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D D Miller

Publications and source records attributed to D D Miller.

At least 145 records · Page 8Linked to original sources
PubMed1994

Plasma clozapine concentrations as a predictor of clinical response: a follow-up study.

We investigated the relationship between plasma clozapine concentrations and clinical response in treatment-refractory schizophrenic patients. In a previous study, we found that plasma drug concentrations above 350 ng/mL maximized clinical response in a group of 29 patients. This study represents a follow-up of these original 29 patients over approximately 2 1/2 years of clozapine treatment. We found that during the initial 6-week trial of clozapine, 38% (N = 11) of the patients were considered to be responders. With continued treatment, we found that 58% (14 of 24) were classified as responders. Consistent with our previous study, we observed that plasma concentrations were helpful in predicting response. Five of 7 patients who had unsatisfactory response became responders when their plasma clozapine concentrations increased to above 350 ng/mL. We conclude that the assessment of plasma clozapine concentrations as a guide to dose adjustment may be useful in maximizing response.

Adult↗
PubMed1993

Halogen-substituted trimetoquinol analogs as thromboxane A2 receptor antagonists in platelets and aorta.

Trimetoquinol (TMQ) is a non-prostanoid compound that blocks prostaglandin H2/thromboxane A2 (TXA2) receptor-mediated responses initiated by a prostaglandin (PG) H2 analog, U46619, in human platelets and rat aorta. Ring fluorine-substituted TMQ analogs selectively antagonized PG-dependent human platelet activation induced by U46619, arachidonic acid, collagen, ADP or epinephrine; and were about 300-fold less potent as inhibitors of PG-independent responses mediated by thrombin or bacterial phospholipase C. For each inducer of the PG-dependent pathway, the rank order of inhibitory potency was identical (TMQ > 8-fluoro-TMQ > 5-fluoro- TMQ). Iodine substitution yielded a similar rank order of antagonism against U46619-induced platelet activation (TMQ > 8-iodo-TMQ > 5-iodo-TMQ), and all TMQ analogs inhibited platelet aggregation in whole blood as well as in platelet-rich plasma. Inhibition of specific [3H]SQ 29,548 binding by TMQ analogs was highly correlated with inhibition of functional responses to U46619. Radioligand binding experiments using TMQ analogs with rat platelets showed no interspecies difference in comparison with human platelets. The rank order of inhibitory potencies for the fluorinated (but not iodinated) TMQ analogs changed in rat thoracic aorta with 8-fluoro-TMQ > TMQ > or = 5-fluoro-TMQ as antagonists of U46619-induced vascular contraction. These findings demonstrate that the primary mechanism of antiplatelet action of TMQ analogs is related to a blockade of TXA2 receptor sites, and ring-halogenated TMQ analogs distinguish between TXA2-mediated functional responses in vascular smooth muscle and platelets.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1993

The interaction of ammonium, sulfonium, and sulfide analogues of metoclopramide with the dopamine D2 receptor.

A series of permanently charged ammonium and sulfonium analogues of metoclopramide as well as a permanently uncharged sulfide analogue were synthesized and evaluated for their ability to inhibit apomorphine-induced responses on mouse striatal slices. Three of the four permanently charged analogues were found to inhibit apomorphine's effects, although at higher concentrations than either metoclopramide or its dimethyl analogue. In contrast, the sulfide analogue was inactive at concentrations up to 100 microM. These findings are consistent with earlier studies of chlorpromazine and sulpiride analogues and provide further evidence that dopamine antagonists bind in their charged molecular forms to anionic sites on the D2 receptor. Further, the results of this study in conjunction with those of our earlier sulpiride study would seem to indicate that differences in the biological profiles of metoclopramide, a type 1 benzamide useful as a gastric prokinetic agent, and sulpiride, a type 2 benzamide useful for its antipsychotic effects, are not due to any appreciable differences in the binding of the basic nitrogen atom of these molecules.

