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Biomedical subjects

Robert L Talbert

Publications and source records attributed to Robert L Talbert.

At least 19 recordsLinked to original sources
PubMed2007

Effectiveness of statins in reducing the rate of severe sepsis: a retrospective evaluation.

STUDY OBJECTIVES: To determine whether use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) is associated with a reduced rate of severe sepsis, and to further characterize the effect of statins on the frequency of organ dysfunction in patients with severe sepsis. DESIGN: Retrospective cohort study. SETTING: University-associated teaching hospital. PATIENTS: Fifty-three patients admitted with sepsis; 16 were receiving statins and 37 were not receiving statins (controls) before admission. MEASUREMENTS AND MAIN RESULTS: Patients were identified by the International Classification of Diseases, Ninth Revision, Clinical Modification codes. Patient demographics, vital signs, and laboratory values were collected from their electronic medical records. The primary end point was rate of severe sepsis, defined in accordance with guidelines from the American College of Chest Physicians and the Society of Critical Care Medicine. Secondary end points were in-hospital mortality rate and rate of five categories of organ dysfunction (cardiovascular, renal, pulmonary, hematologic, and metabolic). Preadmission statin therapy, compared with no statin therapy, was associated with a 30% lower rate of severe sepsis (56% vs 86%, p<0.02). In-hospital mortality was not significantly different between groups (38% vs 49%, p=0.33); however, the rate of cardiovascular dysfunction, defined as hypotension requiring vasopressor therapy, was significantly lower in the statin group (38% vs 73%, p<0.02). No significant differences in the other organ dysfunction categories were noted between groups. CONCLUSION: Statins appear to prevent sepsis from becoming severe, most notably through prevention of sepsis-induced hypotension. This potential role for statins in the prevention and treatment of severe sepsis should be further evaluated in a randomized controlled trial.

Aged↗
PubMed2006

Targeted high lung concentrations of itraconazole using nebulized dispersions in a murine model.

PURPOSE: The purpose of this study was to investigate the delivery of itraconazole (ITZ) particles to a murine lung model by nebulization. METHODS: Three ITZ formulations were prepared and characterized in the dry state using contact angle, dissolution, X-ray powder diffraction, scanning electron microscopy, and Brunauer-Emmett-Teller surface area analysis. Aerodynamic particle size distributions and lung deposition studies in 14 outbred male ICR mice were performed using aqueous dispersions of all the formulations. A separate dosing uniformity study was also performed to qualify use of the chamber. RESULTS: All formulations had an aggregated particle size of approximately 30 microm in diameter. Two formulations showed that 80% of the drug dissolved in less than 5 min. The remaining ITZ formulation had a slower dissolution and the lowest total emitted dose from the nebulizer used. High concentrations of ITZ were shown to be present in the mouse lung during the lung deposition study, up to 16.8 +/- 0.13 microg/g (+/- SE) were achieved. Concentrations of up to 0.76 +/- 0.03 microg/g (+/- SE) could be maintained from the single nebulized dose for at least 24 h. CONCLUSION: An effective method of targeted delivery of ITZ to the deep lung is presented that may be useful for the treatment and prevention of acute fungal infections.

Administration, Inhalation↗
PubMed2006

Single dose and multiple dose studies of itraconazole nanoparticles.

The objective of this study was to determine and compare the lung and serum concentrations in mice following oral and pulmonary dosing of amorphous nanoparticulate itraconazole (ITZ) compositions as well as the Sporanox oral solution (itraconazole/Janssen). Second, the steady state partitioning of ITZ in lung tissue and circulatory compartments following repeated oral and pulmonary dosing was determined. The pulmonary formulation (ITZ-pulmonary) consisted of ITZ, polysorbate 80, and poloxamer 407 in a 1:0.75:0.75 ratio and the oral formulation (ITZ-oral) consisted of ITZ, PEG 8000, poloxamer 188, and sorbitan monooleate 80 in a 1:1:2:1 ratio. Mice were dosed every 12 h by nebulization with ITZ-pulmonary, or by oral gavage with ITZ-oral or Sporanox oral solution (n = 12 per study arm). ITZ-pulmonary achieved significantly greater (>10-fold) lung tissue concentrations compared to the Sporanox oral solution and ITZ-oral. There were no statistical differences between the two oral formulations. ITZ-pulmonary achieved significantly greater lung levels per unit serum concentration compared to the orally dosed ITZ compositions. High and sustained lung tissue concentrations were achieved via inhalation of an amorphous nanoparticulate ITZ-pulmonary composition while maintaining serum levels which are above the minimum lethal concentration (MLC) of Aspergillus fumigatus.

