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Biomedical subjects

T B Cooper

Publications and source records attributed to T B Cooper.

At least 73 records · Page 4Linked to original sources
PubMed1996

5-HT2a/2c receptor blockade by amesergide fully attenuates prolactin response to d-fenfluramine challenge in physically healthy human subjects.

Prolactin responses to d-fenfluramine (d-FEN) challenge (0.5 mg/kg PO) were examined after pre-treatment with and without the 5-HT2a/2c receptor antagonist amesergide in eight physically healthy male volunteers. Compared to pretreatment with placebo, pre-treatment with amesergide completely blocked the prolactin (PRL) response to d-FEN challenge in all subjects. These data are consistent with data demonstrating a complete blockade of the PRL response to d-FEN with the 5-HT2a/2c receptor antagonist ritanserin, and suggest that the PRL response to d-FEN challenge in humans may largely be due to activation of the 5-HT2a/2c receptor.

Adult↗
PubMed1996

Clozapine plasma level monitoring: current status.

Plasma level monitoring of clozapine and metabolites may prove beneficial in treating patients who show unusual drug metabolic activity. A threshold plasma level for patients who will respond to this medication is suggested. The interaction of gender, age, smoking, other medication and side effects with plasma clozapine and metabolites are discussed. Plasma level monitoring of clozapine and/or metabolites is recommended in patients who do not respond at usual therapeutic dose, who show untoward side effects at low dose or who are treated with other medications. Finally monitoring of patients who require more than 600 mg/day should be implemented because there is evidence that the incidence of seizures increases significantly above this dosage level. There is some evidence that high plasma clozapine levels are associated with seizures.

Antipsychotic Agents↗
PubMed1996

5-HT3 receptor antagonism by ondansetron does not attenuate prolactin response to d-fenfluramine challenge in healthy human subjects.

Prolactin responses to d-fenfluramine (d-FEN) challenge (0.5 mg/kg PO) were examined after pre-treatment with and without the 5-HT3 receptor antagonist ondansetron (16 mg PO) in 11 physically healthy male volunteers. Compared to pretreatment with placebo, pre-treatment with ondansetron did not significantly attenuate the PRL response to d-FEN challenge. These data are consistent with other data suggesting little role for 5-HT3 receptors in the PRL response to 5-HT agonist challenge in human subjects.

Adult↗
PubMed1996

Lithium distribution in experimental inflammation of brain and spinal cord.

1. Autoimmune inflammation of the nervous system caused extensive changes in the distribution of lithium injected into rats. 2. Serum lithium levels were greatly increased because of failure of renal excretion caused by pre-renal azotemia, urinary retention and lack of dietary sodium. Brain, spinal cord, pituitary and adrenal levels of lithium were also elevated, reflecting the high serum levels. 3. However, the location and degree of this elevation corresponded to the predominant location of the inflammation. As a result, lithium levels in spinal cord approached and even exceeded the lithium content of brain.

Animals↗
PubMed1996

Spontaneous onset of type I atrial flutter in patients.

OBJECTIVES: This study sought to characterize the spontaneous onset of atrial flutter in patients. BACKGROUND: Temporary epicardial electrodes are routinely placed on the atria of patients at the time of open heart surgery and brought out through the anterior chest wall for potential diagnostic and therapeutic use in the postoperative period. We utilized these electrodes to study the spontaneous onset of type 1 atrial flutter in 16 patients in the postoperative period after open heart surgery. METHODS: Twenty-seven episodes of the spontaneous onset of type I atrial flutter from sinus rhythm were studied in these 16 patients by recording bipolar atrial electrograms simultaneously with at least one electrocardiographic lead during each episode. RESULTS: In all 27 episodes, the onset of type I atrial flutter was through a transitional rhythm of variable duration (mean 9.3 s) precipitated by a premature atrial beat. In 21 episodes, the transitional rhythm was atrial fibrillation; in 3 episodes it was type II atrial flutter that appeared to generate atrial fibrillation; and in 3 episodes it was a brief (3 to 6 beats), rapid, irregular arrhythmia. CONCLUSIONS: Type I atrial flutter does not start immediately after a premature atrial beat. Rather, it starts after a transitional rhythm that is usually atrial fibrillation. Extrapolating from mapping studies of the onset of atrial flutter in the canine pericarditis model, we suggest that a transitional rhythm is required for the initiation of type I atrial flutter because during that rhythm, the requisites for development of the atrial flutter reentry circuit evolve.

Atrial Fibrillation↗
PubMed1996

Pregnancy enhances cocaine-induced stimulation of uterine contractions in the chronically instrumented rat.