Animals↗
PubMed1993

Comparison of the Asymptomatic Cardiac Ischemia Pilot and modified Asymptomatic Cardiac Ischemia Pilot versus Bruce and Cornell exercise protocols.

The Asymptomatic Cardiac Ischemia Pilot (ACIP) and modified ACIP treadmill exercise protocols were developed to test patients with coronary artery disease and to linearly increase work load between stages. The physiologic changes that occurred with ACIP and modified ACIP were compared to those with the Bruce and Cornell protocols in 28 normal subjects and 16 men with coronary artery disease. The exercise protocols were randomly assigned over 2 days, and gas exchange data were obtained continuously with each test. In normal subjects, the peak heart rate, systolic blood pressure, peak oxygen consumption rate (VO2) and minute ventilation were similar for the 4 protocols tested, with exercise time shortest for the Bruce protocol in comparison with the ACIP, modified ACIP and Cornell protocols (10.2 +/- 3.1 vs 13.4 +/- 4.9, 13.9 +/- 4.5, and 15.0 +/- 4.2 minutes, respectively; p < 0.001). The difference between predicted and observed VO2 was smallest for the ACIP protocol (37.0 +/- 11.0 vs 35.8 +/- 13.5 ml/kg/min) and greatest for the Bruce protocol (41.1 +/- 11.8 vs 36.7 +/- 15.0 ml/kg/min) in normal subjects, as well as in patients with coronary artery disease (ACIP protocol 26.9 +/- 7.1 vs 22.5 +/- 6.7, and Bruce protocol 29.1 +/- 7 vs 22.6 +/- 5.7 ml/kg/min, respectively). The ratio of VO2 to work rate, expressed as a slope, was similar in normal subjects for the 4 protocols tested. However, in patients with coronary artery disease, the slope was 0.84 and 0.83 for the ACIP and modified ACIP protocols, respectively, versus 0.61 and 0.71 for the Bruce and Cornell protocols, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Structure-activity relationship of glycine betaine analogs on osmotolerance of enteric bacteria.

Bacterial cells have the ability to accumulate compatible solutes within the cytoplasm to maintain their osmolarity above that of the extracellular milieu. Glycine betaine (GB) and its biosynthetic precursor choline (Chol) are the major compatible solutes that bacteria accumulate when osmotically challenged. Different osmotically triggered active transport mechanisms have been identified for GB and Chol. In the present study we examined the bioisosteric replacement of the carboxylic group of GB with sulfonic, phosphonic or benzenesulfonamido groups. The sulfonic acid analog (sulfobetaine, compound 3) showed osmoprotectant activity equivalent to that of GB. In addition, we tested the possibility of utilizing GB/Chol transport systems to deliver cytotoxic analogs of GB into three strains of E. coli that differed in their salt resistance. We found that N1-betainyl-N4-(haloacetyl)sulfanilamides (compounds 17c-e) that are GB analogs containing alkylating side chain within their structures inhibited the bacterial growth of the tested standard and salt sensitive strains of E. coli. We also showed that the (N-methyl-cyclic ammonio)methanesulfonates (compounds 21a-c) are able to block Chol transport system in both the standard and the salt-sensitive E. coli strains used. At the concentration used (0.1 mM), none of the tested compounds showed any significant effect on the salt-resistant strain used.

Betaine↗
PubMed1993

Effect of novel compound, 1-methyl-1-piperidino methane sulfonate (MPMS), on the osmoprotectant activity of glycine betaine, choline and L-proline in Escherichia coli.

