the right with reduction in maxima. Phentolamine and other alpha 1 or alpha 2 adrenoceptor blockers failed to block the responses of IBI in aorta, whereas verapamil or nifedipine blocked the response significantly. It appears that IBI is acting through calcium-channel-sensitive or calcium-receptor-related mechanism(s). In aspirin-treated platelets from human plasma, a distinct phase of aggregation induced by epinephrine can be blocked by IBI with KB of 2 x 10(-5) M. This indicates a small but selective alpha 2 related action of IBI. The aggregation induced by ADP or second component of aggregation induced by epinephrine were also blocked by IBI at concentrations comparable to that of the alpha 2-adrenoceptor-mediated response. This indicates a lack of specificity of IBI in differentiating various phases of aggregation. Therefore, as compared to tolazoline, IBI presents an interesting paradox in its interaction with various receptors or mechanisms in the vascular tissue and platelets.

Adrenergic alpha-Antagonists↗
PubMed1989

Effect of aromatic fluorine substitution on the alpha and beta adrenoceptor-mediated effects of 3,4-dihydroxytolazoline in the pithed rat.

The alpha and beta adrenoceptor-mediated effects of the catecholimidazoline, 3,4-dihydroxytolazoline, and its 2-, 5- and 6-aromatic fluorine-substituted derivatives have been studied in the cardiovascular system of the pithed rat. All four compounds produced vasopressor responses in beta adrenoceptor blocked (propranolol, 3 mg/kg i.v.) animals. The pressor responses produced by all four compounds were antagonized by the selective alpha-1 adrenoceptor antagonist, prazosin (0.1 mg/kg i.v.), and were relatively unaffected by the selective alpha-2 adrenoceptor antagonist, rauwolscine (0.5 mg/kg i.v.), indicating that vasoconstriction produced by the fluorinated imidazolines was mediated exclusively by postjunctional vascular alpha-1 adrenoceptors. The rank order of potency at the alpha-1 adrenoceptor was: 5-fluoro greater than 2-fluoro greater than desfluoro greater than 6-fluoro. At higher doses, 3,4-dihydroxytolazoline and its fluorinated derivatives produced an alpha-2 adrenoceptor-mediated inhibition of neurogenic tachycardia in animals pretreated with prazosin, with all four compounds being equipotent. In rats with complete alpha adrenoceptor blockade [phenoxybenzamine (3 mg/kg i.v.), prazosin (0.1 mg/kg i.v.) and rauwolscine (1 mg/kg i.v.)] whose blood pressure was elevated by constant infusion of angiotensin II (150 ng/kg/min i.v.), high doses of the 2-fluoro-, but not the 5-, 6- or desfluoro catecholimidazoline derivatives, produced a beta-2 adrenoceptor-mediated vasodepressor response. All four compounds produced a beta-1 adrenoceptor-mediated positive chronotropic response in pithed rats with the rank order of potency being: 2-fluoro = 5-fluoro greater than desfluoro greater than 6-fluoro.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Epinephrine enantiomers: affinity, efficacy and potency relationships in rat smooth muscle tissues.

The purpose of this study was to examine the relationship between affinity and efficacy for the epinephrine enantiomers in rat tissues. Potency and was measured for (-)- and (+)-epinephrine in aorta, longitudinal muscle of portal vein, spleen and vas deferens. After partial alpha-adrenoreceptor inactivation with phenoxybenzamine, dissociation constant was estimated for each enantiomer and used to estimate efficacy. Whereas potency, affinity and efficacy vary between tissues, there is a constant relationship between (-)- and (+)-enantiomer; the enantiomeric ratio is constant for both potency and affinity. Efficacy is similar for the enantiomers in each tissue. The potency difference between epinephrine enantiomers at alpha-adrenoreceptors in rat tissues is due to differences in affinity rather than efficacy.

Animals↗
PubMed1988

Effects of benzylic hydroxyl substitution on the alpha-adrenoceptor blocking activity of tolazoline.

