Background This study was designed to determine the disposition of bupivacaine and its metabolite... more Background This study was designed to determine the disposition of bupivacaine and its metabolites in the maternal, placental, and fetal compartments, using multiple sampling time points in chronically prepared awake pregnant rats. Methods All animals received an intravenous infusion of bupivacaine at a rate of 0.33 mg. kg-1. min-1 over a period of 15 min. The fetuses were delivered either at the end of infusion or at 2 or 4 h after dosing. Maternal and fetal blood and tissue samples were obtained for the assays of bupivacaine and its metabolites using capillary gas chromatography-mass spectrometry. Results The elimination half-life of bupivacaine was 37.7 min. The major metabolite was 3'-hydroxybupivacaine. Bupivacaine and 3'-hydroxybupivacaine were present in all samples at the end of administration. The fetal to maternal concentration ratio of bupivacaine in plasma was 0.29, and in the placenta was 0.63. The amnion contained the highest bupivacaine concentration: threefol...
Glycine transporter-1 (GlyT1) inhibitors may ameliorate cognitive impairments associated with sch... more Glycine transporter-1 (GlyT1) inhibitors may ameliorate cognitive impairments associated with schizophrenia. The dose-related occupancy and target engagement of the GlyT1 inhibitor PF-03463275 were studied to inform optimal dose selection for a clinical trial for cognitive impairments associated with schizophrenia. In substudy 1, the effects of PF-03463275 (10, 20, and 40 mg twice a day) on occupancy of GlyT1 were tested using positron emission tomography andF-MK-6577, and visual long-term potentiation (LTP) in schizophrenia patients (SZs) and healthy control subjects. Furthermore, the capacity of PF-03463275 to attenuate ketamine-induced disruption of working memory-related activation of a "working memory" circuit was tested only in healthy control subjects using functional magnetic resonance imaging. Subsequently, the effects of PF-03463275 (60 mg twice a day) on occupancy of GlyT1 and long-term potentiation were examined only in SZs (substudy 2). PF-03463275 at 10, 20, ...
A liquid chromatographic method coupled with electrochemical detection was developed to measure p... more A liquid chromatographic method coupled with electrochemical detection was developed to measure plasma trazodone and its metabolite 1-m-chlorophenylpiperazine (m-CPP). Following extraction from 1 ml of alkaline plasma with methyl-t-butyl ether, the extracts were chromatographed on a reversed phase trimethylsilyl bonded column using a 0.05 M phosphate buffer and acetonitrile (90:10) with n-nonylamine and sodium heptane sulfonate added to the mobile phase. The compounds were detected via a thin layer electrochemical transducer with glassy carbon electrodes at a potential of + 1.15V vs Ag/AgCl reference electrode. The recovery of trazodone ranged from 91–97% and the coefficient of variation was less than 5% for between run and within-run analyses. The recovery of m-CPP ranged from 82–86% and the coefficient of variation was less than 8% for between run and within-run analysis. Steady state plasma concentration data are presented from several patients.
Canavan disease (CD) is a human early-onset leukodystrophy, genetic in nature and resulting from ... more Canavan disease (CD) is a human early-onset leukodystrophy, genetic in nature and resulting from an autosomally inherited recessive trait. CD is characterized by loss of the axon's myelin sheath, while leaving the axons intact, and spongiform degeneration, especially in white matter. It is an osmotic disease that affects both gray and white matter and is caused by the inability of oligodendrocytes to hydrolyze N-acetyl-L-aspartate (NAA) because of a lack of aspartoacylase activity. As a result, there is a build-up of NAA in brain with both cellular and extracellular edema, as well as NAA acidemia and NAA aciduria. Recent studies have indicated that several compounds have the ability to reduce brain levels of NAA in normal mice and rats. In this investigation, these compounds have been tested, using a CD-like rat model of the human disease to evaluate their potential for use in the treatment of the disease. Of seven substances tested in an acute 5-day study, only lithium chloride treatment resulted in a significant reduction of about 13% in whole-brain NAA levels in the CD-like rat model. This is the first pharmacological investigation of the effect of drugs on the level of brain NAA in an animal model of CD, and the first report of a substance that can reduce the brain NAA level in this model.