A novel compound, 1-methyl-1-piperidino methane sulfonate (MPMS), was found to block the osmoprotectant activity of choline and L-proline, but not glycine betaine in Escherichia coli. MPMS was more active against salt-sensitive than salt-resistant strains, but had no effect on the salt tolerance of a mutant which was unable to transport choline, glycine betaine and proline. Growth of E. coli in NaCl was inhibited by MPMS and restored by glycine betaine, but not by choline or L-proline. Uptake of radiolabeled glycine betaine, choline or L-proline by cells grown at high osmolarity was not inhibited when MPMS and the radioactive substrates were added simultaneously. Preincubation for 5 min with MPMS reduced the uptake of choline and L-proline, but not glycine betaine. Similar incubation with MPMS had no effect on the uptake of radiolabeled glucose or succinate. The toxicity of MPMS was much lower than that of the L-proline analogues L-azetidine-2-carboxylic acid and 3,4-dehydro-DL-proline. The exact mechanism by which MPMS exerts its effect is not entirely clear. MPMS or a metabolite may interfere with the activity of several independent permeases involved in the uptake of osmoprotective compounds, or the conversion of choline to glycine betaine, or effect the expression of some of the osmoregulatory genes.

Azetidinecarboxylic Acid↗
PubMed1993

Rationale for the rational development of new cardiac imaging agents.

There are several prerequisites for the development of new diagnostic cardiovascular radiopharmaceuticals. Agents which are proposed for clinical use must offer significant advantages in one or more of the following categories: I) Radiopharmacy [dosimetry, dose preparation, dose availability]; II) Imaging characteristics [spatial and temporal resolution, radiotracer biokinetics, patient throughput and acquisition protocols]; and III) Measurement of a previously unmeasurable physiologic or pharmacologic event [metabolic pathways, receptors, neural pathways, preclinical disease]. Technetium-99m-based radiopharmaceuticals are particularly attractive, in view of their excellent characteristics for imaging with the Anger gamma camera. In addition, the increasing use of tomographic imaging and reconstruction techniques has magnified the importance of developing radiotracers with minimal soft tissue attenuation effects. Technetium-99m and positron emitting radioisotopes offer this advantage. A wide choice of biologically and pharmacologically relevant ligands are available for complexing with these radiotracers. The clinical studies are underway in order to validate these new agents, and to determine their value in the modern practice of nuclear medicine. Technetium-99m sestamibi is just one example of a novel radiotracer with improved imaging characteristics that has undergone careful pre-clinical and clinical testing, and which has emerged as a useful diagnostic imaging agent. Future studies should be directed towards the development of tracers with well-defined biokinetic characteristics, which are advantageous for tomographic imaging. The future applications of tracer imaging techniques for the pre-clinical diagnosis of cardiovascular, oncologic and other medical conditions are significant and are expanding.(ABSTRACT TRUNCATED AT 250 WORDS)

Heart↗
PubMed1993

Comparative prognostic value of clinical risk indexes, resting two-dimensional echocardiography, and dipyridamole stress thallium-201 myocardial imaging for perioperative cardiac events in major nonvascular surgery patients.

The relative prognostic value of widely accessible resting two-dimensional echocardiographic ventricular function data has not been compared with recognized clinical and scintigraphic risk markers in patients who are unable to exercise before major nonvascular surgery. To this end, 53 consecutive patients aged 67 +/- 13 years undergoing preoperative evaluation (intraabdominal, 23%; orthopedic, 30%; thoracic, 9%; other, 38%) for known or suspected coronary artery disease were followed up to evaluate the prognostic value of these studies for the perioperative cardiac events (cardiac death [n = 4], myocardial infarction [n = 2], unstable angina [n = 3], and pulmonary edema [n = 8]) that occurred in 13 of the 53 patients (25%). Dipyridamole thallium-201 myocardial redistribution defects occurred in 15 (28%) patients. Resting echocardiographic left ventricular dysfunction was present in 21 (40%) patients. Multivariate analysis of clinical, echocardiographic, and scintigraphic risk predictors revealed that cardiac events were not predicted by clinical variables, including Goldman class or score. Cardiac events were independently predicted only by the presence of significant left ventricular dysfunction on resting two-dimensional echocardiography (p < 0.042) and dipyridamole thallium-201 defect redistribution (p < 0.026). A dipyridamole-induced reversible thallium-201 perfusion defect was predictive of subsequent cardiac death or myocardial infarction (p < 0.02), whereas left ventricular dysfunction on resting echocardiography was predictive of perioperative pulmonary edema (p < 0.023). We conclude that stress thallium-201 perfusion imaging and resting two-dimensional echocardiography provide independent prognostic information in patients undergoing major nonvascular surgery who are at significant risk for ischemic cardiac events and who are unable to perform standard exercise stress tests.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1993