The R(-)- and S(+)-enantiomers of alpha-hydroxytolazoline, the benzylic hydroxy-substituted derivative of the alpha-adrenoceptor antagonist, tolazoline, were evaluated at alpha 1- and alpha 2-adrenoceptors in canine saphenous vein. Benzylic hydroxyl substitution of tolazoline in either the R(-) or S(+) configuration significantly decreased affinity at both alpha 1- and alpha 2-adrenoceptors. Differences in affinity between the R(-)- and S(+)-enantiomers were small, which is characteristic of imidazolines, but in marked contrast to phenethylamines where enantiomeric differences are large. The rank order of affinities at alpha 1- and alpha 2-adrenoceptors is tolazoline greater than S(+)-alpha-hydroxytolazoline = R(-)-alpha-hydroxytolazoline, which is different from that order predicted by the Easson-Stedman hypothesis (i.e., R(-) greater than S(+) = desoxy). The findings support our contention that phenethylamines and imidazolines interact differently with alpha-adrenoceptors.

Adrenergic beta-Antagonists↗
PubMed1988

Characterization of the inhibition of U46619-mediated human platelet activation by the trimetoquinol isomers. Evidence for endoperoxide/thromboxane A2 receptor blockade.

Sites of inhibition for the trimetoquinol (TMQ) isomers on 15S-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5Z,13E-dienoic acid (U46619)-, 12-O-tetradecanoylphorbol 13-acetate (TPA)- and A23187-induced human platelet activation were investigated. Experiments using washed human platelets were designed to characterize relationships among functional (aggregation, secretion) and biochemical (protein phosphorylation, metabolism of inositol phospholipids and radioligand displacement analysis) processes of platelet activation by U46619 and the specificity of inhibition by the TMQ isomers. Thromboxane A2 receptor stimulation by U46619 in human platelets resulted in a time- and concentration-dependent breakdown of inositol phospholipids [phosphatidylinositol 4,5-bisphosphate (PIP2), phosphatidylinositol 4-monophosphate (PIP), and phosphatidylinositol (PI)], phosphatidic acid (PA) accumulation, phosphorylation of 20 and 45 kD proteins, aggregation and serotonin secretion. The TMQ isomers stereoselectively inhibited all U46619-mediated platelet activation processes. R(+)-TMQ was 40- and 22-fold more potent than S(-)-TMQ as an inhibitor of U46619-induced platelet aggregation and serotonin secretion respectively. In addition, R(+)-TMQ blocked U46619-induced 20 kD protein phosphorylation, 45 kD protein phosphorylation, PIP2, PIP and PI breakdown, and PA accumulation with a potency which was 8-, 13-, 45-, 37-, 33- and 33-fold greater than the S(-)-isomer respectively. In contrast to S(-)-TMQ, R(+)-TMQ produced a concentration-dependent inhibition of specific [3H]U46619 binding to endoperoxide/thromboxane A2 receptor sites in washed platelets. In other experiments, S(-)-TMQ was more potent than R(+)-TMQ as an inhibitor of TPA- and A23187-induced platelet aggregation and serotonin secretion, and of TPA-induced phosphorylation of 45 and 20 kD proteins. The inhibitory potencies of S(-)-TMQ against TPA- or A23187-induced responses were similar to those needed for antagonism of U46619-mediated platelet activation. In contrast, much higher concentrations of R(+)-TMQ were required for blockade of TPA or A23187 versus U46619-mediated responses in human platelets. Taken collectively, the data show that the TMQ isomers interfered with the endoperoxide/thromboxane A2 receptor-mediated phospholipase C-signal cascade of inositol phospholipid hydrolysis, calcium mobilization, and protein phosphorylation leading to platelet aggregation and secretion. R(+)-TMQ acted as a pharmacologically selective and highly stereospecific [R(+)-TMQ much greater than S(-)-TMQ] antagonist of endoperoxide/thromboxane A2 receptor sites in platelets.(ABSTRACT TRUNCATED AT 400 WORDS)

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