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 2011
This study was designed to replicate an earlier finding of a rapid acute therapeutic action of in... more This study was designed to replicate an earlier finding of a rapid acute therapeutic action of intracerebrally administered antidepressant in chronically depressed rodents. The effects of acute fourth ventricular (ivt.) injections were compared to those of acute peripheral (i.p.) injections of desipramine (DMI) in mice subjected to repeated open-space forced swim. In confirmation, it was found that a single ivt. injection of a low (3 nmol) but not high (30 nmol) dose immediately reversed the immobility and inactivity of the model whereas acute i.p. administration was without effect up to 30 mg/kg. The repeated forced swim stress was also found to significantly reduce the net accumulation of DMI in the brain but not liver after a single i.p. injection of a moderate dose (10 mg/kg). The results suggest that stress-induced alterations of regional drug uptake or metabolism in the CNS may contribute to the therapeutic lag for antidepressants and other compounds in disorders with high dis...
The effect of doxepin on ventricular arrhythmias, the ECG, and left ventricular function was eval... more The effect of doxepin on ventricular arrhythmias, the ECG, and left ventricular function was evaluated in 10 cardiac patients with symptoms with frequent ventricular premature depolarizations in a dose-ranging protocol. Four patients (40%) had greater than or equal to 80% ventricular premature depolarization suppression; four of eight with pairs and four of six with ventricular tachycardia had greater than or equal to 90% suppression. The mean maximal doxepin dose was 115 +/- 41 mg/day; mean nadir total doxepin concentration was 61 +/- 48 ng/ml and mean nadir total desmethyldoxepin concentration was 51 +/- 42 ng/ml. Doxepin increased the heart rate and the PR, QRS, and QTc intervals of the surface ECG (P not significant). There was no significant change in resting mean left ventricular ejection fraction with doxepin: 41% +/- 15% vs. 43% +/- 19% (P not significant). Complaints of sedation (eight patients) limited dose ranging and tolerance to the drug. Although doxepin suppressed ventricular premature depolarizations in four patients, marked sedation limits its usefulness for primary treatment of arrhythmias in this population.
An association between tardive dyskinesia (TD) and severely impaired metabolism of the large neut... more An association between tardive dyskinesia (TD) and severely impaired metabolism of the large neutral amino acid (LNAA), phenylalanine (Phe) was defined in a group of mentally retarded patients. Subsequently, an altered kinetics of Phe was associated with TD in men with schizophrenia based on plasma analyses subsequent to the ingestion of a protein meal. In the present study, a standardized oral challenge of pure Phe (100 mg/kg in 170 ml orange juice) was administered to psychiatric patients of both sexes (n = 312), with and without TD after an overnight fast. Plasma LNAA levels were assayed both fasting and 2 h subsequent to the ingestion of the challenge. The extent of the increase in plasma Phe levels 2 h following a standardized challenge is determined by the sum of the kinetic processes of plasma absorption, tissue distribution, metabolism and elimination. The study hypothesis, that TD would be associated with significantly higher post-challenge plasma Phe indices of an absolute plasma Phe level and plasma Phe/LNAA ratio (a brain availability measure), was verified for the study men (n = 209), but not for the study women (n = 103). The demonstrated altered kinetics of Phe in men with TD indicates a greater availability of Phe to the brain in these men. We suggest that the disorder may be related to the effects of this greater availability. Such effects could be the direct neurotoxic effects of Phe and its metabolites and/or the modulating effects of these compounds on the synthesis of the monoamine neurotransmitters. The fact that TD (Yes/No) group differences in post-challenge plasma Phe indices were not seen for the study women suggests the possibility of a sex difference in the biology of TD that we propose may be reflective of the young age of the study sample.