Administration, Oral↗
PubMed2006

In vivo efficacy of aerosolized nanostructured itraconazole formulations for prevention of invasive pulmonary aspergillosis.

Aerosolized evaporative precipitation into aqueous solution and spray freezing into liquid nanostructured formulations of itraconazole as prophylaxis significantly improved survival relative to commercial itraconazole oral solution and the control in a murine model of invasive pulmonary aspergillosis. Aerosolized administration of nanostructured formulations also achieved high lung tissue concentrations while limiting systemic exposure.

Aerosols↗
PubMed2006

Statin-associated pleiotropy: possible beneficial effects beyond cholesterol reduction.

Because elevated serum cholesterol levels are strongly associated with coronary heart disease, cholesterol reduction by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (or statins) has been assumed to be the predominant, if not the only, mechanism underlying the beneficial effects of these drugs in cardiovascular diseases. Subgroup analyses of large clinical trials, however, have suggested that the beneficial effects of statins may extend to mechanisms beyond cholesterol reduction. Indeed, recent experimental and clinical evidence indicates that some of the cholesterol-independent or "pleiotropic" effects of statins may be mediated through improving or restoring endothelial function, enhancing the stability of atherosclerotic plaques, and decreasing oxidative stress and vascular inflammation.

Atherosclerosis↗
PubMed2006

The challenge of blood pressure management in neurologic emergencies.

Hypertensive crises are commonly seen in the emergency department, and acute stroke is often the inciting etiology of a hypertensive crisis. Cerebral autoregulation is disrupted in acute stroke, and efforts to lower blood pressure may reduce cerebral perfusion and worsen outcomes. Although most patients with stroke have elevated blood pressure, evidence from clinical trials to guide therapy are scarce. Current national guidelines recommend lowering blood pressure after stroke only if end-organ damage is present or if systolic/diastolic blood pressures exceed 220/120 or 185/110 mm Hg in patients ineligible and in those eligible to receive thrombolytic drug therapy, respectively. Recommended pharmacologic interventions for elevated blood pressure after acute ischemic stroke include labetalol, nicardipine, or nitroprusside, depending on the severity of the elevation. Similar recommendations have been made for intracerebral hemorrhage. Subarachnoid hemorrhage is managed with nimodipine and other calcium channel blockers to prevent vasospasm and improve clinical outcomes. Data from ongoing clinical trials may improve guidance about the management of elevated blood pressure after acute stroke.

Acute Disease↗
PubMed2005

Design and evaluation of a restraint-free small animal inhalation dosing chamber.

