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Biomedical subjects

D D Miller

Publications and source records attributed to D D Miller.

At least 181 records · Page 10Linked to original sources
PubMed1991

Lactose, calcium source and age affect calcium bioavailability in rats.

Calcium bioavailability was defined as either retention of 45Ca in tibias (Experiment 1) or retention of 47Ca in carcasses (Experiment 2). In Experiment 1, rats (age 21, 40 or 100 d) were fed purified meals extrinsically labeled with 45Ca. The meals contained either 0.5% Ca (control) or 1% Ca [control supplemented with CaCO3, calcium citrate-malate (CCM), milk or cheese] and either no lactose or 20% lactose. Lactose increased Ca bioavailability (P less than 0.05) from the control and milk meals in all age groups. Increases from CCM and CaCO3 were significantly only in the 21-d-old group. Lactose did not affect bioavailability from cheese. In Experiment 2, suckling rats (age 7, 12 or 17 d) were gavaged with 47Ca-labeled milk (fluid skim or lactose-hydrolyzed fluid skim) or an aqueous CaCl2-casein mixture (containing either no sugar, glucose + galactose, or lactose). Bioavailability from milk was higher than from lactose-hydrolyzed milk in all age groups. Lactose and glucose + galactose increased bioavailability over the sugar-free CaCl2-casein mixture in all age groups. Data from these experiments show that lactose enhances Ca bioavailability at several stages of development and the effect is not markedly diminished by high Ca diets. Lactose increases Ca bioavailability from a variety of sources but the magnitude of the effect may vary among sources.

Aging↗
PubMed1991

The assay of clozapine and N-desmethylclozapine in human plasma by high-performance liquid chromatography.

A high performance liquid chromatographic method for the simultaneous quantitation of clozapine--a member of the dibenzodiazepine class of antipsychotic drugs--and its reduced metabolite in human plasma has been developed. Clozapine and N-desmethylclozapine are concentrated from blood samples by liquid-liquid extraction, followed by reverse-phase liquid chromatography. Accuracy of the determination is ensured by application of an internal standard, protriptyline, which is closely related to clozapine. A detection limit of 15 ng/mL for clozapine and 30 ng/ml for N-desmethylclozapine was achieved.

Chromatography, High Pressure Liquid↗
PubMed1991

In vivo technetium-99m S12 antibody imaging of platelet alpha-granules in rabbit endothelial neointimal proliferation after angioplasty.

To examine the specificity of technetium-99m monoclonal antibody (S12) imaging for identifying activated platelets at interventional injury sites in atherosclerotic rabbit arteries, subgroups of unheparinized rabbits (n = 39) underwent serial percutaneous transluminal aortic angioplasty (PTA) procedures (with or without intravascular stent placement) followed by in vivo and then ex vivo gamma camera imaging, scanning, and immunoelectron microscopy to determine the intravascular loci of S12 Fab' antibody binding. Despite angiographic vessel patency, image-derived ratios of in vivo S12 binding in injured versus uninjured vascular segments were significantly increased (p less than 0.05) after one PTA (1.3 +/- 0.17, n = 7), PTA twice at 6-week intervals (1.4 +/- 0.22, n = 7), and PTA plus stent placement (1.6 +/- 0.28, n = 7) compared with control experiments (1.1 +/- 0.13, n = 7). Ex vivo imaging of blood-free excised aortas confirmed S12 localization at PTA (2 +/- 0.4, n = 3) and PTA plus stent placement (5 +/- 3.8, n = 7) sites (both p less than 0.05 versus controls). S12 antibody uptake decreased significantly (p less than 0.05) at 1 week after PTA plus stent placement in vivo (1.1 +/- 0.10, n = 4) and ex vivo (1.6 +/- 0.7, n = 3). Electron microscopic studies confirmed dense platelet, fibrin, and red blood cell deposition in regions of acute injury, with endothelial neointimal proliferation at 1 week after PTA. Immunoelectron microscopic studies confirmed specific in vivo S12 binding (22:1 versus nonrelevant IgG) at sites of alpha-granule GMP-140 expression in activated platelets. Therefore, S12 studies may be useful to localize sites of platelet-derived mitogen release at arterial PTA injury sites.