Effect of antipsychotic withdrawal on extrapyramidal symptoms: statistical methods for analyzing single-sample repeated-measures data.

Using symptom severity ratings of extrapyramidal side effects (EPS) during a 4-week antipsychotic washout period, we illustrate particular problems associated with repeated measures of symptom severity and demonstrate four analysis methods. The often suggested analysis of variance and multivariate analysis of variance found no mean change in weekly Simpson Angus scores over the 4-week washout despite the fact that 43% had clinically significant EPS prior to drug discontinuation. On the other hand, the Friedman Analysis of Ranks and Cochran-Mantel-Haenszel (CMH) statistics found significant change over the washout period. These two less well-known techniques place fewer restrictions on the data, can be more sensitive to patterns of change, and may be more appropriate for psychiatric data. The CMH method is particularly attractive since it does not require complete data on all subjects as do many other techniques. This minimizes the number of cases lost to missing data and increases the generality of the results.

Adult↗
PubMed1993

Lean beef and beef fat interact to enhance nonheme iron absorption in rats.

Nonheme iron absorption is enhanced when meat replaces non-meat protein sources in a meal. Our objective was to examine the hypothesis that both lean and fat fractions of meat contribute to this enhancement. Weanling rats were assigned, according to a 3 x 3 factorial design, to one of nine nutritionally complete diets formulated to contain various combinations of protein (lean beef, skim milk or egg white) and fat sources (beef fat, milk fat or partially hydrogenated vegetable fat). Diets contained 20% protein and 20% fat. After 4 d of consuming the assigned diets, the rats were deprived of food overnight and offered a meal of their respective diet labeled extrinsically with 59FeCl3. Feeding of the unlabeled diets was continued for 14 d. Iron absorption was estimated from 59Fe retention, monitored by whole-body counting over the 14-d period. Absorption was highest from diets containing beef regardless of the fat source, but the combination of beef and beef fat was highest of all. In the comparison of absorption from the lean beef and other diets, there was significant interaction between lean beef and fat source on iron absorption. These results suggest that the iron absorption-enhancing properties of meat may involve an interaction between the lean and fat fractions of meat.

Absorption↗
PubMed1993

Interactions of nonprostanoid trimetoquinol analogs with thromboxane A2/prostaglandin H2 receptors in human platelets, rat vascular endothelial cells and rat vascular smooth muscle cells.

Trimetoquinol (TMQ), a nonprostanoid compound, inhibits thromboxane A2 agonist-induced responses in platelets and vascular smooth muscle. Sixteen TMQ analogs were used to examine the stereochemical requirements of the interaction with thromboxane A2/prostaglandin H2 (TP) receptor sites in human platelets (HP), and cultured rat vascular endothelial (RVEC) and smooth muscle (RVSMC) cells. [3H]SQ 29548 was used as the ligand for TP receptors. The receptor binding affinities of these TMQ analogs for TP receptors in HP, RVEC and RVSMC were highly correlated with each other, and to their reported inhibitory potency values against U46619-induced HP aggregation and serotonin secretion, and contraction of rat aorta. TP receptor binding affinities of TMQ and 8-fluoro TMQ isomers were highly stereoselective (R-isomer > S-isomer), and only the 8-fluoro TMQ isomers gave qualitatively different functional responses in rat aorta. The affinity of TMQ for TP receptors was increased by addition of iodine and fluorine atoms at the 5- and 8-positions of the catechol ring or by replacement of the methoxy groups with iodine atoms on the 1-benzyl ring system. The results indicate that: 1) the stereochemical requirements of TMQ analogs for interaction with TP receptors in these cell systems are the same; 2) although TMQ analogs act as TP receptor antagonists, differences in functional responses by 8-fluoro TMQ isomers in platelets and aorta are not explained by their relative binding affinities to TP receptors; and 3) asymmetric halogenated TMQ analogs should be useful as affinity probes for further characterization of TP receptors.