The aim of research was to design a small, restraint free, low stress animal dosing chamber for inhalation studies, and to investigate distribution of a model drug within the chamber. A small animal dosing chamber was designed that consisted of a polymethylmethacrylate (PMMA) airtight box (40.6 x 11.4 x 21.6 cm) with a hinged top, having a nominal wall thickness of 1.25 cm. The chamber was designed to hold up to 14 mice, each having a floor area of approximately 63 cm2, in accordance with Institutional Animal Care and Use Committee (IACUC) guidelines. A "rodent proof" distribution fan was attached to the center of the hinged closure lid. The chamber was divided into 1 inch2 zones (120 in total) to enable a profile of drug distribution within the chamber to be obtained. Small holes were drilled into the side of the chamber and sealed using Parafilm to allow access to the sampling zones. Syringes (5 mL) with appropriate length polytetrafluoroethylene (PTFE) tubing were inserted into the holes to reach the sampling zones (eight on either side of the chamber giving a total of 16 zones). An aqueous caffeine solution (2% w/v) in glycerol (25% w/v) was prepared and nebulized into the chamber using an Aeroneb Pro nebulizer. Caffeine containing droplets were circulated into the chamber at a flow rate of 1.5 L/min(-1), and the air was recirculated in a closed system for a total of 20 minutes to ensure a high concentration of caffeine droplets throughout. Following nebulization, air samples (5 mL) were withdrawn from the 16 sampling zones of the sealed chamber. The process was repeated in quadruplet until a total of 64 sampling zones had been sampled. The entire experiment was also repeated with the absence of the "rodent-proof" distribution fan. Drug concentrations were calculated from a calibration curve of caffeine using UV absorbance at 272 nm. An average mass of caffeine (Standard Deviation; S.D.) of 5.0 (4.2) mg was detected throughout the chamber when the distribution fan was fitted, and caffeine 12.6 (9.7) mg was detected without the fan. This indicated that presence of the fan caused impingement of the drug on both the chamber walls and fan components; effectively removing nebulized drug from circulation within the chamber. The distribution of drug was plotted using a 3D graph; this revealed a lower concentration at the periphery and a higher concentration in the center of the chamber both with and without the distribution fan in place. In conclusion, a humane, nonrestraint rodent dosing chamber was designed for the efficient delivery of nebulized drugs for up to 14 mice simultaneously. The highest levels of the model drug caffeine were detectable throughout the small animal dosing chamber without the distribution fan. A circulation flow rate of 1.5 L/min(-1) was found to be adequate to distribute drug in the chamber. Surprisingly, the results demonstrate that avoiding the use of a distribution fan altogether maximizes the drug concentration within the chamber by reducing impingement of the nebulized drug. The small animal, restraint-free dosing chamber represents an advancement in reproducible dosing via the pulmonary route in the small animal model. The dosing chamber may be adapted to present the lung with an almost unlimited array of compounds, encompassing drugs, toxic compounds, and even pathogens, while still maintaining a relatively stress-free microenvironment for the test subject and furthermore, total safety for the operator.

Animals↗
PubMed2005

Aspirin resistance: an evaluation of current evidence and measurement methods.

Aspirin resistance is a poorly characterized phenomenon, whereby certain patients do not benefit from the antithrombotic effect of aspirin. The frequency of aspirin resistance is unknown, but estimates range from 5-60%. The mechanism of aspirin resistance also is unknown; proposed mechanisms are poor patient compliance, poor aspirin absorption, increased isoprostane activity, platelet hypersensitivity to agonists, increased cyclooxygenase-2 activity, a cyclooxygenase-1 polymorphism, and the platelet alloantigen 2 polymorphism of platelet glycoprotein IIIa. Aspirin resistance appears to be dose related in some patients and therefore may be overcome with high doses. Evidence indicates that aspirin resistance is a dynamic state, with significant intrapatient variability in aspirin sensitivity with time. To date, a sensitive and specific assay of aspirin effect that reliably predicts treatment failure has not emerged. However, several commercially available products are being marketed for this purpose without convincing clinical data. Despite a wealth of literature on the topic, aspirin resistance remains an enigma. Further investigation is needed regarding strategies to identify and treat patients resistant to aspirin.

Antigens, Human Platelet↗
PubMed2004

Pharmacokinetics and pharmacodynamics of beta blockers in heart failure.

