Peter Bieck- MD PhD
- Vanderbilt University
Peter Bieck
- MD PhD
- Vanderbilt University
About
144
Publications
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Introduction
Peter Bieck has been working at the Division of Clinical Pharmacology, Vanderbilt University. Peter does research in Clinical Trials, Clinical Pharmacology and Addiction Medicine. One of the projects was 'Reversible MAO inhibitors.'
Current institution
Additional affiliations
October 1993 - September 1998
Position
- Director Substance Abuse Treatment Program (SATP)
Description
- •Reorganization and establishment of a clinically well functioning program •Integration of clinical activities between Med. and Psych. Service •ASAM Certification 1996 •Member ASAM Task Force and the Drug Utilization Evaluation Committee
October 1967 - October 1970
October 1970 - October 1973
Publications
Publications (144)
![FIGURE 2. Mean inhibition of ex vivo binding of [3H]-nisoxetine to...](profile/Peter-Bieck/publication/309279390/figure/fig2/AS:455897609707521@1485705868063/Mean-inhibition-of-ex-vivo-binding-of-3H-nisoxetine-to-norepinephrine-transporter-P_Q320.jpg)
To assess the primary metabolite of norepinephrine, 3,4-dihydroxyphenylglycol (DHPG), as a sensitive biomarker for norepinephrine transporter (NET) function and the relationship of DHPG measured peripherally and centrally, NET was antagonized with 80 mg/d atomoxetine for 18 days. Twelve healthy subjects were treated with atomoxetine in an open-labe...
Introduction:
SEP-432 is a triple monoamine reuptake inhibitor of norepinephrine (NE), serotonin (5-HT), and dopamine (DA), based on in vitro binding studies. We sought evidence that SEP-432 engages these monoamine systems by measuring concentrations of monoamines and/or their main metabolites in cerebrospinal fluid (CSF) and plasma and comparing...
Inaugural-Dissertation Julius Maximilians Universität Würzburg zur Erlangung der medizinischen Doktorwürde
Poster presented at Amer. College of Neuropsychopharmacology Dec 7-11, 2003, Puerto Rico
Covering the latest advances in CNS drug development, this book will guide all those involved in pre-clinical to early clinical trials. The authors describe how recent innovations can accelerate the development of novel CNS compounds, improve early detection of efficacy and toxicity signals, and increase the safety of later-stage clinical trials. T...
Animal models are used in preclinical trials to screen compounds before they are tested in humans, and can provide insight into the mechanism of action and rationale for clinical trials. Most animal models are only capable of reproducing certain aspects of a neurological condition; therefore, multiple animal models are needed to analyze different c...
Animal models provide a good starting point for identifying a compound's safety and efficacy, but do not always mirror results in humans. Early indicators of efficacy in humans are needed to minimize costs and time required for clinical trials, by providing reliable information on whether a novel compound warrants further development. Biomarkers pr...
A bridging study is a late Phase 1 (Phase 1b) or early Phase 2 (Phase 2a) safety/tolerability study conducted in the target population. The goal of the bridging study is to assess the tolerance profile and identify the maximum-tolerated dose (MTD) of a compound in the patient population in order to optimize dose selection for phase 2/3 efficacy tri...
Preclinical testing of new chemical or biological entities is essential for inferring potential beneficial and deleterious effects of exogenous compounds on the human body, as well as guiding the planning and expected outcomes of clinical trials. Considerable experience is required in the selection and sequence of a preclinical testing procedure to...
Both neuroimaging and cognitive assessments play a valuable role in early clinical trials, and are important components of the modern CNS drug developer's toolkit. This chapter reviews some of the major neuroimaging techniques and cognitive assessments showing utility in early drug development studies, including fMRI, structural MRI, PET imaging (F...
The current stagnation in central nervous system (CNS) drug development is evidenced by the lack of novel treatments across a number of neurologic and psychiatric disorders, including disease modifiers for Alzheimer's disease and novel antipsychotics. The decline in drug approvals is in harsh disparity to the ever-burgeoning costs and timelines req...
