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T W Morris

Publications and source records attributed to T W Morris.

90 records · Page 5Linked to original sources
PubMedDate not supplied

Application of nearest-neighbor and cluster analyses in pharmaceutical lead discovery.

High throughput screening (HTS) programs based on diverse collections of compounds can rapidly identify leads for potential drug candidates. In cases where the compound collection is truly diverse, one may only identify a few compounds of interest. However, where a large number of hits are identified, it becomes necessary to examine the structures to determine the true number of compound classes involved so that follow-up studies may be conducted as efficiently as possible. In this case, cluster analysis is applied to determine the structural relationship among HTS hits. To efficiently expand around the region of the hit (or a class of hits) in chemical space, we have applied nearest neighbors analysis to select additional compounds from collections of a large number of commercial vendors, achieving an average hit rate in excess of 15%. Applying these techniques in a number of different cases, we obtained results that are useful for subsequent investigations of hits from HTS and other relevant molecular structures from the literature.

Anti-Bacterial Agents↗
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Cerebral water content, blood flow and EEG changes after cardiac arrest in the dog.

Changes of cerebral water content, blood flow and cortical EEG following cardiac arrest (8-14 minutes) were studied in 14 mongrel dogs. With five hours of maintenance, changes in the water content both in grey and white matter were found to be insignificant. (Grey matter: control 78.68 +/- 2.62%; arrest 79.91 +/- 1.76%. White matter: control 66.66 +/- 4.10%; arrest 67.76 +/- 1.88%). Blood flow was measured using 15 micron microspheres labeled with Sr, 85 Ce141 and Yb.169 Flow in grey matter was decreased to 47% at 3 hours and 53% at 5 hours; while in white matter it was 67% at 3 hours and 75% at 5 hours from baseline. Deterioration of the cortical electrical activity was observed in all animals having an arrest of more than 8 minutes. In aminals having arrest of longer than 12 minutes there is either no return (isoelectric) or marked slowing of cortical electrical activity. From this and previous studies, it is concluded that with more than 8 minutes of cardiac arrest and up to 5 hours of maintenance there is impairment of cortical perfusion which is not associated with a significant increase in total water content. The lack of increase in total water content, however, does not mean there is no local swelling or edema such as in endothelial cells.

Animals↗
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Renal renin and hemodynamic responses to selective renal artery catheterization and angiography.

Selective renal artery catheterization and renal angiography are commonly performed diagnostic procedures; however, the effects of these procedures on renal blood flow (RBF) and renin release have only been partially described. A biphasic RBF response has been well documented furing selective angiography in dogs. The renal autoregulatory mechanisms governing the responses are uncertain. The renin-angiotensin system and the major parameters of contrast media, hypertonicity and viscosity, have been suggested as important factors. In the canine model, we examined the acute changes in renal venous renin activity along with the renal hemodynamic effects of hypertonicity and viscosity. Our results do not support a primary effect mediated by the renin-angiotensin system. Hypertonicity and the contrast medium per se are significant in active and passive autoregulatory responses at the smooth muscle cellular level.

Angiography↗
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A comparison of the hemodynamic responses to metrizamide and meglumine/sodium diatrizoate in canine renal angiography.

Selective renal angiography causes a biphasic change in renal blood flow and vascular resistance. In this study, 5 ml of meglumine/sodium diatrizoate (288 mg I/ml, 1455 mosm/kg), metrizamide (290 mg I/ml, 593 mosm/kg), isontonic saline (287 mosm/kg) and hypertonic saline (1500 mosm/kg) were injected into the renal arteries of seven adult mongrel dogs to determine whether the minimum flow (or maximum resistance) was related to the osmolality of the injected agent. The maximum resistance response was significantly smaller for metrizamide (20 +/- 4%) and isotonic saline (19 +/- 2%) than for diatrizoate (36 +/- 6%) or hypertonic saline (50 +/- 7%). Hypertonic saline produced two distinct types of responses: the typical biphasic response or a severe immediate drop in flow. Thus the maximum resistance response was related to agent osmolality. The "injection artifact," or flow changes occurring during the injection, were different for the four agents, and these differences appeared correlated to agent viscosity. Although both contrast media caused relatively small changes in renal hemodynamics, metrizamide caused significantly smaller changes than meglumine/sodium diatrizoate.

Animals↗
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Deleterious synergism of a cardiac glycoside and sodium diatrizoate.