Background This study was designed to determine the disposition of bupivacaine and its metabolite... more Background This study was designed to determine the disposition of bupivacaine and its metabolites in the maternal, placental, and fetal compartments, using multiple sampling time points in chronically prepared awake pregnant rats. Methods All animals received an intravenous infusion of bupivacaine at a rate of 0.33 mg. kg-1. min-1 over a period of 15 min. The fetuses were delivered either at the end of infusion or at 2 or 4 h after dosing. Maternal and fetal blood and tissue samples were obtained for the assays of bupivacaine and its metabolites using capillary gas chromatography-mass spectrometry. Results The elimination half-life of bupivacaine was 37.7 min. The major metabolite was 3'-hydroxybupivacaine. Bupivacaine and 3'-hydroxybupivacaine were present in all samples at the end of administration. The fetal to maternal concentration ratio of bupivacaine in plasma was 0.29, and in the placenta was 0.63. The amnion contained the highest bupivacaine concentration: threefol...
Glycine transporter-1 (GlyT1) inhibitors may ameliorate cognitive impairments associated with sch... more Glycine transporter-1 (GlyT1) inhibitors may ameliorate cognitive impairments associated with schizophrenia. The dose-related occupancy and target engagement of the GlyT1 inhibitor PF-03463275 were studied to inform optimal dose selection for a clinical trial for cognitive impairments associated with schizophrenia. In substudy 1, the effects of PF-03463275 (10, 20, and 40 mg twice a day) on occupancy of GlyT1 were tested using positron emission tomography andF-MK-6577, and visual long-term potentiation (LTP) in schizophrenia patients (SZs) and healthy control subjects. Furthermore, the capacity of PF-03463275 to attenuate ketamine-induced disruption of working memory-related activation of a "working memory" circuit was tested only in healthy control subjects using functional magnetic resonance imaging. Subsequently, the effects of PF-03463275 (60 mg twice a day) on occupancy of GlyT1 and long-term potentiation were examined only in SZs (substudy 2). PF-03463275 at 10, 20, ...
A liquid chromatographic method coupled with electrochemical detection was developed to measure p... more A liquid chromatographic method coupled with electrochemical detection was developed to measure plasma trazodone and its metabolite 1-m-chlorophenylpiperazine (m-CPP). Following extraction from 1 ml of alkaline plasma with methyl-t-butyl ether, the extracts were chromatographed on a reversed phase trimethylsilyl bonded column using a 0.05 M phosphate buffer and acetonitrile (90:10) with n-nonylamine and sodium heptane sulfonate added to the mobile phase. The compounds were detected via a thin layer electrochemical transducer with glassy carbon electrodes at a potential of + 1.15V vs Ag/AgCl reference electrode. The recovery of trazodone ranged from 91–97% and the coefficient of variation was less than 5% for between run and within-run analyses. The recovery of m-CPP ranged from 82–86% and the coefficient of variation was less than 8% for between run and within-run analysis. Steady state plasma concentration data are presented from several patients.
Canavan disease (CD) is a human early-onset leukodystrophy, genetic in nature and resulting from ... more Canavan disease (CD) is a human early-onset leukodystrophy, genetic in nature and resulting from an autosomally inherited recessive trait. CD is characterized by loss of the axon's myelin sheath, while leaving the axons intact, and spongiform degeneration, especially in white matter. It is an osmotic disease that affects both gray and white matter and is caused by the inability of oligodendrocytes to hydrolyze N-acetyl-L-aspartate (NAA) because of a lack of aspartoacylase activity. As a result, there is a build-up of NAA in brain with both cellular and extracellular edema, as well as NAA acidemia and NAA aciduria. Recent studies have indicated that several compounds have the ability to reduce brain levels of NAA in normal mice and rats. In this investigation, these compounds have been tested, using a CD-like rat model of the human disease to evaluate their potential for use in the treatment of the disease. Of seven substances tested in an acute 5-day study, only lithium chloride treatment resulted in a significant reduction of about 13% in whole-brain NAA levels in the CD-like rat model. This is the first pharmacological investigation of the effect of drugs on the level of brain NAA in an animal model of CD, and the first report of a substance that can reduce the brain NAA level in this model.