The purpose of this chapter is to summarize the information provided in the previous chapters using a real-world example; by creating a plausible, early clinical development program for a fictitious H3 receptor inverse agonist. This exercise takes us from the earliest preclinical assays to evaluation of safety, pharmacology, and toxicity in preclin...
This review focuses on the current status of biomarkers and/or approaches critical to assessing novel neuroscience targets with an emphasis on new paradigms and challenges in this field of research. The importance of biomarker data integration for psychotropic drug development is illustrated with examples for clinically used medications and investi...
Use of a biomarker of norepinephrine transporter (NET) inhibition to assess atomoxetine effects during clinically recommended dosing
Authors: PR Bieck, M Leibowitz, L Ereshefsky, DR Lachno, Q Lin, E Ledent, R Padich, AJ Allen, S Jhee, D Michelson
Background/Aims:
The degree of NET blockade can be assessed in the periphery using the plasma or urine...
To assess the sensitivity of biochemical, physiological, and pharmacological markers of peripheral norepinephrine (NE) transporter (NET) function, we chronically antagonized NET by a range of doses of duloxetine [(+)-N-methyl-3-(1-naphthalenyloxy)-2 thiophenepropanamine], which blocks the NE reuptake process.
Duloxetine was administered in a random...
Evidence suggests that compounds that increase the synaptic availability of more than one neurotransmitter have greater efficacy in the treatment of depression than single-acting drugs. Preclinical studies indicate that duloxetine acts to inhibit serotonin (5-HT) and norepinephrine (NE) transporters. The ability of duloxetine to alter 5-HT and NE r...
It has been accepted that CSF concentrations may be useful as a reflection of target concentrations for drugs that pass the blood-brain-barrier and blood-CSF-barrier following systemic administration. Added value in obtaining this matrix lies in the potential to assess biomarker and proteomic changes caused by drugs affecting the central nervous sy...
Interaktionen von pharmakologisch wirksamen Substanzen mit MonoaminoxidaseHemmern
(MAOH) konnen pharmakokinetisch und pharmakodynamisch begründet sein. Oft handelt es sich um eine Kombination der kinetischen und dynamischen Vorgange.
Wegen der betrachtlichen interindividuellen Variabilitat konnen solche Interaktionen zwar erwartet, aber ihr Ausmaß...
Die Monoamin-Oxidase (MAO, EC 1.4.2.4; Amin: Sauerstoff-Oxidoreduktase [desaminierend]) ist ein relativ unspezifisches mitochondriales Enzym. Es metabolisiert monoaminerge Neurotransmitter (wie Adrenalin, Noradrenalin, Dopamin) und Neuromodulatoren (wie (α-Phenethylamin), andere endogene und exogene Monoamine (wie Tyramin), aber auch tertiäre Amine...
Duloxetine (DU) is a potential antidepressant with a mechanism of action involving inhibition of serotonin (5-HT) and norepinephrine (NE) reuptake. The capacity of DU to alter these processes was tested in 12 healthy males. Placebo (n=12), desipramine (DMI) 50mgBID (n=12) and two regimen of DU, 80mgQD and 60mgBID (n=6 each), were compared in a rand...
In einer Cross-over-Studie an 12 gesunden Freiwilligen wurden unter Berücksichtigung einer Applikationspause von zumindest einer Woche in einem Versuch ein INSIDON®-Dragée und im anderen Versuch eine wäßrige lösung (jeweils 50 mg Opipramol-Dihydrochlorid als Wirkstoff) eingesetzt. Blutabnahmen erfolgten vor Applikation und bis 48 Stunden danach. Di...
Patients with a loop stoma were used to provide direct access to the transverse colon. The ease of delivery offers the chance to study absorption of human calcitonin (hCT) in a defined region of the large intestine difficult to access in healthy volunteers; i.v. infused hCT elicited a standard pharmacokinetic profile in eight loop stoma patients sh...
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The pharmacokinetics of brofaromine, a selective inhibitor of monoamine oxidase A, was evaluated in 12 frail elderly patients (66-92 y) and 12 healthy volunteers (20-35 y).
