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Biomedical subjects

R F Suckow

Publications and source records attributed to R F Suckow.

At least 37 records · Page 2Linked to original sources
PubMed1991

Effects of chronic fluoxetine treatment on behavioral and neuroendocrine responses to meta-chlorophenylpiperazine in obsessive-compulsive disorder.

To investigate the effect of fluoxetine on serotonergic sensitivity in obsessive-compulsive disorder (OCD), the partial serotonin agonist metachlorophenylpiperazine (mCPP) was compared to placebo under double-blind conditions in six patients with OCD before and during treatment with fluoxetine. Readministration of oral mCPP (0.5 mg/kg) after at least 12 weeks of fluoxetine treatment did not increase obsessive-compulsive (OC) symptoms, in contrast to exacerbation of OC symptoms produced by mCPP before treatment. Chronic fluoxetine treatment resulted in a significant increase in prolactin and cortisol response to mCPP. This may be accounted for, however, by substantially increased plasma mCPP levels during fluoxetine treatment. Chronic fluoxetine treatment diminished the behavioral sensitivity to mCPP and did not diminish, but may have partially normalized, the neuroendocrine response to mCPP in patients with OCD. These adaptive homeostatic effects may reflect fluoxetine's antiobsessional mechanism.

Adult↗
PubMed1991

Saliva and plasma desipramine levels in Asian and Caucasian volunteers.

Thirty-seven healthy volunteers (18 Asian, 19 Caucasian) ingested a single desipramine (DMI) dose of 1.0 mg/kg of body weight. Saliva and plasma samples were obtained at 1, 3, 5, 7, 12, 24, 48, 72, and 96 hrs after dosing. A nested repeated-measures analysis of variance (ANOVA) design was used to determine if the plasma/saliva DMI ratio varied between Asians and Caucasians over time. Regression analysis was used to assess the ability of saliva DMI to predict plasma DMI at any time point. The ANOVA results indicated no significant differences in DMI plasma/saliva ratios between Asians and Caucasians. There was a major effect of sampling time on the DMI plasma/saliva ratio (p = 0.0001), with the ratio falling from 1.78 at 1 hr to 0.15 at 96 hrs. At any given time at least 24 hrs after the dose, there was a significant relationship between saliva and plasma levels across individuals. However, across subjects, the 95 percent confidence limits for predicting plasma DMI from saliva DMI levels were relatively large. The potential roles and limitations of saliva DMI in pharmacokinetic studies and clinical drug monitoring are discussed.

Adult↗
PubMed1991

2-Hydroxydesipramine and desipramine plasma levels and electrocardiographic effects in depressed younger adults.

Desipramine was given to 34 outpatients aged 20 to 51 years who had primary major depressive disorder but who were otherwise in good health. Daily dosage at bedtime was constant for the final 3 weeks of the 5-week study (mean, [SD] 169.1 [46.1] mg). Electrocardiograms done predrug and after 5 weeks were read by a cardiologist blind to the order in which they were performed. Plasma samples drawn 14 hours after the final study dose were assayed by high performance liquid chromatography; mean (SD) levels were 140.2 (140.0) ng/ml for desipramine and 56.5 (29.4) ng/ml for 2-hydroxydesipramine (2-OH-DMI). Heart rate and PR, QRS and QTc intervals were significantly greater at the end of the study than at baseline, while QT intervals were significantly less. Changes in heart rate and PR, QT and QTc intervals were significantly negatively correlated with the value of the respective cardiac parameters at baseline. Changes in PR interval were significantly positively correlated with log desipramine, log 2-OH-DMI and log (desipramine + 2-OH-DMI). Stepwise multiple regression analyses showed that, for PR interval, each of the three plasma level variables showed a significant ability to improve R2 over that obtained from baseline PR alone. These findings suggest that both 2-OH-DMI and desipramine plasma levels predict a prolongation of intracardiac conduction in younger adults and that monitoring both levels may be useful in the clinical management of certain younger adult patients.