Studies were performed in mice to determine if the cardiac glycoside, Strophanthin-K, and the contrast medium, sodium diatrizoate, interact synergistically to produce death. Intravenous injections of lethal and near lethal doses of the two agents produced a significantly greater mortality than the individual agents alone. Low or near clinical doses of Strophanthin-K, when given with doses of diatrizoate in the lethal range, produced mortalities significantly greater than did the diatrizoate alone. Similarly, low or near clinical doses of diatrizoate given with doses of Strophanthin-K in the lethal range produced mortalities significantly greater than for the Strophanthin-K alone. Isotonic or hypertonic saline, when substituted for diatrizoate or Strophanthin-K did not produce synergistic increases in mortality. Thus neither the injection volume, nor agent hypertonicity or ionic strength, seem to be the primary factors in the synergism to produce death. The diatrizoate anion appears to be an important factor. Until more information is available from other animal models it appears that patients receiving cardiac glycoside should be considered to have a higher than normal risk of serious reactions to contrast media in intravenous urography.

Animals↗
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Cardiovascular radiology. Possible factors in intravascular contrast media toxicity.

(I.) Toxicity of ionic coronary arteriography contrast media has been shown to depend on their cationic and anionic composition and their osmolality. Using a right coronary injection technique in the dog, the authors have shown a relationship between toxicity as manifested by occurrence of ventricular fibrillation and the presence of calcium binders in the contrast media. Sodium citrate and EDTA have been identified as the specific agents in certain contrast media that significantly increase the incidence of fibrillation in laboratory experiments. (II.) A deleterious synergism between water-soluble angiographic and urographic media and digitalis compounds has now been demonstrated, based on mortality studies (LD50) using bolus intravenous injections in white mice. The testing of a number of other classes of drugs for a similar effect has shown thus far that only the digitalis class exhibits this synergism. Surprisingly, the nonionic contrast medium, metrizamide, has been shown to have a greater synergistic effect with digitalis drugs than diatrizoate ionic media. (III.) In dog experiments under Nembutal anesthesia in which aortic flow, pulmonary artery and vein pressures, systemic arterial pressure, and EKG were monitored, left atrial pressure increases as soon as or before pulmonary artery pressure rises, even at low doses of ionic contrast media administered intravenously. This may indicate 1) flow to the left heart increases dramatically, or 2) there is a very early myocardial depression. The significance of the above findings and application to clinical practice will be discussed.

Angiography↗
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The effects of media viscosity on hemodynamics in selective arteriography.

Radiographic contrast media used for arteriography are generally more viscous than plasma or blood; however, little consideration is given to the hemodynamic effects of contrast media viscosity. In this study, in vivo and in vitro injection of isotonic solutions of saline and polyvinylpyrrolidone, having viscosities from 0.8 to 26 centipoise, have been made. The results demonstrate that, when the viscous saline reaches the microcirculation, the resistance to flow increases. The viscous saline thus significantly decreases flow immediately after the injection. At that time the pressure in the artery equals aortic pressure, but the local vascular resistance is elevated because of the viscous material present in the arterioles. Viscous contrast media would cause similar hemodynamic changes during and immediately following an injection. The effects of contrast media hypertonicity, however, modify the viscosity-related changes shortly after the contrast media reaches the capillaries.

Angiography↗
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Calcium binding by radiopaque media.

This study quantified the binding of ionic calcium by contrast media with disodium edetate and trisodium citrate versus those with only calcium disodium edetate. First, calcium binding by sodium diatrizoate with calcium disodium edetate was measured using an ion-selective electrode at ionic strengths of .08, .16, and .80 molal. Significant binding of calcium was observed, and the probable reaction product is calcium chloride diatrizoate. Second, solutions were mixed containing Renografin 76 (or Hypaque 76) and NaCl at a physiologic ionic strength. The Renografin, which contains disodium edetate and trisodium citrate, caused significantly more binding than did the Hypaque. However, 60% of the drop in ionic calcium was observed with Hypaque and is related to the diatrizoate anion. The nonionic agent iopamidol produced no decrease in ionic calcium. Significant reductions in ionic calcium are produced by both the diatrizoate anion and by edetate and citrate additives.

Calcium↗
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Tissue fluid shifts during renal arteriography with conventional and low osmolality agents.

The osmotic effects caused by conventional and low osmolality radiopaque agents have been studied in the isolated perfused canine kidney. Changes in vein flow, hematocrit, osmolality, and iodine content were measured at injection doses of 0.25 and 0.5 ml/kg (300 mgI/ml). Increases in osmolality and decreases in hematocrit were significantly greater with the conventional ionic monomer meglumine/sodium diatrizoate than with the low osmolality agents iohexol, iopamidol, and ioxaglate. The standard renal vein flow response for all agents was an increase (loss of renal water) followed by a decrease (gain of renal water). Diatrizoate produced the greatest increase in outflow at 0.25 ml/kg, but the differences between agents were not statistically significant. At the 0.5 ml/kg dose the differences in peak renal vein flow between agents were negligible. Renal vein iodine was highest with the dimer, ioxaglate and lowest with the diatrizoate. The nonionics iohexol and iopamidol produced essentially the same renal vein iodine levels and clearance. The new low osmolality agents have significantly less effect on osmolality and hematocrit and produce higher venous iodine levels than a conventional ionic monomer. The only difference between the low osmolality agents was the higher venous iodine seen with the dimer ioxaglate.