Angioplasty, Balloon↗
PubMed1991

Clozapine and norclozapine plasma concentrations and clinical response of treatment-refractory schizophrenic patients.

OBJECTIVE: Clozapine, an atypical antipsychotic, has been estimated to be effective in 30% of treatment-refractory schizophrenic patients. The authors hypothesized that if a dose-response relationship was obvious for this drug, the response rate could be significantly amplified. METHOD: Following an 8-24-day dose titration phase, 29 inpatients with treatment-resistant schizophrenia diagnosed according to DSM-III-R were given a clozapine dose of approximately 400 mg/day for 4 weeks; blood samples were obtained weekly during this period. RESULTS: A receiver operator curve demonstrated that the threshold clozapine plasma concentration for therapeutic response was 350 ng/ml. Sixty-four percent of the patients with clozapine plasma concentrations greater than 350 ng/ml responded, whereas only 22% of the patients with concentrations less than 350 ng/ml responded. CONCLUSIONS: Use of clozapine blood levels as a predictor for treatment response in treatment-refractory schizophrenic patients appears worthwhile, since the measurement's sensitivity for response was 64% and the specificity for nonresponse was 78%.

Adult↗
PubMed1991

A case of clozapine-induced neuroleptic malignant syndrome.

The treatment of psychotic symptoms in patients with a previous history of neuroleptic malignant syndrome (NMS) remains a dilemma. The authors describe a case in which clozapine caused NMS in a schizophrenic man who had previously experienced NMS during treatment with various antipsychotics. To their knowledge, this is the first report of "classical" NMS caused by clozapine alone.

Antipsychotic Agents↗
PubMed1991

Demonstration of differential post-stenotic myocardial technetium-99m-teboroxime clearance kinetics after experimental ischemia and hyperemic stress.

The clearance kinetics of the perfusion tracer 99mTc-teboroxime were evaluated in post-stenotic and normal myocardium using dynamic planar gamma camera imaging in pre-instrumented dogs in the control state (n = 9) and following total occlusion (2 min), pharmacologic stress with adenosine [80 and 160 micrograms/kg/min] or dipyridamole, and rapid atrial pacing (220/min). Technetium-99m-teboroxime clearance in normal myocardium was accelerated by adenosine and by dipyridamole compared to the control state (8.9 +/- 1.1 and 9.3 +/- 1.9 min versus 11.9 +/- 1.8 min; p less than 0.05). Post-stenotic 99mTc-teboroxime clearance half-time was most significantly prolonged compared to nonoccluded contralateral perfusion zones by 160 micrograms/kg/min adenosine stress (11.2 +/- 3.7 versus 6.3 +/- 1.5 min) and by complete coronary occlusion (12.1 +/- 3.3 versus 6.6 +/- 1.2 min; both p less than 0.05). Differential tracer clearance from post-stenotic versus nonoccluded zones produced quantitative evidence of relative defect "redistribution" in 71% of maximal stress studies at a mean of 8.8 +/- 2.5 min postinjection. Sensitivity, specificity, and diagnostic accuracy of prolonged regional 99mTc-teboroxime clearance rates for post-stenotic perfusion abnormalities were 62%, 100% and 81% in maximal stress studies. Future clinical trials of exercise and nonexercise stress 99mTc-teboroxime imaging should consider these kinetic characteristics and examine the correlates of perfusion defect "redistribution."

Adenosine↗
PubMed1991

Effect of phenytoin on plasma clozapine concentrations in two patients.