Quantitative liver function tests were performed to show whether brofaromine elimination in the elderly could be predicted from noninvasive assessment of CYP1A2 activity (caffei...
The comparison of two different modes of data processing and two different approaches to statistical testing both applied to the same set of EEG recordings was the main objective of this pharmacological study. Brofaromine (CGP 11,305 A), a new selective and reversible monoamine oxidase type A inhibitor was used as an example for investigating a pot...
The literature indicates that morphine can inhibit the growth of both small cell and non small cell lung cancer cell lines and that nicotine can reverse this inhibition. In this report we present data showing that mammalian lung tissue contain the opiate alkaloids morphine and codeine and that these alkaloids are also to be found in normal lung cel...
The present study compared the extent and duration of MAO inhibition by the selective and reversible MAO-A inhibitor brofaromine with the selective and irreversible MAO-A inhibitor clorgyline using amine pressor tests and excretion of urinary amine metabolites (MHPG, tryptamine). The pharmacological characterization of clorgyline as an irreversible...
CGP 28,014 is a specific inhibitor of catechol-O-methyltransferase (COMT) in vivo. In humans, the inhibition was assessed by measuring urinary excretion of isoquinolines and with the levodopa test. Following administration of CGP 28,014, urinary excretion of isoquinolines was significantly increased. In rats, CGP 28,014 reduced plasma and striatal...
The optically active isomers of the racemic tetracyclic antidepressant oxaprotiline, R (−) oxaprotiline CGP 12 103 A (levoprotiline) and the S (+) oxaprotiline CGP 12 104 A, have been used as tools for a methodological Phase I study.
Only the S (+) enantiomer CGP 12 104 A inhibits noradrenaline uptake.
Intravenous amine pressor tests and ex vivo me...
Traditional monoamine oxidase inhibitors (MAOIs) have long been associated with tyramine-related hypertension--the cheese effect. Despite their undoubted clinical efficacy, this problem has restricted their use. New, selective, and reversible MAO-A inhibitors--which act only on the A isoenzyme--appear not to have this effect. Our investigations of...
The metabolic fate of brofaromine (CGP 11 305 A), a new, reversible, selective MAO-A inhibitor, has been assessed in poor (PM) and extensive (EM) metabolizers of debrisoquine.
Compared to EM, PM had significantly longer t1/2 (136%) and larger AUC(0−∞) (110%) of the parent compound brofaromine and a lower Cmax (69%) and AUC (0–72 h) (40%) of its O-d...
C6 rat glioma cells were utilized as a model system to probe the 'serotonin/norepinephrine link' at the level of preproenkephalin (PPE) gene expression. The beta adrenoceptor mediated increase in PPE mRNA was attenuated by the selective beta 1 adrenoceptor antagonist metoprolol which blocked the isoproterenol induced cyclic AMP generation by 97%. T...
Die Monoaminoxidase (EC 1.4.3.4; Amin: Sauerstoff-Oxidoreduktase (desaminierend) (MAO), ein Enzym der äußeren Mitochondrienmembran, oxidiert eine Reihe von monoaminergen Neurotransmittern und Neuromodulatoren sowie exogene bioaktive Monoamine nach folgender ReaktionsGleichung: RCH2NH2+O2+H2O→RCHO+NH3+H2O2 Aufgrund unterschiedlicher Substratspezifit...
1. Human calcitonin was administered into the distal colon and by intravenous infusion in eight healthy subjects in an open, fixed sequence, cross-over bioavailability study.
2. Intravenously infused human calcitonin elicited a standard pharmacokinetic profile in eight healthy subjects with a biphasic elimination with half-lives of 10.2 ± 0.7 min a...
C6 rat glioma cells were utilized as a model system to probe the ‘serotonin/norepinephrine link’ at the level of preproenkephalin (PPE) gene expression. The β adrenoceptor mediated increase in PPE mRNA was attenuated by the selective β1 adrenoceptor antagonist metoprolol which blocked the isoproterenol induced cyclic AMP generation by 97%. The subt...
