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Biomedical subjects

Sheldon H Preskorn

Publications and source records attributed to Sheldon H Preskorn.

At least 19 recordsLinked to original sources
PubMed2007

Comparison of duloxetine, escitalopram, and sertraline effects on cytochrome P450 2D6 function in healthy volunteers.

This study is the first to directly compare the relative effects of duloxetine, escitalopram, and sertraline on the functional activity of the drug-metabolizing cytochrome P450 2D6 enzyme as assessed by changes in the pharmacokinetics of the cytochrome P450 2D6 model substrate drug, metoprolol. Single-dose pharmacokinetics of metoprolol were measured before and after 17 days of treatment with escitalopram 20 mg/d, duloxetine 60 mg/d, or sertraline 100 mg/d in young healthy male and female participants. The outcome measures were changes in metoprolol peak plasma levels, area under the plasma concentration-time curve, and clearance. The results were tested using paired t tests and independent t tests. The addition of each drug produced statistically significant changes in metoprolol pharmacokinetics. The rank order for the change in metoprolol area under the plasma concentration-time curve was duloxetine (180%) > escitalopram (89%) > sertraline (48% and 67%). Compared with sertraline, duloxetine produced statistically significantly larger changes in metoprolol pharmacokinetic parameters. The changes produced by escitalopram and sertraline were not statistically different.

Adult↗
PubMed2006

Pharmacogenomics, informatics, and individual drug therapy in psychiatry: past, present and future.

The modern era of psychopharmacology began in the 10 year period from the late 1940s to the late 1950s. During this period, the first antidepressants, antipsychotics, anxiolytics and mood stabilizers were all discovered. In the 1960s, the pharmacology of these drugs was elucidated and theories about the mechanisms of action proposed. In the 1970s and 1980s, new, more selective compounds were developed based on improved structure-activity relationships derived from in vitro receptor binding studies and animal models. These compounds entered clinical testing in the 1980s and began to be marketed in the late 1980s and 1990s. All of these agents were approved to treat psychiatric syndromes which are conditions defined by a cluster of signs and symptoms. None of these agents was developed based on an understanding of the pathophysiology of the illnesses being treated. None of these agents are curative and virtually all have limited clinical efficacy. In the earliest days of the modern era, there were few drugs available to combine and many had such broad actions that they were often marginally tolerated or unsafe when used in combination (tricyclic antidepressants and monoamine oxidase inhibitors). With the advent of more medications, the frequency and extent of polypharmacy has exploded. In addition to simply having more drugs from which to select with different pharmacological profiles, many newer medications are also more selective in their pharmacological actions and thus are often better tolerated and safer when used in combination. In addition, there is the concern that the trade-off for more selective pharmacology may have been better tolerability at the expense of reduced efficacy, which clinicians then compensate for by using more medications in combination. For all of the above reasons, polypsychopharmacology has been present from the beginning of the modern era of psychopharmacotherapy and continues to be the rule rather than the exception. In fact, the frequency and the complexity of such polypsychopharmacology are both enormous and increasing. The percentage of patients being discharged from the Biological Branch of the National Institute of Mental Health on more than three psychiatric medications increased more than ten times between 1974-79, and 1990-95. The majority of patients seen in the Veterans Administration Medical System in the United States are on unique combinations of medications and the frequency and complexity of such polypharmacotherapy is increased in patients on psychiatric medications. Throughout the modern era, there have been attempts to determine whether there are populations of patients selectively responsible to specific agents (e.g. serotonin versus norepinephrine reuptake inhibitors). However, no compelling data have so far emerged. Instead, clinicians generally resort to combining drugs on the basis of symptoms such as psychosis and depression or anxiety and depression. Science has primarily informed the clinician about safety concerns rather than efficacy concerns when using such combinations. That will change in the future with a better understanding of the pathophysiology of psychiatric illnesses which in turn will lead to improved therapies and the potential for more rationally derived combination treatments.

Clinical Trials as Topic↗
PubMed2006

Single enantiomer drugs: should they be developed?

Biological interactions are stereoselective; thus the interactions of drugs with corresponding biological targets must also be stereoselective. However, many drugs used today are racemic mixtures. For example, approximately 25% or 1 in 4 marketed drugs are mixtures of agents (racemates) rather than single chemical entities (enantiomers). One of these enantiomers can be inactive or even counterproductive to the therapeutic use of the drug: either by reducing the efficacy of the active enantiomer or by causing unnecessary tolerability problems or even toxicity through differential pharmacodynamics. The presence of a therapeutically inactive or counterproductive enantiomer can also complicate the pharmacokinetics of the active enantiomer and the interpretation of the therapeutic drug monitoring (e.g., plasma levels) if the assay is not capable of separately quantitating the two enantiomers. This article reviews the history of stereoisomers and the relevant pharmacological principles, then discusses recent changes in rules governing drug approval and the potential advantages to the patient and the manufacturer of developing single enantiomers.

Drug Monitoring↗
PubMed2005

Complexity of medication use in the Veterans Affairs healthcare system: Part I: Outpatient use in relation to age and number of prescribers.