OBJECTIVE: Our purpose was to test whether cocaine stimulates uterine activity in nonpregnant and pregnant rats. STUDY DESIGN: The carotid artery and jugular vein were chronically catheterized, and a microballoon probe was inserted into the uterine cavity of 15 pregnant and 14 nonpregnant female rats. Conscious animals received a bolus dose of either cocaine or saline solution intravenously. Cardiovascular and uterine contractile responses were studied. RESULTS: Cocaine (2.5 mg/kg) induced a marked increase in uterine activity and arterial blood pressure in both pregnant and nonpregnant animals without producing systemic toxicity. The maximum change in uterine contractions was greater in the pregnant group than in the nonpregnant group, and blood pressure responses were transient in both. CONCLUSION: This study is the first demonstration that cocaine stimulates the rat uterus in vivo, with a greater increase in contractions in pregnant compared with nonpregnant animals. These differences are not related to the hemodynamic response or pharmacokinetic profile of cocaine.

Animals↗
PubMed1996

Hormonal responses to d- and d,l-fenfluramine in healthy human subjects.

Two different doses of d-fenfluramine HCl and d,l-fenfluramine HCl (0.5 mg/kg and 1.0 mg/kg) were administered to 11 healthy male volunteers to compare the neuroendocrine responses to these two forms of fenfluramine in human subjects. Prolactin (PRL) responses to d- and d,l-fenfluramine were significantly greater than those to placebo and were equivalent at both dose levels. Adrenocortiatrophic-releasing hormone (ACTH) and cortisol (CORT) responses to d-fenfluramine at both dose levels were also significantly greater than those to placebo. In contrast, the higher dose of d,l-fenfluramine was associated only with a significant CORT response in comparison to placebo. PRL responses to d-fenfluramine were higher than the PRL response to d,l-fenfluramine at either dose level. The PRL response to d-fenfluramine at 0.5 mg/kg was very highly correlated with the PRL responses to d,l-fenfluramine at 1.0 mg/kg (r = 0.97, n = 10). Homovanillic acid (HVA) were not altered by either d, or d,l-fenfluramine at either dose in a subsample of subjects (n = 4). ACTH/CORT responses to d- and d,l-fenfluramine were modestly intercorrelated. These data suggest that the PRL response evoked by d-fenfluramine is quantitatively very similar to that evoked by d,l-fenfluramine.

Adrenocorticotropic Hormone↗
PubMed1996

Placebo washout in trials of antipsychotic drugs.

For antipsychotic phase 3 clinical trials, we compare the relative merits of a placebo washout period with an alternate design strategy using a low-dose antipsychotic treatment. Evaluations are made with respect to the achievement of specific clinical trial design goals including the effect on power for detecting between-treatment and within-treatment pre-post differences. The relative merits of these two designs are discussed separately for those patients who enter the initial leadin period after withdrawal from previous antipsychotic medication and for those not on medication immediately before that period.

Antipsychotic Agents↗
PubMed1996

2-Hydroxydesipramine and desipramine plasma levels: how are they related to antidepressant response?

Thirty-six outpatients aged 20 to 51 with RDC primary major depressive disorder (MDD) completed a 5-week trial of desipramine following a week of single-blind placebo. Five had a past history of hypomanic disorder. For all but one patient, daily dosage at bedtime was constant for the final 4 weeks, with a mean (S.D.) of 168.1 (46.5) mg. Plasma samples drawn at the three final weekly visits were assayed by high-performance liquid chromatography for 2-hydroxydesipramine (2-OH-DMI) and desipramine. Mean (S.D.) plasma levels were 59.8 (30.0) ng/ml for 2-OH-DMI and 142.9 (138.6) ng/ml for desipramine. Thirteen patients (36%) had a final 17-item Hamilton depression rating < and = 6 and were classified as responders. According to receiver operating characteristics analysis, patients with plasma 2-OH-DMI levels > and = 58 and < 92 ng/ml had a greater likelihood of responding than those with lower or higher levels (p = 0.005, Fisher's exact test), while patients with plasma desipramine levels > and = 64 ng/ml were more likely to respond than those with lower levels (p = 0.032, Fisher's exact test). Results using an alternate response criterion were similar. These findings suggest that in desipramine-treated outpatients with primary MDD the relationship between therapeutic response and plasma levels is curvilinear for 2-OH-DMI and linear for desipramine.

Adult↗
PubMed1996

Hostility is associated with a low prolactin response to meta-chlorophenylpiperazine in abstinent alcoholics.