Adult↗
PubMed1990

Tryptophan treatment of aggressive psychiatric inpatients.

This double-blind, placebo-controlled study tested the effectiveness of tryptophan (TRP) in the treatment of aggressive psychiatric inpatients. After a baseline observation period of 1 month, patients were randomly assigned to treatment either with TRP (up to 6 g/day) or with placebo. There were 10 subjects in each treatment group. These treatments were administered for 25-35 days, after which the patients were observed for 1 month. Throughout this study, patients were receiving other medications. Injections of antipsychotics and sedatives were administered as needed to control agitated or violent behavior. Blood levels of TRP and other large neutral amino acids were obtained repeatedly, and ratios between TRP and other amino acids were computed. These analyses confirmed significant increases of TRP ratios in TRP-treated patients. TRP treatment had no effect on the number of violent incidents, but it significantly reduced the need for injections of antipsychotics and sedatives. The study thus provided indirect support for beneficial effects of TRP in aggressive psychiatric inpatients.

Adult↗
PubMed1990

Effects of m-chlorophenylpiperazine in normal subjects: a dose-response study.

m-Chlorophenylpiperazine (MCPP), a direct 5HT receptor agonist, was administered orally to 20 normal subjects in two doses (0.25 and 0.5 mg/kg) in a placebo-controlled design. Behavioral responses; ACTH, cortisol, prolactin and MCPP blood level; temperature and pulse rate were measured over a 210-min period after administration of tablets. Non-linear dose-response relationships between MCPP and ACTH, cortisol and prolactin response were found. On the higher dose, a significant increase in the number of physical symptoms was also noted and three subjects (15%) had a panic attack, while one subject (5%) had a panic attack on the lower dose. No effects on other behavioral variables, pulse rate and temperature were found using either dose. These findings attest to the usefulness of MCPP as a challenge agent to assess 5HT receptor hypersensitivity when given at a low oral dose (i.e. around 0.25 mg/kg), and to assess 5HT receptor hyposensitivity when given at higher oral doses (i.e. around 0.5 mg/kg).

Adrenocorticotropic Hormone↗
PubMed1990

Relationship of hydroxynortriptyline to nortriptyline concentration and creatinine clearance in depressed elderly outpatients.

Plasma concentration of E-10-hydroxynortriptyline is increased in the elderly and may be related to both renal clearance of hydroxynortriptyline and rate of liver hydroxylation of nortriptyline. In 25 ambulatory, depressed elderly outpatients treated with therapeutic doses of nortriptyline, relationships among plasma levels of nortriptyline and E-10-hydroxynortriptyline, and an estimate of creatinine clearance were examined. Plasma levels of E-10-hydroxynortriptyline (corrected for varying dosage) were significantly correlated with age and inversely correlated (r = -0.50) with creatinine clearance but not with notriptyline or Z-10-hydroxynortriptyline concentration. E-10-hydroxynortriptyline concentration was about 5 1/2 times that of Z-10-hydroxynortriptyline. By best subsets multiple regression analyses, the ratio of E-10-hydroxynortriptyline to nortriptyline level was best predicted by plasma nortriptyline concentration, creatinine clearance, and age, all of which accounted for 63% of the variance. These results corroborate and extend previous findings in elderly inpatients in whom creatinine clearance was measured directly. In addition, age had an effect on E-10-hydroxynortriptyline independently of creatinine clearance. Since E-10-hydroxynortriptyline concentration has been related to both therapeutic efficacy and toxicity during nortriptyline treatment, it may be important to assess nortriptyline hydroxymetabolites in elderly patients and in those with renal insufficiency.

Aged↗
PubMed1989

Plasma levels of nortriptyline and 10-hydroxynortriptyline and treatment-related electrocardiographic changes in the elderly depressed.