The beta-adrenoceptor-coupled adenylate cyclase system in rat C6 glioma cells displays many characteristics observed in brain tissue: using nonlinear regression analysis of agonist competition binding curves, we demonstrated that the bulk of beta-adrenoceptors show high nanomolar affinity for isoproterenol; like in brain tissue, Gpp(NH)p does not s...
The interaction between the sympathomimetic agents phenylephrine and phenylpropanol-amine (as used in cold remedies or anorexiants) and the new selective and reversible MAO-A inhibitor brofaromine (Consonar®) 75mg administered twice daily for 10 days was assessed in 6 volunteers, with particular attention to the occurrence of hypertensive episodes....
To investigate the pharmacokinetics and the disposition of levoprotiline after i.v. and p.o. administration and to assess the absolute bioavailability, 12 healthy volunteers (11 women, 1 man) were given a 10 min i.v. infusion of 15 mg and a p.o. dose of 75 mg in a two-way crossover study. Blood and urine samples were collected after each dose. Unch...
Nano- and micromolar isoproterenol concentrations were compared by studying cyclic AMP, beta-adrenoceptor density and beta 1-adrenoceptor mRNA in rat C6 glioma cells. 1 microM isoproterenol significantly changed all parameters at 15-30 min. The beta 1-antagonist metoprolol attenuated the response. No effects of nanomolar isoproterenol on these earl...
The pressor effect of intravenous tyramine (TYR) and noradrenaline (NA) has been evaluated, respectively, in 157 tests in 19 healthy unmedicated subjects, and in 202 tests in 24 similar subjects, all of whom took part in ≥3 test sessions.
The pressor dose (PD) that raised systolic blood pressure by 30 mm Hg (PD30) ranged from 2 to 8 mg for TYR, and...
Traditional monoamine oxidase inhibitors (MAO!s) have long been associated with tyramine-related hypertension-the cheese effect. Despite their undoubted clinical efficacy, this problem has restricted their use. New, selective, and reversible MAO-A inhibitors-which act only on the A isoenzyme-appear not to have this effect. Our investigations of the...
MAO-B activity was compared in healthy volunteers following oral treatment with clinically effective doses of the selective MAO-A inhibitors brofaromine (100 mg q.d. for 14 days), moclobemide (150 mg t.i.d. for 14 days) and clorgyline (5 mg t.i.d. for 10 days). Brofaromine and clorgyline did not alter platelet MAO activity. Following moclobemide tr...
Magnesium deficiency can occur in several diseases. such
as malabsorption syndromes, diabetes mellitus and renal
disorders. It can be treated with oral magnesium compounds,
of which several preparations are currently available:
various complex salts, and the oxide or hydroxide of
magnesium [1]. In the present study, two formulations of
magnesium-L-...
CGP 28014 A is a specific inhibitor of catechol-O-methyl transferase (COMT). The effect on COMT was assessed with the levodopa test in 5 unmedicated subjects and after pretreatment with 200-600 mg CGP 28014 p.o. Plasma concentrations of DOPA, 3-O-methyldopa (3OMD), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid were measured. CGP 2801...
In an open clinical trial 13 depressives significantly improved under the reversible and selective type-A monoamine oxidase (MAO) inhibitor brofaromine. The inhibitory potency of deproteinated plasma on a crude MAO preparation from human placenta was measured as a parameter for plasma brofaromine. There were no significant differences in plasma MAO...
Most drugs are administered orally, and the gastrointestinal tract is frequently exposed to high concentrations of substances given with the aim of acting at low concentrations elsewhere in the body. It is known that a number of drugs influence physiological and morphological patterns, and may lead to clinically important problems. Drugs alter gast...
The effect of the monoamine oxidase inhibitor selegiline on tyramine metabolism and intravenous and oral tyramine pressor sensitivity was studied in healthy subjects. After oral doses of tyramine, which caused systolic blood pressure to increase by 30 mm Hg, we determined plasma concentrations of p-hydroxyphenylacetic acid (HPAA) and of conjugated...