Little is known about interactions of other drugs with the recently marketed antipsychotic clozapine. Two cases in which the addition of phenytoin caused a decrease in plasma clozapine concentrations and worsening of psychoses are described, and possible explanations are discussed.

Adult↗
PubMed1991

Evaluation of the patient with stable angina following coronary artery bypass surgery.

Bypass graft stenosis and occlusion are relatively common events, occurring eventually in the majority of patients who survive beyond 5 years after coronary artery bypass graft surgery. These processes, in combination with progressive native coronary artery disease, lead to recurrent angina and an increased need for medication in most patients late after surgery. Patients with unstable ischemic symptoms generally should proceed directly to coronary arteriography, whereas patients with stable angina may be candidates for noninvasive testing to evaluate their risk and the extent of myocardial jeopardy. If the initial revascularization procedure is successful, preoperative thallium 201 imaging abnormalities should be reversed. Persistent abnormalities beyond 6 months after revascularization indicate incomplete revascularization or perioperative infarction. Defects noted in the immediate postoperative period may be areas of myocardial stunning or hibernation, which can require up to 6 months to reverse. If chest pain recurs after revascularization, a normal thallium 201 perfusion pattern indicates that the symptom is probably not ischemic in nature. Thallium 201 perfusion abnormalities may precede symptoms by several months and may be the only indication of significant myocardial ischemia in patients with silent ischemia. Advanced tomographic imaging techniques, such as single photon emission computed tomography (SPECT), should theoretically improve disease detection and localization following revascularization. Practically speaking, only the left anterior descending coronary bed is well evaluated by these tomographic imaging techniques. The sensitivity and specificity of SPECT imaging for evaluation of posterior circulation abnormalities remains unacceptably low. Complexities of competitive flow and collateralization that may exist in the postoperative period make it difficult to relate perfusion abnormalities to a specific graft stenosis. However, tomographic perfusion imaging may provide useful correlative information on the functional impact of bypass graft stenoses in patients with recurrent angina who have undergone coronary angiography and in whom the angiographic indications for repeat surgery or angioplasty are not compelling. Newer tomographic and metabolic imaging techniques such as CT, NMRI, and PET remain unproven as diagnostic tests for the evaluation of unselected patient populations presenting with recurrent angina following revascularization surgery.

Angina Pectoris↗
PubMed1990

Pharmacological evaluation of the beta-adrenoceptor agonist properties of N-benzyl substituted trimetoquinol analogues.

The beta 1- and beta 2-adrenoceptor agonist properties of trimetoquinol (TMQ, I) and N-benzyl ring substituted TMQ analogues (II, 4'-methylbenzylTMQ; III, 4'-chloro-benzylTMQ; IV, 4'-methoxybenzylTMQ; V, 4'-nitrobenzylTMQ; VI, 3',4'-dichlorobenzylTMQ; and VII, 4'-aminobenzylTMQ) were studied in guinea pig atria and trachea. All compounds gave concentration-dependent responses in atria and trachea, and the rank order of beta-adrenoceptor agonist potency was I greater than VII greater than II greater than V greater than IV greater than VI greater than III and I greater than VII greater than IV = VI greater than V greater than III greater than II, respectively. Whereas the N-benzyl substitution reduced potency for beta-agonist activity, the beta 2/beta 1-selectivity ratio was enhanced by addition of groups to the N-benzyl ring, and the rank order of beta 2-selectivity was VI (10-fold) greater than III (8-fold) = IV (8-fold) greater than VII (3-fold) greater than V = I greater than II. The results show that varying the nature of substituents on the N-benzyl ring of TMQ produces compounds which retain greater beta 2-selectivity.

Adrenergic beta-Agonists↗
PubMed1990

Pharmacological evaluation of the beta-adrenoceptor agonist and thromboxane receptor blocking properties of 1-benzyl substituted trimetoquinol analogues.