Thirty-one elderly depressed patients were treated for seven weeks with nortriptyline with plasma levels kept between 50-180 ng/ml. Electrocardiograms were taken at the third and seventh weeks of treatment. There were significant increases in the PR interval, QTc interval, and heart rate from before and after treatment. However, there were no consistent correlations between electrocardiographic changes during treatment and plasma levels of nortriptyline, 10-hydroxynortriptyline and either of its two isomers (E-10-hydroxynortriptyline, Z-10-hydroxynortriptyline). Increased QRS duration after seven weeks of treatment was correlated with daily dose of nortriptyline.

Aged↗
PubMed1989

10-Hydroxynortriptyline and treatment effects in elderly depressed patients.

Sixty-four elderly depressed outpatients were treated with nortriptyline for seven weeks. Plasma nortriptyline and its main metabolite, 10-hydroxynortriptyline, were measured weekly. No relationship was found between levels of 10-hydroxynortriptyline and clinical response. Plasma levels of the trans isomer, E-10-hydroxynortriptyline, were significantly lower when dizziness and symptoms of orthostatic hypotension were reported, although there was no significant correlation with actual orthostatic drop in systolic pressure. Plasma level of 10-hydroxynortriptyline was not significantly correlated with the other reported side effects.

Aged↗
PubMed1989

Pharmacokinetics of desipramine in Asian and Caucasian volunteers.

The pharmacokinetic differences of tricyclic antidepressants (TCAs) in Asians and Caucasians remain controversial. Thirty-seven age-matched healthy volunteers (18 Asians and 19 Caucasians) ingested a single desipramine (DMI) dose of 1.0 mg/kg of body weight. Blood was obtained at 1, 3, 5, 7, 12, 24, 48, 72, and 96 hours after dosing. Serial 24-hour urine samples were collected for 5 days. There were no statistically significant differences in plasma levels between the two groups. DMI concentrations peaked a median of 5 hours after ingestion in Asians vs. 3 hours in Caucasians. Total clearances of DMI (CL DMI) and hydroxylated DMI (OH-DMI) were greater in Caucasians. These differences were no longer significant when corrected for body weight. Clearances appeared to follow tri-modal distributions. The proportions of Asians and Caucasians falling into the slow, intermediate, and rapid clearance groups were not significantly different, but there was a tendency for more Caucasians to be in the rapid clearance group.

Adult↗
PubMed1988

Isolation and identification of the glucuronide conjugate of 2-hydroxydesipramine by preparative liquid chromatography.

A semi-preparative column liquid chromatographic procedure for the isolation and purification of milligram quantities of the glucuronide conjugate of 2-hydroxydesipramine, a major metabolite of desipramine, is presented. Urine from patients receiving desipramine was collected and passed through a column of XAD-2 resin. The methanolic extract was chromatographed on a reversed-phase octadecyl semi-preparative column followed by further purification on a silica gel column of the same dimension, yielding a product 95% pure. Fast atom bombardment and thermospray mass spectroscopy, as well as ultraviolet photodiode-array spectroscopy and hydrolysis with beta-glucuronidase confirmed the identification and purity of 2-hydroxydesipramine glucuronide. This important glucuronide metabolite will be a useful tool as an authentic standard for pharmacokinetic and metabolism studies and for determining its pharmacological characteristics in laboratory animals.

Chromatography, High Pressure Liquid↗
PubMed1988

A highly sensitive and specific radioimmunoassay for quantitation of plasma fluphenazine.