Although beta-blockers have been used for nearly three decades in the management of heart failure, only recent randomized clinical trials have demonstrated substantial benefit in reducing morbidity and mortality. Carvedilol, metoprolol succinate and bisprolol have evidence supporting their use in heart failure while other beta blockers either lack evidence supporting their use or have not been shown to be useful in heart failure. The only currently approved beta-blockers in the U.S. for heart failure are metoprolol succinate and carvedilol.Beta-blockers differ in their pharmacokinetic and pharmacodynamic properties. It should not be assumed that potential benefit in heart failure is a class effect since differences in the half-life, volume of distribution, protein binding, and route of elimination may give rise to differences in duration of beta blockade and potential drug interactions. Furthermore, pharmacodynamic differences exist because of selectivity for beta(1), beta(2) or alpha(1) adrenoreceptor blockade among the beta-blockers. Receptor kinetics also differ among the beta-blockers and this may influence the extent and duration of beta and alpha blockade across the category. Carvedilol is an inherently long-acting beta-blocker while the duration of beta blockade for metoprolol is dependent on the salt and formulation, which is used. Metoprolol tartrate is a short-acting form of metoprolol while metoprolol succinate is a longer acting salt and the commercially available product is designed as a once daily formulation. A recently published trial, the Carvedilol or Metoprolol European Trial (COMET) tested carvedilol given twice daily versus metoprolol tartrate given twice daily in patients with chronic heart failure. Although carvedilol reduced all cause mortality when compared with metoprolol tartrate, extrapolation to similar findings with metoprolol succinate are not possible since the pharmacokinetic and pharmacodynamic effects of these two formulations are different. Furthermore, the dosing of metoprolol tartrate in COMET may have been inadequate based on prior studies. Additional studies are needed to compare carvedilol directly to metoprolol succinate before concluding inequivalency exists for these two beta-blockers in heart failure.

Adrenergic beta-Antagonists↗
PubMed2004

Pharmacodynamics of beta-blockers in heart failure: lessons from the carvedilol or metoprolol European trial.

Heart failure is a growing public health problem in the United States, and the approach to the treatment of heart failure has undergone a radical transformation in the past decade. The use of beta-blocker therapy in heart failure patients is now widely recommended, based on evidence from large-scale clinical trials demonstrating that bisoprolol, carvedilol, and extended-release metoprolol succinate significantly reduce morbidity and mortality in patients with heart failure. Although these agents appear to provide similar benefits, the question remains whether pharmacologic differences among them could translate to differences in clinical outcomes. The Carvedilol Or Metoprolol European Trial (COMET) compared nonselective blockade of the beta1-/beta2-/alpha1-adrenergic receptors with carvedilol versus selective beta1-blockade with immediate-release metoprolol tartrate in patients with chronic heart failure. The trial found that carvedilol significantly reduced all-cause mortality compared with immediate-release metoprolol tartrate, although there were no differences in hospitalizations. Herein we review the pharmacokinetics and pharmacodynamics of metoprolol and carvedilol. In doing so, several issues regarding the design of COMET are identified that could alter the interpretation of the results of this trial. These include the choice of dose and dosage regimen of immediate-release metoprolol tartrate, a dosage form that has never been shown to reduce mortality in patients with heart failure. Additional studies are needed to fully understand whether there are any advantages of selective versus nonselective adrenergic blockade and whether there are any clinically meaningful differences in effectiveness between beta-blockers with proven benefit in the management of chronic heart failure. The results of COMET demonstrate that all beta-blockers and dosage forms are not interchangeable when prescribed for heart failure. Clinicians should choose only those agents (and dosage forms) that have been proven to reduce mortality in this patient population.

Adrenergic beta-Antagonists↗
PubMed2003

Role of the National Cholesterol Education Program Adult treatment panel III guidelines in managing dyslipidemia.

Using recently updated guidelines to evaluate and manage lipid disorders is discussed. Coronary heart disease (CHD) is a costly chronic condition associated with significant morbidity and mortality. Epidemiologic data further indicate that dyslipidemia and associated conditions, which may lead to CHD, are grossly undertreated. In 2001, the third National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP III) released updated guidelines for the evaluation and treatment of lipid disorders. Significant changes to the updated guidelines include designation of a CHD risk equivalent category identifying patients who require aggressive management, recommendation of Framingham-based CHD risk assessment in patients with multiple risk factors, revised target levels for several of the lipids and lipoproteins, and criteria for the identification of patients with the metabolic syndrome. Low-density lipoprotein cholesterol (LDL-C) continues to be the primary target of therapy. In addition, non-high-density lipoprotein cholesterol (HDL-C) is now defined as a secondary treatment target in patients with hypertriglyceridemia. Increased emphasis is placed on the metabolic syndrome, low HDL-C levels, and the presence of multiple and emerging risk factors in guiding the intensity of therapy. The NCEP ATP III guidelines acknowledge challenges in implementing and maintaining patient adherence to both lifestyle changes and pharmacotherapy regimens and provide strategies for increasing treatment success. Implementation of these new guidelines will likely enhance identification, management, and treatment success rates among patients at risk for CHD in the United States.