The beta 1- and beta 2-adrenoceptor agonist and thromboxane A2 (TXA2) antagonist properties of trimetoquinol (TMQ, I) and 1-benzyl substituted TMQ analogues [3'-iodo-4',5'-dimethoxy TMQ, II; 3',5'-diiodo-4'-dimethoxy TMQ, III; 3',4'-dimethoxy-5'-nitro TMQ, IV; 3',4'-dimethoxy-5'-amino TMQ; V; and 3',4'-dimethoxy TMQ, VI] were studied in guinea pig atria (beta 1) and trachea (beta 2), and in rat thoracic aorta and human platelets, respectively. The rank order of agonist activities in beta 1- and beta 2-adrenoceptor tissues was IV greater than or equal to I greater than II greater than V greater than III greater than VI and I greater than II = IV = V greater than VI greater than III, respectively. An increase of beta 2/beta 1-selectivity (2- to 3-fold) was observed for analogues V and VI as compared to TMQ. The rank order of inhibitory potency against U46619-induced contraction of rat aorta and human platelet aggregation and secretion was the same (I = II = III greater than IV greater than V greater than VI). The results show that varying the substituents at the 3'- and 5'-positions of the trimethoxybenzyl group of TMQ produces compounds which give different profiles of biological activity for beta-adrenoceptor agonism versus TXA2 antagonism. Certain TMQ analogues, notably analogue V, showed a greater selectivity as beta 2-receptor agonists and TXA2 antagonists in vascular smooth muscle than the parent drug (TMQ), and the iodinated analogues (II and III) have promise as potential radioligands or photoaffinity probes for thromboxane A2 receptors.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1990

Reduced haloperidol plasma concentration and clinical response in acute exacerbations of schizophrenia.

Twenty-nine hospitalized patients suffering acute exacerbations of schizophrenia were treated for 2 weeks with fixed daily oral doses of haloperidol prospectively calculated to achieve a haloperidol plasma concentration of either 8-18 ng/ml or 25-35 ng/ml. Reduced haloperidol as well as haloperidol concentrations were assayed to determine if the former enhanced the predictability of response. Wee 2 haloperidol plasma concentrations were negatively correlated to clinical response as measured by the percentage change in the BPRS score from baseline (r = -0.43, P less than 0.05). In contrast, week 2 plasma concentrations of reduced haloperidol, total haloperidol (haloperidol + reduced haloperidol), and reduced haloperidol/haloperidol ratio did not correlate with the change in the BPRS score. Chi-square analysis concluded that patients with ratios greater than one were no less likely to be treatment responders (less than 25% improvement in BPRS from baseline and week 2 BPRS less than 55) than those with ratios less than one. Although these data lend additional support to reports of a curvilinear relationship between haloperidol plasma concentration and clinical response, they also suggest that reduced haloperidol plasma concentrations are of no value in predicting treatment response.

Acute Disease↗
PubMed1990

Radionuclide evaluation of aortic regurgitation.

The timing for valve replacement in patients with aortic regurgitation remains a complex clinical problem. Rest radionuclide angiography measurement of ejection fraction is a simple informative study to help evaluate the appropriate timing for valve replacement in the asymptomatic patients or those with mild symptoms. In patients with normal ejection fractions the disease probably has not yet evolved to the phase in which valve replacement is essential. If the ejection fraction is mildly depressed (0.40 to 0.49) the time is right for intervention. By the time the ejection fraction falls to less than 0.40 the left ventricle is likely damaged and unlikely to regain normal function. If the patient has severe symptoms with maximal medical therapy, surgery is indicated no matter what the ejection fraction. The latter situation can arise especially when aortic regurgitation evolves over a short period, as might be the case in patients with bacterial endocarditis. A single ejection fraction measurement is not as reliable as serial studies. If, for example, the ejection fraction (under similar circumstances) falls from the greater than or equal to 0.50 range to the 0.40 to 0.49 range, the physician should be altered to the possibility that the left ventricle is deteriorating, and surgery should be considered. It should be understood that multiple hemodynamic factors in aortic regurgitation can alter the ejection fraction and could limit its use as the sole measure of left ventricular performance. Other systolic or diastolic parameters cannot be relied on in isolation as an indication or contraindication for aortic valve replacement. The exercise ejection fraction response reflects the total stroke volume and does not distinguish between regurgitant flow and forward flow. It is therefore possible to observe a decrease in ejection fraction in association with an increase in forward stroke volume during exercise as a result of an increase in heart rate and a decrease in peripheral resistance. Accordingly, it is not appropriate to compare the ejection fraction during exercise in aortic insufficiency with the expected response of the normal ventricle. Exercise position (sitting vs. supine) affects loading conditions and ejection fraction response. Because of the complexity of the exercise ejection fraction response, it is not clear that there is a role for exercise ejection fraction measurements in determining the appropriate time for aortic valve replacement. Criteria based on supine exercise may not be applicable to studies in the upright position.(ABSTRACT TRUNCATED AT 400 WORDS)