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 2011
This study was designed to replicate an earlier finding of a rapid acute therapeutic action of in... more This study was designed to replicate an earlier finding of a rapid acute therapeutic action of intracerebrally administered antidepressant in chronically depressed rodents. The effects of acute fourth ventricular (ivt.) injections were compared to those of acute peripheral (i.p.) injections of desipramine (DMI) in mice subjected to repeated open-space forced swim. In confirmation, it was found that a single ivt. injection of a low (3 nmol) but not high (30 nmol) dose immediately reversed the immobility and inactivity of the model whereas acute i.p. administration was without effect up to 30 mg/kg. The repeated forced swim stress was also found to significantly reduce the net accumulation of DMI in the brain but not liver after a single i.p. injection of a moderate dose (10 mg/kg). The results suggest that stress-induced alterations of regional drug uptake or metabolism in the CNS may contribute to the therapeutic lag for antidepressants and other compounds in disorders with high dis...
The effect of doxepin on ventricular arrhythmias, the ECG, and left ventricular function was eval... more The effect of doxepin on ventricular arrhythmias, the ECG, and left ventricular function was evaluated in 10 cardiac patients with symptoms with frequent ventricular premature depolarizations in a dose-ranging protocol. Four patients (40%) had greater than or equal to 80% ventricular premature depolarization suppression; four of eight with pairs and four of six with ventricular tachycardia had greater than or equal to 90% suppression. The mean maximal doxepin dose was 115 +/- 41 mg/day; mean nadir total doxepin concentration was 61 +/- 48 ng/ml and mean nadir total desmethyldoxepin concentration was 51 +/- 42 ng/ml. Doxepin increased the heart rate and the PR, QRS, and QTc intervals of the surface ECG (P not significant). There was no significant change in resting mean left ventricular ejection fraction with doxepin: 41% +/- 15% vs. 43% +/- 19% (P not significant). Complaints of sedation (eight patients) limited dose ranging and tolerance to the drug. Although doxepin suppressed ventricular premature depolarizations in four patients, marked sedation limits its usefulness for primary treatment of arrhythmias in this population.
An association between tardive dyskinesia (TD) and severely impaired metabolism of the large neut... more An association between tardive dyskinesia (TD) and severely impaired metabolism of the large neutral amino acid (LNAA), phenylalanine (Phe) was defined in a group of mentally retarded patients. Subsequently, an altered kinetics of Phe was associated with TD in men with schizophrenia based on plasma analyses subsequent to the ingestion of a protein meal. In the present study, a standardized oral challenge of pure Phe (100 mg/kg in 170 ml orange juice) was administered to psychiatric patients of both sexes (n = 312), with and without TD after an overnight fast. Plasma LNAA levels were assayed both fasting and 2 h subsequent to the ingestion of the challenge. The extent of the increase in plasma Phe levels 2 h following a standardized challenge is determined by the sum of the kinetic processes of plasma absorption, tissue distribution, metabolism and elimination. The study hypothesis, that TD would be associated with significantly higher post-challenge plasma Phe indices of an absolute plasma Phe level and plasma Phe/LNAA ratio (a brain availability measure), was verified for the study men (n = 209), but not for the study women (n = 103). The demonstrated altered kinetics of Phe in men with TD indicates a greater availability of Phe to the brain in these men. We suggest that the disorder may be related to the effects of this greater availability. Such effects could be the direct neurotoxic effects of Phe and its metabolites and/or the modulating effects of these compounds on the synthesis of the monoamine neurotransmitters. The fact that TD (Yes/No) group differences in post-challenge plasma Phe indices were not seen for the study women suggests the possibility of a sex difference in the biology of TD that we propose may be reflective of the young age of the study sample.
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