We determined fluoxetine (Prozac#{174})and its major me-tabolite norfluoxetine in plasma by liqui... more We determined fluoxetine (Prozac#{174})and its major me-tabolite norfluoxetine in plasma by liquidchromatography with fluorescence detection. After liquid-liquid extraction from 1 mL of plasma, the extract was denvatized at room temperature with dansyl chloride, and the highly fluores-cent derivatives were chromatographed with a reversed-phase C15 column and a mobile phase of phosphate buffer and acetonitrile. Dansylated fluoxetine, norfluoxet-me, and the internal standard were eluted in <14 mm with no interference from endogenous material. The calibra-tioncurve was linear over the concentrationrange 25-800 tg/L with inter- and intra-assay imprecision (CV) of <10%. Validity of the assay was checked by comparing results for 110 patients ’ samples with those by a liquid-chromatographic method with ultraviolet detection (r = 0.993 for fluoxetine, 0.957 for norfluoxetine). The identity of the dansylated derivatives was verified by positive chemical ionization mass spectroscopy. The lower limitof detection was-3 g/L. Because no major antidepres-sant, neuroleptic, or respective drug metabolites interfere with the quantificationof fluoxetine and noriluoxetine, this is a useful procedure for pharmacokinetic studies and in clinical settings. AddItional Keyphraaes: antidepressant drugs. chromatogra-phy,reversed-phase
To evaluate serotonergic (5-hydroxytryptamine) function in obsessive-compulsive disorder, behavio... more To evaluate serotonergic (5-hydroxytryptamine) function in obsessive-compulsive disorder, behavioral and neuroendocrine responses to m-chlorophenylpiperazine (m-CPP; 0.5 mg/kg orally) and fenfluramine hydrochloride (60 mg orally) were examined in 20 patients and 10 healthy controls under double-blind, placebo-controlled conditions. Following m-CPP, but not fenfluramine or placebo, 55% (11/20) of the patients with obsessive-compulsive disorder experienced a transient exacerbation of obsessive-compulsive disorder. Prolactin response was blunted in patients following m-CPP but not following fenfluramine. Patients with greater behavioral response to m-CPP had smaller prolactin responses. Cortisol response to m-CPP and fenfluramine did not significantly differ between the groups. Behavioral and neuroendocrine responses appeared divergent. This does not suggest simply upregulation or downregulation of 5-hydroxytryptamine receptors, but rather complex mechanisms involving multiple neurotransmitter and neuromodulator systems.
Bupropione is a chemically unique antidepressant whose mechanism of action is not known. In this ... more Bupropione is a chemically unique antidepressant whose mechanism of action is not known. In this study they have evaluated the effect of chronic treatment with bupropione on the receptor-mediated release of inositol phosphates (IP) from brain slices in rats. Animals were implanted with Alzet osmotic pumps that delivered bupropione at a constant rate (40mg/kg/day) for 2 weeks. Cross-chopped slices of cerebral cortex from control and drug-treated rats were prelabelled with myo-/sup 3/H-inositol in HEPES buffer containing 11 mM LiCl. Accumulation of IP was measured in the presence and absence of the following agonists: Carbamylcholine (100..mu..m); norepinephrine (5..mu..M) and serotonin (10..mu..M). All agonists stimulated release of IP from slices of control animals but appeared to inhibit IP release in bupropione-treated rats. These results indicate that a phospholipase C inhibitor may appear following the activation of this enzyme by the agonist, and that the agonist-induced formation of the apparent inhibitor may be markedly enhanced after treatment with bupropione.
The uptake of norepinephrine into cortical punches from the brain of the rat was studied in the p... more The uptake of norepinephrine into cortical punches from the brain of the rat was studied in the presence of buffer and plasma from patients containing bupropion and its metabolites. Even though bupropion and its metabolite (compound II) were equipotent in inhibiting the uptake of NE in buffer, compound II was twice as active as bupropion in the presence of human plasma. When the inhibition of uptake of NE in the presence of plasma, obtained from patients on bupropion on steady-state, was correlated with levels of bupropion and its metabolites (II, III, IV) a highly significant correlation was seen in the presence of compound II. Since this compound accumulated in plasma from patients 20-100 times that of the parent compound, the mode of action of bupropion may in part be due to the effect of this compound on the uptake of NE.
Ketamine shows promise as a rapidly-acting treatment for depression and suicidal ideation, but si... more Ketamine shows promise as a rapidly-acting treatment for depression and suicidal ideation, but side effects and abuse potential limit its use. Understanding its mechanism of action could help develop analogous but safer drugs. This post hoc study explored relationships of ketamine and metabolites, including hydroxynorketamine enantiomers, (2S,6S)- and (2R,6R)-HNK, to clinical response in a subgroup from a published trial in suicidal depression. Depressed adults with clinically significant suicidal ideation were randomized to double-blind infusion of sub-anesthetic ketamine or midazolam. Ketamine and metabolites were measured after infusion (N=53). Plasma (2R,6R)-HNK was associated with change (higher levels correlated with less clinical improvement) from baseline to 24h post-infusion of depression (HDRS-24: Spearman r=0.37, p=0.009) and suicidal thoughts (SSI: Spearman r=0.29, p=0.041). There were similar correlations with weekly follow-up clinical rating scores for both HNK enantiomers and dehydronorketamine (DHNK). Ketamine and norketamine were not associated with change in depression or suicidal ideation (unadjusted p>0.28).