Healthy ambulatory subjects took 6 different MAO inhibitors (MAOIs) orally for 2 to 4 weeks. The new reversible MAO-A inhibitors brofaromine and moclobemide were compared with the irreversible MAOIs clorgyline, selegiline, phenelzine and tranylcypromine. Pressor responsiveness to oral tyramine was assessed before, during and after treatment. In unm...
The two monoamine oxidase (MAO) inhibitors phenelzine and brofaromine given for 2 to 3 weeks were compared in six volunteers. Blood pressure sensitivity to intravenous tyramine increased 2.6-fold during phenelzine (60 mg/day) and 4.8-fold during brofaromine, whereas sensitivity to oral tyramine increased more during phenelzine (15.7-fold vs 8.5-fol...
Healthy ambulatory subjects were treated p.o. for 2 to 4 weeks with 6 different MAO inhibitors (MAOI). MAOI drugs were given to (n) subjects. Brofaromine (Brof): 100-150 mg/d (39); moclobemide (Mocl): 450 mg/d (8); clorgyline (Clor): 5, 10, 15 mg/d (5); selegiline (Sel): 5, 20 mg/d (7); phenelzine (Phen): 30, 45, 60 mg/d (6); tranylcypromine (TCP):...
In a placebo-controlled, randomized, double-blind cross-over study in 12 healthy volunteers the effect of acute alcohol intake during treatment with transdermally administered scopolamine (TTS-scopolamine) was investigated. One group of six subjects reached maximal blood alcohol concentrations (BAC) of 80 mg/dL and another group of six subjects a B...
The pressor effect of orally administered tyramine (TYR) has been evaluated in 124 tests of 49 healthy unmedicated volunteers, in 99 tests of 29 subjects treated with the reversible selective monoamine oxidase (MAO) A inhibitor brofaromine (BROF), and in 73 tests of 12 subjects treated with tranylcypromine (TCP). In unmedicated subjects, pressor do...
A rapid high-performance liquid chromatographic (HPLC) method for the determination of the novel benzodiazepine receptor antagonist 2-phenylpyrazolo[4,3-c]quinolin-3(5H)-one (CGS 8216) and its hydroxy metabolite is described. The method involves a solid-phase extraction with C18 disposable columns and quantification by HPLC with UV-detection. In pl...
1. Plasma melatonin was used to determine the influence of two monoamine oxidase inhibitor drugs in 11 normal subjects. 2. Acute oral administration of the selective reversible MAO-A inhibitor brofaromine but not of the - in low doses - selective MAO-B inhibitor pargyline increased daytime melatonin with large variations in onset, degree and durati...
The specific alpha 2-adrenoceptor binding (Bmax and KD) of (3H-methyl)yohimbine to intact platelets of healthy young volunteers was not significantly different in 7 males and 7 females. Its extent was not dependent on the menstrual cycle. The intraindividual variability was relatively high with means between 6% and 38% for Bmax and between 10% and...
2-Phenylpyrazolo[4,3-c]quinolin-3(5H)-one (CGS 8216) is pharmacologically characterized as benzodiazepine antagonist with low inverse agonistic effects. Single oral doses up to 650 mg and subchronic doses up to 100 mg daily for seven days are well tolerated by young healthy volunteers. Plasma concentrations of CGS 8216 are variable, not dose-relate...
In the studies presented, the relative extent of tyramine (TYR) deamination to p-hydroxyphenylacidic acid (HPAA) and of TYR conjugation was determined before and during treatment with 5 different MAO inhibitor (MAOI) drugs. Healthy ambulatory subjects were treated p.o. for 2 – 4 weeks. Data were evaluated from (n) subjects. MAOI drugs were: Brofaro...
In order to assess the safety of the reversible MAO inhibitor moclobemide, towards the so-called "cheese-effect", Korn et al. (1986) used an oral tyramine interaction test. Volunteers received, before and following treatment with either moclobemide or tranylcypromine, oral doses of 50 mg (tyramine in capsules) and of 65 mg (tyramine content of chee...
The specific binding (Bmax) of (3H-methyl)yohimbine to alpha2-adrenoceptor binding sites on intact platelets was increased by 43% in 6 out of 7 young male volunteers 4 days after a single i.m. injection of 10 mg sustained release oestradiol, and it had returned to the starting value 4 weeks after drug administration. Mean plasma oestradiol was 331...