CONTEXT: Multiple medication use is associated with an increased incidence of adverse drug-drug interactions (DDIs), medication errors, noncompliance, hospitalization, and healthcare costs. Drugs acting systemically or gastrointestinally ("SG" drugs) are of particular concern because of their potential to interact. A better understanding is needed of the relationship between multiple medication use, particularly of SG drugs, and age, number of prescribers, and common drug regimens. OBJECTIVE: to determine the levels of multiple SG medication use in relation to age, number of prescribers, and common drug regimens in an outpatient population served by U.S. Veterans Integrated Service Network 15 (VISN 15). DESIGN, SETTING, AND PARTICIPANTS: cross-sectional analysis of the subset of 5,003 currently active patients from a stratified random sample of 7,000 potentially active outpatients (1,000 each from 7 sites comprising VISN 15) selected from the prescription database on a single day. MAIN OUTCOME MEASURES: number of SG drugs/patient; number and frequency of SG drug entities and regimens. RESULTS: Most patients (97%) were dispensed at least one SG drug: 80% received > or =2 SG drugs, of which 42% received 2-4 SG drugs, 24%, 5-7 SG drugs, and 14%, > or =8 SG drugs. 394 different SG drugs were dispensed, only 88 of which occurred in 1% or more of patients. A significant increase (p < 0.0001) in level of multiple medication use occurred with increasing age and number of prescribers. Proportions of patients receiving 8 or more SG drugs approximately doubled with each additional prescriber, up to 4 or more prescribers. No drug regimen containing 2 or more drugs occurred in 1% or more of patients; 71% of patients were receiving a unique drug regimen (based on specific SG drugs without regard to dose or administration schedule). CONCLUSIONS: The uniqueness of SG drug regimens suggests no single prescriber could have extensive clinical experience with even a small fraction of the drug regimens patients receive. These findings suggest that potential DDIs cannot be predicted based on occurrence of common drug regimens in a general patient population. A follow-up study (reported separately) investigated whether common drug regimens can be identified by selecting for a specific drug treatment (e.g., an antidepressant). The improved ability to predict DDIs is particularly relevant for psychiatric patients, who are at increased risk for DDIs because of greater frequency of multiple medication use. In addition, DDIs may present in this population in ways that mimic worsening of primary symptoms, which may lead to increased doses of the medication that is actually responsible for the problem, causing still more toxicity.

Adult↗
PubMed2005

Complexity of medication use in the Veterans Affairs healthcare system: Part II. Antidepressant use among younger and older outpatients.

CONTEXT: A previous study, described in Part I of this report, found that 71% of a sample of 5,003 general outpatients in the Veterans Affairs healthcare system were receiving a unique drug regimen (i.e., total specific drug entities regardless of dose, formulation, or administration schedule). The simplest regimens contained only one drug, while the most complex regimens exceeded 20 different drugs. The purpose of the present study was to determine if patients receiving a specific therapeutic class of medications (e.g., antidepressants) have more homogeneous drug regimens. OBJECTIVE: to examine the extent and complexity of multiple medication use in younger and older adult outpatients receiving antidepressants compared with those not receiving antidepressants. The study focused on drugs that act systemically or gastrointestinally and hence have the potential to interact. DESIGN, SETTING, AND PARTICIPANTS: Two subsets of stratified random samples of outpatients selected from prescription databases of U.S. Veterans Integrated Service Network 15. The first group involved 1,991 patients deemed to be on antidepressants (AD patients): 891 aged < 60 years and 1,100 aged > or = 60 years. The second group involved 3,732 patients who had received no antidepressants within the previous 365 days but who had a supply of at least one other current prescription (NoAD patients): 1,195 aged < 60 years and 2,535 aged > or = 60 years; 2 missing age information. MAIN OUTCOME MEASURES: number of drugs, frequency of drug regimens, level of multiple medication use including and excluding antidepressants. RESULTS: Younger AD patients received 3 more drugs than younger NoAD patients. 23.6% of younger AD patients, versus 5.9% of younger NoAD patients, received > or = 8 drugs. Older AD patients received 2 more drugs than older NoAD patients. 37.6% of older AD patients, versus 12.8% of older NoAD patients, received > or = 8 drugs. In both the AD and NoAD groups, 62%-96% of patients of all ages were receiving unique drug regimens. Each drug regimen containing 2 or more drugs occurred in fewer than 1% of patients. CONCLUSIONS: AD patients were receiving more complex drug regimens and had a higher frequency of unique drug regimens than NoAD patients, even when the results were adjusted for age group and number of prescribers. The high prevalence of unique drug combinations in all patient groups in this study indicates that clinicians in this system have only limited experience with the total effects of all of the medications their patients are receiving and thus cannot rely on experience to guard against adverse multi-drug interactions. This fact is a particular concern with psychiatric medications because adverse DDIs involving these medications can mimic psychiatric symptoms and may therefore be more difficult to detect.

Adolescent↗
PubMed2005

Examining concentration-dependent toxicity of clozapine: role of therapeutic drug monitoring.

Highly variable plasma concentrations are found in patients receiving the same dose of clozapine. Therefore, rational dose adjustment of clozapine that is guided by therapeutic drug monitoring (TDM) can improve efficacy while reducing risk of toxicity. As a background to the discussion of the use of TDM for clozapine, the pharmacodynamics and pathways of clozapine biotransformation are first reviewed, in particular the role of the primary enzymes involved. These are CYP1A2, the primary enzyme involved in converting clozapine to norclozapine, and CYP3A4, the primary enzyme involved in converting clozapine to clozapine-N-oxide. The factors that can influence plasma levels of clozapine are next reviewed; these include dose, gender, smoking, age, body weight, caffeine intake, and drug-drug interactions. The authors then examine the concentration-dependent toxicity of clozapine based on a review of published data. Finally, the authors present four cases illustrating the issues involved and how TMD can be used to improve clinical care of patients being treated with clozapine, both in terms of improving efficacy and minimizing potential toxicity.

Adult↗