Aortic Valve↗
PubMed1990

Hemodynamic effects of 1-[3,4-dihydroxyphenyl]-1,2-diaminoethane versus norepinephrine during ventricular fibrillation and cardiopulmonary resuscitation.

We hypothesized that substitution of the hydroxyl group (OH) on the beta carbon of norepinephrine (NE) with an amino group would yield a compound, 1-(3,4-dihydroxyphenyl)-1,2-diaminoethane (DHPDAE), that would maintain the hemodynamic properties of NE during CPR, but would decrease the rate of post-defibrillation dysrhythmias. Six mixed breed swine weighing greater than 28 kg were studied. The animals were instrumented for cerebral (CBF) and myocardial blood flow (MBF) measurements. Ventricular fibrillation (VF) was induced. After 10 min of VF, CPR was begun. After 3 min of CPR, 2.5 mg/kg of DHPDAE was administered and CPR continued. Defibrillation was attempted 3.5 min after drug administration. CBF, MBF and defibrillation rates were compared to an historical control group receiving 0.16 mg/kg of NE. Outcome variables were compared using a Wilcoxon Rank Sum test and Fisher-exact test. NE significantly improved CBF and MBF compared to DHPDAE. All the animals in the NE group were successfully defibrillated into a perfusing rhythm. Sixty percent of the NE treated animals experienced post-defibrillation ventricular dysrhythmias. None of the animals in the DHPDAE were successfully defibrillated into a perfusing rhythm. Substitution of the hydroxyl group on the beta-carbon of NE with an amino group significantly decreases the hemodynamic properties of the parent molecule.

Animals↗
PubMed1990

Synthesis and alpha 2-adrenoceptor effects of substituted catecholimidazoline and catecholimidazole analogues in human platelets.

It is known that the steric requirements for the interactions of catecholamines and catecholimidazolines with alpha 1- and alpha 2-adrenoceptors are different. New analogues of desoxycatecholimidazoline (1), desoxycatecholimidazole (3), benzylic hydroxyl substituted imidazole (4), and the aromatic fluorine substitution analogues of 1 at the 2 (5), 5 (6), and 6 (7) positions, and a set of asymmetric 4-substituted catecholimidazolines, S-8 and R-8, were prepared and tested for interaction with alpha 2-adrenoceptors in human platelets. With the exception of 3, all compounds were selective for alpha-adrenoceptor-mediated responses in human platelets. Introduction of a double bond in imidazoline 1 to give an imidazole 3 or the introduction of a benzylic hydroxyl group to 3, as in 4, reduced the inhibition of platelet aggregation with a rank order potency of 1 greater than 3 greater than 4. Fluorine atom substitution at the 2-, 5-, or 6-positions only slightly modified the inhibitory activity of 1. Each analogue (1, 3-7) produced alpha 2-mediated inhibition of platelet adenylate cyclase and can be classified as a partial agonist. The inhibition potency of S-8 and R-8 against epinephrine-induced aggregatory responses were greatly different, and only R-8 and 4 were alpha 2-agonists on human platelet function. Our studies provide further evidence for the differential interaction of catecholamines and catecholimidazolines in alpha 1- and alpha 2-adrenoceptor systems.