Angiography↗
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Trapped plasma vs. osmolality in canine microcapillary hematocrits.

The trapped plasma in the packed red cell portion of the microcapillary hematocrit of hypertonic canine blood was measured with I-125 labelled albumin. Blood osmolalities were raised by the addition of sodium chloride and meglumine/sodium diatrizoate. The trapped plasma was 1.12 +/- 0.15%, 1.75 +/- 0.27% and 1.77 +/- 0.22% at 300, 580, and 723 mOsm/kg, respectively, for sodium chloride solutions. At 924 mOsm/kg some of the blood plus sodium chloride samples hemolyzed. In the group without hemolysis the trapped plasma was 5.84 +/- 1.35% while in the group with hemolysis it measured 12.43 +/- 1.90%. The trapped plasma with diatrizoate solutions was 1.41 +/- 0.11, 2.15 +/- 0.18 and 5.32 +/- 0.56 at 458, 531 and 602 mOsm/kg, respectively. Above an osmolality of 458 mOsm/kg the trapped plasma was significantly greater for the diatrizoate solutions than for the sodium chloride solutions. At osmolalities below 458 mOsm/kg only a small correction is needed for trapped plasma with either sodium chloride or meglumine/sodium diatrizoate solutions.

Animals↗
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Cardiovascular responses to the intravertebral artery injection of hypertonic contrast media in the dog.

Central nervous system-mediated cardiovascular responses to contrast medium (CM) are believed the result of a vagal or of a sympatholytic response; these effects may be enhanced in the setting of dehydration. The purpose of this investigation was to evaluate neurally mediated effects of intravertebral artery CM injections on blood pressure (BP), heart rate (HR) and regional vascular resistances in euvolemic and dehydrated dogs. Animal preparation consisted of food and water ad libitum (n = 7) vs. 2.0 ml/kg i.m. furosemide and 48 hours thirsting (n = 7). During pentobarbital anesthesia BP, HR and renal and femoral blood flows were continuously monitored and meglumine iothalamate 60% (1 ml/kg) injected via a left vertebral artery catheter at 3 ml/sec; matched volume injections of normal saline served as control. Decreases in BP, HR and femoral and renal vascular resistances post CM injection were observed in the first 10 seconds before the CM had reached the systemic circulation. Significant decreases in both BP (-10.6 +/- 1.7%) and HR (-11.5 +/- 1.6%) post CM injection were noted with dehydration (n = 7). In the euvolemic dogs (n = 7) the decrease in HR (-7.3 +/- 2.0%) was significant but the decrease in BP (-3.9 +/- 2.4%) was not. The decrease in femoral vascular resistance was -22.7 +/- 9.0% in euvolemic dogs and -21.9 +/- 8.8% in dehydrated dogs. No significant changes were noted with the intravertebral artery injections of normal saline in control euvolemic and dehydrated animals. The early cardiovascular responses to CM suggest a direct action on the vasomotor center of the medulla. The effects on BP and HR are more severe in the dehydrated than in the euvolemic state.

Animals↗
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Neural tissue uptake and clearance of iohexol following lumbar myelography in rabbits.

The diffusion of water-soluble contrast media (CM) into the extracellular space of the central nervous system following injection into the subarachnoid space has previously been shown. As a result of this, water-soluble CM will come in direct contact with the neurons and may interfere with their normal function. The toxic effects would thus be a result both of the molecular properties of the CM as well as the local tissue concentration. The neuronal tissue uptake and clearance of metrizamide in rabbits following lumbar myelography was described in a previous study by our group. This study indicated some retention of metrizamide in the spinal cord probably as a result of binding of the CM to the cell membrane. The mechanism for this has not yet been shown although it may relate to the binding of metrizamide via its 2-deoxy-D-glucose (2-DG) portion and the specific glucose membrane carrier. The present investigation was performed to evaluate the diffusion kinetics of a new non-ionic CM. With iohexol, which lacks a 2-DG component in its molecule a direct relationship between the neural tissue and CSF concentration was found which seems to follow a simple diffusion model. Since iohexol shows no sign of entrapment in the tissue, the contact time for neurons will be shorter than that seen with metrizamide assuming that their rate of drainage from the CSF is identical.

Animals↗
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Canine model of contrast medium induced fibrillation.