The prolactin response to the administration of serotonin agonists is an index of central nervous system serotonin (5HT) activity. This index is blunted in association with hostile aggression in personality-disordered individuals without substance abuse. We tested whether prolactin response to the partial 5HT agonist meta-chlorophenylpiperazine (MCPP) (0.35 mg/kg po) was associated with measures of trait hostility in alcoholics who were completing a 3-week rehabilitation program after medical detoxification. We also tested whether the same 5HT index differed in the group of alcoholics compared with the healthy volunteers. The prolactin response to MCPP was inversely associated with the main index of trait hostility and was similarly inversely associated with an index of depression. There was, however, no difference in neuroendocrine or temperature responses to MCPP between the alcohol-dependent group and the healthy volunteers.

Adult↗
PubMed1996

Response of patients with treatment-refractory schizophrenia to clozapine within three serum level ranges.

OBJECTIVE: This study sought to determine the relationships between serum clozapine levels and therapeutic response. METHOD: Fifty-six inpatients who met the DSM-III-R criteria for chronic schizophrenia and who had not responded to extended treatment with classical antipsychotics were randomly assigned to 12 weeks of double-blind treatment with clozapine at one of three serum level ranges: low (50-150 ng/ml), medium (200-300 ng/ml), or high (350-450 ng/ml). Baseline clinical assessments were completed before the patients' regular antipsychotic and anticholinergic drugs were discontinued. During clozapine treatment, serum levels were ascertained weekly to allow adjustment of clozapine doses so as to maintain each patient near the midpoint of his or her assigned serum level range. Clinical assessments were completed after 6 and 12 weeks of treatment. RESULTS: The analyses of the results of treatment supported the superior efficacy of the 200-300 ng/ml and 350-450 ng/ml serum clozapine level ranges over the 50-150 ng/ml range, with no advantage for 350-450 ng/ml over 200-300 ng/ml. Sleepiness increased with increasing serum levels. CONCLUSIONS: Serum clozapine levels per unit of daily dose were at the lower end of the range noted in previous reports, possibly reflecting the current study's dosing schedules of twice or three times a day, the 11- to 13-hour postdose sampling time, and the moderate doses given. Serum clozapine levels, if interpreted in relation to daily clozapine dosing schedules, postdose sampling time, and total daily dose, may help to guide dosing to provide adequate opportunities for therapeutic response and to limit certain side effects of clozapine treatment.

Clozapine↗
PubMed1996

Demonstration in vivo of reduced serotonin responsivity in the brain of untreated depressed patients.

OBJECTIVE: For over 25 years, it has been hypothesized that major depression is due to a deficiency of available serotonin or subsensitivity of key serotonin receptors in relevant brain regions. Direct evidence supporting this hypothesis has been lacking because of the difficulty in studying regional brain serotonergic function. The authors have developed a method for visualizing in vivo regional brain responses to serotonin release by comparing regional brain glucose metabolism after administration of the serotonin-releasing drug dl-fenfluramine, relative to placebo. METHOD: Results with healthy subjects (N = 6) were compared to those obtained with drug-free inpatients with moderately severe major depression (N = 6). RESULTS: Healthy subjects had several areas of statistically significant increases in metabolism, mostly in the left prefrontal and temporoparietal cortex, and areas of decreased metabolism, such as in the right prefrontal cortex. In contrast, the depressed patients had no areas of increase or decrease in metabolism, differing significantly from healthy subjects. Results with patients resembled those with healthy subjects (N = 10) who were scanned twice without active drug on either occasion. CONCLUSIONS: This study provides the first direct visualization of blunted regional brain responses to serotonin release in the brain of patients with major depression, a finding that supports the hypothesis of impaired serotonergic transmission in depression.

Adult↗
PubMed1996

Blunted change in cerebral glucose utilization after haloperidol treatment in schizophrenic patients with prominent negative symptoms.

OBJECTIVE: The purpose of this report was to determine 1) the effects of chronic haloperidol treatment on cerebral metabolism in schizophrenic patients, 2) the relation between negative symptoms and haloperidol-induced regional changes in cerebral glucose utilization, and 3) the relation between metabolic change and clinical antipsychotic effect. METHOD: Cerebral glucose utilization, as determined by position emission tomography (PET), was studied in 18 male schizophrenic subjects before and after chronic treatment with haloperidol at a standardized plasma level. RESULTS: Overall, haloperidol caused a widespread decrease in absolute cerebral glucose metabolism. The cerebral metabolic response to haloperidol was blunted in patients with high pretreatment negative symptom scores. CONCLUSIONS: Taken together with the results from a previously reported PET study of the effects of an acute amphetamine challenge (in which 14 of the current subjects participated), these data suggest that the negative symptom complex is associated with diminished cerebral response to change in dopaminergic activity. This deficit cannot be solely accounted for by structural differences.