Blood Platelets↗
PubMed1990

Amino acid sequence requirements for the association of apocytochrome c with mitochondria.

To examine the amino acid sequence requirements for the biphasic association of Drosophila melanogaster apocytochrome c with mouse liver mitochondria in vitro, recombinant constructs of the protein were prepared. Removal of the C-terminal sequence to residue 58 had little influence, but truncation to residue 50 decreased the association to low levels and removal to residue 36 was even more effective. However, a mutant missing the segment between residues 35 and 66 was fully functional, but, when the C-terminal segment from residue 36 was replaced with a noncytochrome c sequence, the high-affinity phase of the association was lost. A mutant in which residues 90, 91, 92, 96, and 100 were replaced by lysine, leucine, proline, proline, and proline, respectively, to prevent the possible formation of the C-terminal alpha-helix and another mutant in which the C-terminal segment from residue 90 to residue 120 was a noncytochrome c sequence had normal association. In contrast, replacing lysine-5, -7, and -8 by glutamine, glutamic acid, and asparagine, respectively, resulted in loss of the high-affinity phase. The same mutations in the apoprotein lacking the segment between residues 35 and 66 caused, in addition, a decrease of the low-affinity phase association. Thus, the N-terminal region is most critical for apocytochrome c association, but alternative segments of the central and/or C-terminal region can be utilized, where noncytochrome c sequences are ineffective. These results emphasize the wide disparity between the structural requirements for association with mitochondria and for the production of a functional holoprotein.

Amino Acid Sequence↗
PubMed1990

Haloperidol plasma levels and acute clinical change in schizophrenia.

Twenty-five inpatients with acute exacerbations of schizophrenia (by Research Diagnostic Criteria) or schizoaffective disorder underwent a prospective haloperidol dosing procedure and were assigned fixed doses chosen to yield a distribution of haloperidol plasma levels above and below a hypothesized upper therapeutic limit of 18 ng/ml. Changes in Brief Psychiatric Rating Scale scores after 1 week of treatment were negatively correlated with haloperidol plasma levels, and the statistically optimum cutoff point fell near the predicted 18 ng/ml. Plasma level/response relationships over the subsequent 3 weeks were weaker but patients with higher plasma levels had consistently less improvement.

Adult↗
PubMed1990

Effects of thromboxane A2 on thoracic aorta of young and old rats: use of selective thromboxane receptor antagonists.

Thromboxane A2 (TXA2) is a bioactive metabolite of arachidonic acid which produces vascular smooth muscle contraction and blood platelet aggregation. The goal of this study is to establish whether there are age-dependent differences of vascular contractility to TXA2. Thoracic aorta of F-344 rats of age 4-6 months (young) and 22-23 months (old) were used as a model to examine responses to U46619 [(15S)-hydroxy-11 alpha, 9 alpha-(epoxymethano)prosta-5Z,13E-dienoic acid; a TXA2 agonist] alone or in the presence of prostanoid (SQ 29,548) or nonprostanoid (trimetoquinol, TMQ) endoperoxide/TXA2 receptor antagonists. Maximal contractile responses (84 and 89% relative to KCl) and EC50 values (23 and 55 nmol/l, respectively) to U46619 were the same in aortic strips of young and old animals. Experimentally determined pA2 and pKB values for SQ 29,548 and TMQ as antagonists of U46619-mediated contraction were unchanged in aorta of young (9.09 and 5.83, respectively) and old (9.41 and 6.10, respectively) rats. We conclude that the reactivity and population of TXA2 receptors in rat vascular smooth muscle are unaffected by the aging process.

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