Absorption of single doses of Oxprenolol (80 mg) and of diclofenac-Na (100 mg) administered by colonoscopy into the cecum and the left flexure of the colon was compared with that after oral dosing in healthy volunteers. Plasma concentration/ time profiles of both drugs after oral and colonic dosing followed similar time courses. Oxprenolol reached...
1.
CGS 8216 is metabolised to the hydroxy metabolite CGS 11 361 in rat and in man with a much higher metabolite/parent drug ratio in man (2.5 vs 0.1).
2.
The brain/plasma concentration ratio of the parent drug in the rat 30 min after 10 and 25 mg/kg IP is low, suggesting slow penetration of the drug into the brain tissue.
3.
No hydroxy metabolite o...
The pharmacokinetics of CGP 15 210 G, a new 5-HT uptake inhibitor in poor and extensive metabolisers of debrisoquine, give indirect evidence of an association between its metabolism and polymorphic hydroxylation of the debrisoquine type.
In order to evaluate the absorptive capacity of the colonic mucosa, colonoscopy was used to investigate in six healthy volunteers the colonic absorption of the nonsteroidal anti-inflammatory drug diclofenac (Voltaren). Oral and colonic administration of 100 mg of diclofenac resulted in comparable peak plasma concentrations and areas under the plasm...
The systemic availability of oxprenolol after colonic and oral administration has been compared in a crossover study involving six healthy male volunteers. Drug administration into two regions of the colon (caecum and left flexure) was achieved by means of a colonoscopic technique. There were no obvious differences in plasma concentrations after dr...
In 6 healthy, young volunteers the kinetics of L-tryptophan (TRP) following 3 different single oral doses (1.5, 3, 6 g) simultaneously with urinary tryptamine (TA) excretion were examined. Blood and urine samples were collected hourly before and for 14 h after TRP. TRP in plasma and TA in urine were analysed by specific and sensitive HPLC methods u...
The new substance CGP 4718 A (4-(5-chloro-2-benzofuranyl)-1-methylpiperidine hydrochloride) in animal experiments shows both 5-HT-uptake blocking and (preferentially) MAO-A inhibiting properties. CGP 4718 A was studied in man to evaluate its effects on the noradrenergic, dopaminergic and serotonergic systems by measuring urinary metabolites. In a r...
The so-called “cheese-reaction” — a hypertensive crisis during treatment with monoamine oxidase (MAO) inhibitors — is generally considered to result from ingestion of food containing high amounts of tyramine (TYR). In order to evaluate this effect in a controlled setting as close as possible to the clinical situation TYR has to be given orally. Add...
A probable neurobiological role for the trace amines began to emerge as soon as techniques sufficiently sophisticated to detect them were developed. Techniques for quantitative analyses included radioenzymatic procedures and, more recently, HPlC-EC and auto mated GC-MS. The methods are applied after separation of the sub stances to be analyzed an...
These results demonstrate that vigilance and sensorimotor abilities during continuous transdermal administration of scopolamine are not impaired. This is due to the dose of scopolamine being high enough to evoke an antiemetic effect but with minimal elicitation of undersired side effects. Wesnes and Warburton (1984), who used two oral doses in a pu...
Measurement of urinary tryptamine excretion has been used extensively in the past as indicator for monoamine oxidase (MAO) inhibition in man. Basal tryptamine excretion (ug/g creatinine) differs between sexes (p< 0.001). The values obtained (x ± SD) were: 66 ± 26 in 13 males (n = 90) and 112 ± 42 in 9 females (n = 60). The higher basal tryptamine e...
Questions
Question (1)
I have used Prism6 for laboratory data. There were several samples BLQ because of the lower limit of quantitation (LLQ) of the method, e.g. 5 ng/ml or less. I marked these values together with the outliers (determined with the Rout method, 1% rule, before doing the calculations). The question was raised by the laboratory whether excluding BLQ values from the analysis would cause a bias on the data.