The injection of radiocontrast media into coronary arteries will produce a low incidence of ventricular fibrillation. This study establishes the injection duration (or contact time) required to produce fibrillation during right coronary angiography in dogs using a 370 mg I/ml, meglumine/sodium diatrizoate formulation (Renografin 76, Squibb). The mean contact time required to induce fibrillation was 18.8 +/- 5.8 seconds for 66 injections in 47 dogs. Prolonged ischemia of greater than 170 s did not produce either fibrillation or arrhythmias, therefore fibrillation is caused by properties of the media. The contact time was not significantly influenced by test injections and was not significantly different in repeated experiments. The canine contact time model of contrast media induced ventricular fibrillation is reproducible and will facilitate the study of risk factors that increase the possibility of fibrillation.

Angiocardiography↗
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Factors modifying contrast media induced fibrillation.

Factors effecting contrast media induced ventricular fibrillation were studied in anesthetized dogs using contact time as the measured parameter. Injections of meglumine/sodium diatrizoate (370 mg I/ml) were made into the right coronary artery at 0.4 ml/s until fibrillation occurred. A contrast medium containing calcium chelators was found to produce fibrillation in a significantly shorter contact time than a similar medium without calcium chelators. Pre-treatment by the cardiac glycoside, ouabain, increased the contact time for fibrillation as did the production of a sub-acute infarction in the left coronary artery and a previous fibrillation and resuscitation. The data suggest that calcium binding additives increase the risk of fibrillation while pre-treatment with cardiac glycosides, the presence of stable infarcts in the non-injected areas, or a previous fibrillation and resuscitation do not increase risk.

Animals↗
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Cardiovascular responses to the intracarotid injections of ionic contrast media and iohexol in the dog.

Hypotension and bradycardia are the most significant cardiovascular responses resulting from intracarotid injections of hypertonic contrast media (CM). We have assessed both local and systemic vascular responses to the selective intracarotid injections of ionic and non-ionic CM in twelve pentobarbital anesthetized dogs. Alterations in blood pressure, heart rate, and femoral, renal and carotid blood flows were monitored following right common carotid artery injections of ionic contrast media (282-288 mg I/ml), isotonic saline, and iohexol (300 mg I/ml). Ionic CM led to early (0 to 10 s) decreases in blood pressure, heart rate and femoral vascular resistance. Isotonic saline induced no significant early changes in these same parameters while iohexol caused a decrease in heart rate. Our observations suggest that the early (0 to 10 s) decreases in femoral vascular resistance, heart rate and pressure that occur with the intracarotid injection of hypertonic CM are mediated via the autonomic nervous system and initiated from a site in the carotid circulation. During the 15 to 40 s period when the CM has reached the systemic circulation, iohexol produced smaller effects on systemic blood pressure and peripheral vascular resistances than did the ionic CM. During this 15 to 40 s period there were decreased vascular resistances in the carotid and renal vascular beds that probably result from local effects of the CM, however, the femoral resistance was actually increased. This later increase in femoral resistance probably represents the results of increased sympathetic nervous system activity working to offset the decrease in renal and carotid resistances and thus maintain pressure at baseline values.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
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Iotrol, iodixanol, and 2-deoxy-D-glucose effects on neural tissue CO2 production.

In vivo and in vitro experiments have demonstrated that the myelographic agent metrizamide decreases neural tissue glucose metabolism whereas iohexol and iopamidol do not. This study compares the changes in slices of rat hippocampus CO2 production caused by the nonionic dimers iotrol and iodixanol with the effects of metrizamide and 2-deoxy-D-glucose. After 6-hr incubations, 70-mmol/l concentrations of iotrol and iodixanol increased CO2 production by 11 +/- 20% and 31 +/- 35%, respectively, as compared with the artificial CSF control medium. Metrizamide at 70 mmol/l and 2-deoxy-D-glucose at 35 mmol/l decreased CO2 production by 32 +/- 13% and 96 +/- 1%, respectively. The increases in CO2 production with iotrol and iodixanol appear to indicate that these molecules have some effect on cell metabolism. The mechanism for the increase in CO2 production could involve an effect on the glucose metabolic pathway or could be indirect via a mechanism that increases cell energy utilization. These in vitro effects have not been verified with in vivo experiments.

Animals↗
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A comparison of the cardiovascular responses to carotid injections of ionic and nonionic contrast media.

Selective injection of contrast media into the canine common carotid artery results in alterations in carotid flow, heart rate, and systemic arterial pressure. In this study the responses to injections of the nonionic agents metrizamide and iopamidol were compared to the responses to the ionic agents meglumine iothalamate, meglumine sodium diatrizoate, mannitol, and saline solution. Heart rate and pressure responses were smallest for metrizamide, greater for iopamidol, and greater still for the hypertonic ionic agents: responses were roughly correlated to agent osmolality. Carotid flow increased with all agents and was roughly proportional to the agent's osmolality. The exception was metrizamide which despite its lowest osmolality, produced a large increase in flow which was maintained much longer than for other agents. The total response to the nonionic agents was judged less severe than to the ionic agents; however, the responses to all agents were transient and not life threatening.

Animals↗