Adrenergic beta-Agonists↗
PubMed1993

Haloperidol dosing requirements: the contribution of smoking and nonlinear pharmacokinetics.

Previous data suggest the possibility that haloperidol daily dosing requirements may be confounded by smoking and, at higher doses, capacity-limited metabolism. Forty hospitalized patients suffering from an acute exacerbation of schizophrenia were treated for 2 weeks with fixed oral doses of haloperidol ranging from 10 to 70 mg/day (0.13 to 0.95 mg/kg/day) that produced mean steady-state concentrations between 4.5 and 55.4 ng/ml. No significant differences between the smoking and nonsmoking groups were obvious for the factors of weight, age, sex, daily doses, steady-state clearance, and steady-state haloperidol concentrations in plasma at week 1, week 2, and their mean. The hypothesis that the relationship between haloperidol dose and steady-state haloperidol concentration in plasma was affected by patients' smoking status and metabolic capacity was tested by multiple linear regression analysis and initially rejected. The relationship of dose to haloperidol concentration was fitted as a linear function. To improve the curve fit, the haloperidol concentrations and doses were transformed to their natural logs and then the regression line was refitted. The multiple regression analysis was repeated with the data in their transformed state. It was found that, although smoking status and dose of the drug did not independently affect the average haloperidol concentration, together they interacted in such a way that individual haloperidol concentrations were dependent on the smoking status at specific doses. Thus, two haloperidol dosing equations were generated, one for smokers and one for nonsmokers.

Adult↗
PubMed1992

Comparison of accuracy for detecting coronary artery disease and side-effect profile of dipyridamole thallium-201 myocardial perfusion imaging in women versus men.

Intravenous dipyridamole planar thallium-201 imaging is a safe and effective test for detection and prognosis of coronary artery disease (CAD) in the general population. The relative diagnostic accuracy and side-effect profile of dipyridamole thallium-201 stress imaging in women is not defined. Forty-three consecutive female and 71 male patients who underwent dipyridamole thallium-201 imaging (0.56 mg/kg) within 3 months of cardiac catheterization were studied. Scans were considered abnormal if fixed or reversible perfusion defects were detected. Stenosis severity of greater than or equal to 50% luminal diameter reduction of any artery defined CAD. Overall sensitivity for detection of CAD was 0.87 in women and 0.94 in men; specificity was 0.58 in women and 0.63 in men (p = not significant). Sensitivity for detection of 1-vessel CAD was 0.60 in women and 0.94 in men (p = 0.001). The sensitivity for detection of multivessel CAD (with or without surgical revascularization) was 1.0 and 0.94 in women and men, respectively. Adverse effects were reported in 62% of women and in 38% of men (p = 0.01). There was no significant difference in the incidences of chest pain, headache, nausea, flushing or electrocardiographic changes. The incidences of severe ischemia and dizziness were higher in women. Possible explanations for this difference in adverse effects include gender differences in the volume of distribution of dipyridamole due to varied fat-to-muscle ratios and different subjective nocioceptive sensitivities to the effects of dipyridamole. Overall sensitivity and specificity are comparable between the sexes.

Chi-Square Distribution↗
PubMed1992

Selective irreversible inhibitors of aldose reductase.