Antisera of high sensitivity and selectivity were obtained from rabbits immunized with conjugates of hemisuccinylated fluphenazine and porcine thyroglobulin. The antiserum selected (titer 1:6000) for the development of the RIA was obtained after a priming dose and a single iv booster injection three months later. This antiserum had negligible crossreactivity with known available metabolites of fluphenazine (FPZ) and an affinity constant of 2 X 10(10) L/mol. Tritiated FPZ was further purified by HPLC and used as a ligand. The method detects as little as 20 pg/mL of plasma (4 pg/RIA tube) after 1 mL of plasma is extracted. The extraction was performed at a basic pH with heptane: isoamyl alcohol (99:1); the solvent was then back extracted using an acetic phosphate buffer. Recoveries were uniformly high (88.6 +/- 2.1%), and this aqueous buffer extract was used directly in the RIA procedure. The assay has intra- and interassay coefficients of variation of 5.8 and 8.2%, respectively, in a plasma concentration of 95 pg/mL. Results using this procedure have been cross validated against an HPLC procedure (r = 0.952, slope = 1.032, intercept = 0.009, n = 18). In a single-dose FPZ study (10 mg, po), plasma FPZ levels in 25 normal volunteers could be monitored greater than 48 h post dose. Single plasma level profiles, after an initial injection of 12.5 mg of FPZ decanoate, could be measured greater than 36 d, and, in some cases, up to 100 d post dose.

Administration, Oral↗
PubMed1986

Brain regional [3H]flunitrazepam binding in rats chronically treated with bupropion or B.W.306U.

After 21 days of twice daily i.p. injections of bupropion (10 mg/kg), B.W.306U (10 mg/kg) or saline, 5 rat brain regions were removed for [3H]flunitrazepam binding assay. Scatchard analysis of the binding data revealed no change in the Bmax in any brain regions in drug-treated rats compared to controls. There was, however, a significant change in the Kd value in the limbic forebrain of B.W.306U-treated rats.

Animals↗
PubMed1986

Effect of plasma from patients containing bupropion and its metabolites on the uptake of norepinephrine.

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.

Animals↗
PubMed1986

Down regulation of beta-receptors by bupropion and its major metabolite in mouse brain.

Mice were treated with bupropion Compound II (major metabolite of bupropion) or desmethylimpramine (DMI) twice a day intraperitoneally for either 1 or 3 weeks. The binding of dihydroalprenolol and spiroperidol in the frontal cortex and limbic forebrain areas were analyzed. There was a significant reduction in beta-receptors in the frontal cortex induced by DMI at both times examined. Bupropion showed a significant reduction of beta-receptor in the frontal cortex by 3 weeks. Though propiophenone did not have any significant effect on beta-receptors in the frontal cortex, it down-regulated beta-receptors in the limbic forebrain area significantly by 1 and 3 weeks. There was no significant effect of buropion or propiophenone on the binding of spiroperidol either in the cortex (S2 receptor) or in the limbic forebrain (dopaminergic). These results show that bupropion may exert part of its clinical effect through its metabolite propiophenone.

Animals↗
PubMed1985

Trazodone and m-chlorophenylpiperazine. Concentration in brain and receptor activity in regions in the brain associated with anxiety.

Trazodone, its active metabolite 1-(m-chlorophenyl)piperazine (mCPP) and two isomers of mCPP were tested for affinity to the binding sites for [3H]flunitrazepam ([3H]FLU) and [3H]p-aminoclonidine ([3H]pAC) in the frontal cortex, amygdala and hippocampus of the rat. When tested at the binding site for [3H]flunitrazepam, trazodone showed an average IC50 of 1.7 mM in all three regions of the brain while mCPP yielded an average IC50 of 0.36 mM. These same two compounds, when tested at the binding site for [3H]p-aminoclonidine, resulted in an average IC50 of 4.5 microM for trazodone and 0.6 microM for mCPP. When plasma values of trazodone and mCPP in the rat were similar to those obtained in patients given therapeutic doses, the concentrations of trazodone were found to be between 6 and 7 microM and between 2 and 3 microM for mCPP in the same brain regions of the brain used in the binding assays. Thus, a sufficient concentration of trazodone and mCPP can accumulate in brain tissue to displace approx. 50% of the [3H]p-aminoclonidine from its binding site but very little [3H]flunitrazepam from its binding site. These results, combined with the reported anxiolytic effects of the alpha-2 agonist, clonidine and the noradrenergic hyperactivity theory of anxiety, indicate that the mechanism of the anxiolytic activity of trazodone, may be a direct action on the central alpha-2 binding site.

Animals↗