We determined fluoxetine (Prozac#{174})and its major me-tabolite norfluoxetine in plasma by liqui... more We determined fluoxetine (Prozac#{174})and its major me-tabolite norfluoxetine in plasma by liquidchromatography with fluorescence detection. After liquid-liquid extraction from 1 mL of plasma, the extract was denvatized at room temperature with dansyl chloride, and the highly fluores-cent derivatives were chromatographed with a reversed-phase C15 column and a mobile phase of phosphate buffer and acetonitrile. Dansylated fluoxetine, norfluoxet-me, and the internal standard were eluted in <14 mm with no interference from endogenous material. The calibra-tioncurve was linear over the concentrationrange 25-800 tg/L with inter- and intra-assay imprecision (CV) of <10%. Validity of the assay was checked by comparing results for 110 patients ’ samples with those by a liquid-chromatographic method with ultraviolet detection (r = 0.993 for fluoxetine, 0.957 for norfluoxetine). The identity of the dansylated derivatives was verified by positive chemical ionization mass spectroscopy. The lower limitof detection was-3 g/L. Because no major antidepres-sant, neuroleptic, or respective drug metabolites interfere with the quantificationof fluoxetine and noriluoxetine, this is a useful procedure for pharmacokinetic studies and in clinical settings. AddItional Keyphraaes: antidepressant drugs. chromatogra-phy,reversed-phase
To evaluate serotonergic (5-hydroxytryptamine) function in obsessive-compulsive disorder, behavio... more To evaluate serotonergic (5-hydroxytryptamine) function in obsessive-compulsive disorder, behavioral and neuroendocrine responses to m-chlorophenylpiperazine (m-CPP; 0.5 mg/kg orally) and fenfluramine hydrochloride (60 mg orally) were examined in 20 patients and 10 healthy controls under double-blind, placebo-controlled conditions. Following m-CPP, but not fenfluramine or placebo, 55% (11/20) of the patients with obsessive-compulsive disorder experienced a transient exacerbation of obsessive-compulsive disorder. Prolactin response was blunted in patients following m-CPP but not following fenfluramine. Patients with greater behavioral response to m-CPP had smaller prolactin responses. Cortisol response to m-CPP and fenfluramine did not significantly differ between the groups. Behavioral and neuroendocrine responses appeared divergent. This does not suggest simply upregulation or downregulation of 5-hydroxytryptamine receptors, but rather complex mechanisms involving multiple neurotransmitter and neuromodulator systems.
Bupropione is a chemically unique antidepressant whose mechanism of action is not known. In this ... more Bupropione is a chemically unique antidepressant whose mechanism of action is not known. In this study they have evaluated the effect of chronic treatment with bupropione on the receptor-mediated release of inositol phosphates (IP) from brain slices in rats. Animals were implanted with Alzet osmotic pumps that delivered bupropione at a constant rate (40mg/kg/day) for 2 weeks. Cross-chopped slices of cerebral cortex from control and drug-treated rats were prelabelled with myo-/sup 3/H-inositol in HEPES buffer containing 11 mM LiCl. Accumulation of IP was measured in the presence and absence of the following agonists: Carbamylcholine (100..mu..m); norepinephrine (5..mu..M) and serotonin (10..mu..M). All agonists stimulated release of IP from slices of control animals but appeared to inhibit IP release in bupropione-treated rats. These results indicate that a phospholipase C inhibitor may appear following the activation of this enzyme by the agonist, and that the agonist-induced formation of the apparent inhibitor may be markedly enhanced after treatment with bupropione.
The uptake of norepinephrine into cortical punches from the brain of the rat was studied in the p... more The uptake of norepinephrine into cortical punches from the brain of the rat was studied in the presence of buffer and plasma from patients containing bupropion and its metabolites. Even though bupropion and its metabolite (compound II) were equipotent in inhibiting the uptake of NE in buffer, compound II was twice as active as bupropion in the presence of human plasma. When the inhibition of uptake of NE in the presence of plasma, obtained from patients on bupropion on steady-state, was correlated with levels of bupropion and its metabolites (II, III, IV) a highly significant correlation was seen in the presence of compound II. Since this compound accumulated in plasma from patients 20-100 times that of the parent compound, the mode of action of bupropion may in part be due to the effect of this compound on the uptake of NE.
Ketamine shows promise as a rapidly-acting treatment for depression and suicidal ideation, but si... more Ketamine shows promise as a rapidly-acting treatment for depression and suicidal ideation, but side effects and abuse potential limit its use. Understanding its mechanism of action could help develop analogous but safer drugs. This post hoc study explored relationships of ketamine and metabolites, including hydroxynorketamine enantiomers, (2S,6S)- and (2R,6R)-HNK, to clinical response in a subgroup from a published trial in suicidal depression. Depressed adults with clinically significant suicidal ideation were randomized to double-blind infusion of sub-anesthetic ketamine or midazolam. Ketamine and metabolites were measured after infusion (N=53). Plasma (2R,6R)-HNK was associated with change (higher levels correlated with less clinical improvement) from baseline to 24h post-infusion of depression (HDRS-24: Spearman r=0.37, p=0.009) and suicidal thoughts (SSI: Spearman r=0.29, p=0.041). There were similar correlations with weekly follow-up clinical rating scores for both HNK enantiomers and dehydronorketamine (DHNK). Ketamine and norketamine were not associated with change in depression or suicidal ideation (unadjusted p>0.28).
Uploads
Papers by Raymond Suckow