Cholesterol, LDL↗
PubMed2003

Lessons from the Stroke Prevention in Atrial Fibrillation trials.

Atrial fibrillation predisposes to left atrial thrombus formation and carries a sixfold increased risk for stroke. Antithrombotic therapies are the mainstay for stroke prevention. The National Institute of Neurological Disorders and Stroke-sponsored Stroke Prevention in Atrial Fibrillation (SPAF) studies assessed the value of warfarin, aspirin, and their combination for preventing stroke in six multicenter trials involving 3950 participants. This review presents the major results and implications, which offer unique perspectives on antithrombotic therapies for stroke prevention in atrial fibrillation. Warfarin and aspirin reduce stroke. Anticoagulation substantially benefits high-risk patients with atrial fibrillation, while many younger patients with atrial fibrillation have a low stroke rate when given aspirin. Pathogenetic and transesophageal echocardiographic correlations shed light on mechanisms by which antithrombotic agents prevent stroke. Warfarin inhibits formation of atrial appendage thrombi and markedly reduces cardioembolic strokes, while aspirin primarily prevents smaller, noncardioembolic strokes. The SPAF III stroke risk stratification scheme has been validated for identifying patients with high versus moderate versus low risk for stroke. Women with atrial fibrillation benefit from anticoagulation significantly more than men do. Many elderly patients with recurrent paroxysmal atrial fibrillation have high rates of stroke. Antithrombotic prophylaxis should be individualized on the basis of the estimated risk for stroke during aspirin therapy and the risk for bleeding during anticoagulation. Overall, nearly one third of patients with atrial fibrillation are low risk and should be treated with aspirin, and about one third are high risk and should receive warfarin if it can be given safely. For patients at moderate risk for stroke, patient preferences and access to reliable anticoagulation monitoring are particularly relevant.

Anticoagulants↗
PubMed2003

Influence of hydroxypropyl methylcellulose polymer on in vitro and in vivo performance of controlled release tablets containing alprazolam.

The purpose of this study was to investigate the influence of hydroxypropyl methylcellulose (HPMC) molecular weight on pharmacokinetic and pharmacodynamic parameters of controlled release formulations containing alprazolam. Tablet formulations contained alprazolam, excipients, and either HPMC K4MP or HPMC K100LVP. A ten patient in vivo clinical trial using a randomized, open-label, four-way crossover design was conducted in the fed and fasted states. Plasma alprazolam concentrations were determined for 72 h. The pharmacodynamic effects of alprazolam were monitored using subject rated sedation on visual analogue scale for wakefulness, observer rated sedation, and symbol digit modalities test (SDMT). Results indicated that the tablet formulations containing either HPMC K4MP or HPMC K100LVP had similar dissolution profiles, and the dissolution profiles did not change through 6 months at 40 degrees C/75% RH or 12 months at 25 degrees C/65% Relative Humidity (RH). The area under the plasma concentration-time curve, time to peak concentration, and peak plasma concentration were not significantly different between the two tablet formulations investigated in either the fed or fasted states. Pharmacodynamically, no significant differences in SDMT scores between the two formulations were found. In vitro dissolution results predicted in vivo pharmacokinetic and pharmacodynamic results irrespective of formulation or diet used in the controlled release tablet. The controlled release tablets were bioequivalent and pharmacodynamically equivalent irrespective of the tablet formulation.

Adolescent↗