A series of 5-substituted-1,3-dioxo-1H-benz[de]isoquinoline-2(3H)-acetic acid analogues have been examined as irreversible inhibitors of aldose reductase. The 5-alpha-bromoacetamide and 5-alpha-iodoacetamide analogues 5 and 6 gave irreversible inhibition of aldose reductase while the 5-alpha-chloroacetamide analogue 3 did not show this type of inhibition. Protection studies indicate that irreversible inhibitions are occurring at the inhibitor binding site. Comparative irreversible inhibition studies with rat lens aldose reductase (RLAR) and rat kidney aldehyde reductase (RKALR) indicate that 5-alpha-haloacetamide analogues 5 and 6 are much more effective inhibitors of RLAR.

Aldehyde Reductase↗
PubMed1992

Synthesis and alpha-adrenergic activities of 2- and 4-substituted imidazoline and imidazole analogues.

Seven analogues of medetomidine and naphazoline were synthesized and evaluated for their alpha 1 (aorta) and alpha 2 (platelet) activities. The analogues were composed of 2- and 4-substituted imidazoles and imidazolines attached through a methylene bridge to either the 1- or 2-naphthalene ring system. In general the 1-naphthalene analogues were the most potent inhibitors of epinephrine-induced platelet aggregation. Of considerable interest was the fact that the 1-naphthalene analogues (2, 5-7) were partial agonists while the 2-naphthalene analogues (3, 8, 9) were antagonists in an alpha 1-adrenergic system (aorta). Thus, appropriately substituted naphthalene analogues of medetomidine and naphthazoline provide a spectrum of alpha 1-agonist, alpha 1-antagonist, and alpha 2-antagonist activity.

Adrenergic alpha-Agonists↗
PubMed1992

Synthesis of halogenated trimetoquinol derivatives and evaluation of their beta-agonist and thromboxane A2 (TXA2) antagonist activities.

The 5,8-difluoro (4), 5-iodo (5), 8-iodo (6), and 5-trifluoromethyl (7) derivatives of trimetoquinol (TMQ, 1) have been synthesized and evaluated for their ability to stimulate beta 1 (guinea pig atria) and beta 2 (guinea pig trachea) adrenoceptors as well as for their inhibitory activity against U46619 [a thromboxane A2 (TXA2) mimetic]-mediated contraction of rat thoracic aorta and human platelet aggregation. Both 5 and 6 were considerably less active than TMQ on both beta-adrenergic systems and gave a rank order of stimulatory potency of 1 much greater than 6 greater than or equal to 5. Similarly, iodine substitution at either position also caused a reduction in TXA2 antagonist activity with a rank order potency of 1 greater than 6 much greater than 5. Compared to 1, however, 5-iodo-TMQ (5) showed a marked selectivity for blockade of U46619 responses in rat aorta over human platelets. On beta-systems, 4 had reduced potency compared to TMQ and was similarly nonselective. Introduction of a trifluoromethyl group at the 5-position of TMQ completely abolished both beta 1- and beta 2-adrenergic agonist activities while imparting weak antagonist activity on beta 1 receptors. On TXA2 systems, both 4 and 7 possessed significantly decreased inhibitory activity compared to TMQ. The synthetic approaches to the synthesis of 8-(trifluoromethyl)-TMQ (8) are also described. The enantiomers of the 8-fluoro derivative (3) of TMQ were separated on a preparative Chiralcel OD column and evaluated on beta-adrenergic systems and TXA2 systems. On beta-adrenergic systems, (S)-(+)-8-fluoro-TMQ was at least 10-fold more potent than (R)-(-)-8-fluoro-TMQ. Conversely, (R)-(-)-8-fluoro-TMQ was approximately 14-fold more potent as an antagonist of TXA2-mediated aggregation in human platelets than (S)-(+)-8-fluoro-TMQ. In contrast to platelets, (S)-(+)-8-fluoro-TMQ was an agonist in rat aorta whereas (R)-(-)-8-fluoro-TMQ was an antagonist.

Adrenergic beta-Agonists↗