Adult↗
PubMed1996

Effect of varying haloperidol plasma levels on negative symptoms in schizophrenia and schizoaffective disorder.

Double-blind haloperidol was administered during two consecutive 3-week periods to 65 patients with acutely exacerbating schizophrenia or schizoaffective disorder. Two plasma levels were targeted. low (2 ng/mL) and moderate (10 ng/mL). The subjects were randomly assigned to four treatment sequences (low-low, low-moderate, moderate-moderate, or moderate-low). Data from 28 patients were available for the analyses of the second study period. In that period, decrease of plasma levels reduced mild but not severe negative symptoms. Thus, lowering of the plasma levels after the first 3 weeks of treatment may improve mild negative symptoms. Conversely, increasing the plasma levels may make mild negative symptoms worse.

Adult↗
PubMed1995

Serotonin in violent patients with schizophrenia.

CSF levels of 5-hydroxyindolacetic acid (5-HIAA), the serotonin metabolite, were assayed in 10 violent and 10 matched nonviolent patients with schizophrenia. Mean group levels of 5-HIAA in cerebrospinal fluid were found to be nearly identical. Possible explanations, including effects of medications, are discussed.

Adult↗
PubMed1995

Plasma haloperidol levels and clinical effects in schizophrenia and schizoaffective disorder.

BACKGROUND: Plasma haloperidol levels between 5 and 11 ng/mL may be clinically optimal for acutely exacerbated schizophrenia, but the evidence for this therapeutic window has been inconsistent. METHODS: Haloperidol was administered in a double-blind manner during two consecutive 3-week experimental periods to 65 patients with acutely exacerbated schizophrenia or schizoaffective disorder. Two plasma levels were targeted: "low" (2 ng/mL) and "moderate" (10 ng/mL). The subjects were randomly assigned to four treatment sequences (low-low, low-moderate, moderate-moderate, or moderate-low). RESULTS: In the first 3 weeks, the antipsychotic efficacy of haloperidol increased with plasma levels up to approximately 12 ng/mL. In the second 3 weeks, decrease of plasma levels reduced negative symptoms. CONCLUSION: For most patients, plasma levels not exceeding 12 ng/mL yield the best results in the first 3 weeks of treatment. Subsequent lowering of the plasma levels may improve negative symptoms.

Adult↗
PubMed1995

Determination of 8-hydroxydeoxyguanosine by an immunoaffinity chromatography-monoclonal antibody-based ELISA.

The postulated importance of oxidative damage to DNA in aging and age-related degenerative pathologies such as cancer has prompted efforts to develop sensitive quantitation methods. 8-Hydroxy-2'-deoxyguanosine (8-OHdG) is a widely used marker for oxidative damage to DNA. To develop an immunoassay for quantitation of 8-OHdG, two monoclonal antibodies have been developed and characterized by competitive enzyme-linked immunosorbent assay (ELISA). Antibody 1F7 has 50% inhibition at 5 pmol 8-OHdG and 1 x 10(5) pmol dG, while antibody 1F11 has 50% inhibition at 2.5 pmol 8-OHdG and 2000 pmol dG. Both antisera crossreact with guanosine and several structurally related derivatives, including 6- and 8-mercaptoguanosine, 8-bromoguanosine, 8-methylguanine, and 7-methylguanosine. Immunoaffinity columns were prepared with antibody 1F7, which exhibits higher selectivity than 1F11, to isolate 8-OHdG from DNA hydrolyzates followed by ELISA quantitation with antibody 1F11. This method allows the analysis of approximately one 8-OHdG/10(5) dG using 100 micrograms DNA. To validate the assay, DNA extracted from human placental tissues were assayed by both ELISA and HPLC with electrochemical detection. Values by both methods correlated well (r = 0.87, p < 0.001), but the levels determined by ELISA were approximately sixfold higher than those determined by HPLC. This may be due to oligonucleotides detected by the ELISA but not the HPLC method or crossreactivity with other damaged bases present in the immunoaffinity purified material. Placental samples from current smokers had significantly higher 8-OHdG by ELISA than those from nonsmokers (p < 0.05). The method of immunoaffinity purification combined with ELISA quantitation has sufficient sensitivity for detecting 8-OHdG in human DNA samples. Although absolute values are higher than those determined by HPLC, the method provides a good alternative to the HPLC-EC method for monitoring relative oxidative damage in molecular epidemiological studies.

8-Hydroxy-2'-Deoxyguanosine↗