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Biomedical subjects

B G Pollock

Publications and source records attributed to B G Pollock.

At least 109 records · Page 6Linked to original sources
PubMed1992

Debrisoquine hydroxylation phenotyping in geriatric psychopharmacology.

The metabolic ratios (MRs) between debrisoquine (DBQ) and 4-hydroxydebrisoquine in urine after a single dose of 10 mg DBQ was determined in 175 unmedicated, healthy subjects older than age 59 (mean of 75 years). Creatinine clearance was determined on the same 8-hour urine collection. Test procedures were well tolerated in all cases. Although age was significantly correlated with creatinine clearance (r = -.38), there was no relationship between age and MR. Analysis by kernel density estimation revealed a bimodal distribution of MRs with an antimode of 11.6. Six subjects (3.4%) were categorically slow DBQ metabolizers (MR greater than 11.6). The proportion of elderly slow metabolizers approaches the lower range determined in a younger population. Our findings, that DBQ oxidative metabolism does not necessarily change with aging, alone, and that (genetic) slow DBQ metabolizers endure into old age, remaining at risk for treatment with many commonly used psychotropics, suggests the need to study the relevance of metabolic phenotyping in elderly psychiatric patients.

Aged↗
PubMed1992

Nortriptyline and weight change in depressed patients over 60.

Weight change in pounds and body mass index was documented in 29 geriatric patients with recurrent depression successfully treated with nortriptyline over a 30-week period of acute and continuation therapy (925 patient-weeks of nortriptyline treatment). Weight before index episode as documented by physician records, and weight at three points (beginning of treatment, end of acute therapy, and end of continuation therapy) were recorded. Weight changes over the interval between these times and net weight change over the entire interval were then calculated. Only five patients (17.2%) gained a clinically significant (greater than 10 lb) amount of weight during treatment, ranging from 10 to 43 lb above premorbid weights. Seven of 29 patients (24.1%) showed a net weight loss below premorbid levels (maximum loss 12.5 lb), and 6 patients (20.7%) showed no weight change. The pattern of weight gain was variable; no correlations were found between initially high body mass index and weight gain over the entire interval. These data suggest that nortriptyline is apparently not a potent weight promoter in this group.

Aged↗
PubMed1992

Comparative cardiotoxicity of nortriptyline and its isomeric 10-hydroxymetabolites.

The potential cardiotoxicity of the hydroxymetabolites of nortriptyline (NT) has been raised by inferential data from clinical studies and by the experimentally demonstrated cardiac effects of 2-OH-imipramine. Cardiac output, arterial pressure, and a continuous electrocardiogram were assessed after intravenous de novo administration of NT or its hydroxymetabolites to 41 swine. NT at doses ranging from 3.5 to 7 mg base per kilogram caused significantly more arrhythmias than did E-10-hydroxynortriptyline (E-10-OH-NT) but was not significantly different from Z-10-hydroxynortriptyline (Z-10-OH-NT) in this effect. Z-10-OH-NT, in contrast, to its geometrical isomer caused marked bradycardia, and decrements in blood pressure and cardiac output. NT and Z-10-OH-NT, but not E-10-OH-NT, produced dose-correlated declines in cardiac output. The hydroxymetabolites had smaller volumes of distribution, shorter half-lives and larger free fractions compared with NT. The differing cardiotoxicity of the hydroxymetabolites could not be accounted for by differing pharmacokinetic properties.

Animals↗
PubMed1991

Fluvoxamine versus desipramine: comparative polysomnographic effects.

Electroencephalogram sleep measures over a 4-week period were obtained on 35 inpatients with major depression (unipolar) who received either fluvoxamine or desipramine in a randomized double-blind trial. Fluvoxamine showed immediate rapid eye movement (REM) sleep suppression and an alerting effect on sleep continuity measures. In contrast, desipramine administration was associated with REM suppression and sleep continuity improvement. The "alerting" quality of fluvoxamine, similar to other serotonergic antidepressants, appears to be unrelated to a lack of clinical efficacy, but may be related to persistent REM sleep suppression. However, it is premature to comment on the serotonin specificity for REM sleep.

Adult↗
PubMed1991

S-mephenytoin 4-hydroxylation in older Americans.

To examine whether a drug-metabolizing enzyme changes with normal aging, the S:R index of S-mephenytoin 4-hydroxylation was determined in 150, unmedicated elderly Americans (mean age 75.4). Ten (6.7%) were identified as categorically slow metabolizers (S:R ratios greater than or equal to .95). This increased incidence of slow metabolizers was accounted for by a significant and previously unreported, increased proportion of slow metabolizers among the black (18.5%) as compared to the white subjects (4.1%) (P = .017). There was no relationship found between S:R ratios and age or creatinine clearance.

Aged↗
PubMed1991

Immediate effects of intravenous clomipramine on sleep and sleep-related secretion in depressed patients.

An i.v. challenge dose of clomipramine (12.5 mg) was given to eight outpatients with major depression. The procedure facilitated the examination of all-night sleep and sleep-related neuroendocrine changes (cortisol, growth hormone, and prolactin). In comparison to baseline saline nights, the patients experienced a profound suppression of rapid eye movement (REM) sleep throughout the night with no rebound recovery in the second half of the night. Furthermore, REM-suppressing effects were noted on the following no-drug night. In contrast, little effect on delta wave sleep was found, except for increased consolidation of delta waves within stage 3 and 4 sleep. Delta sleep measures were significantly correlated with levels of cortisol and growth hormone.

Adult↗
PubMed1991

Sleep in late-life recurrent depression. Changes during early continuation therapy with nortriptyline.

The sleep of thirty elderly patients with recurrent unipolar depression was examined at baseline (before acute treatment of the index episode) and again in a state of symptomatic remission with nortriptyline (mean steady-state level: 82.1 ng/ml). Continuation therapy with nortriptyline was associated with improvement of polysomnographic sleep maintenance (mainly in the third and fourth sleep cycles, to a level similar to that of controls), prolongation of rapid-eye-movement (REM) sleep latency (exceeding that of controls), and potentiation of slow-wave activity during the first non-REM (NREM) sleep period. Clinical improvement, as measured by the Hamilton Depression Rating Scale, was significantly associated with shift of delta activity toward sleep onset (p less than 0.002), prolongation of REM sleep latency (p less than 0.0001), and improvement in sleep maintenance (p less than 0.0002). Multiple regression analysis showed that the single best correlate of clinical change was prolongation of REM sleep latency (i.e., prolongation of first NREM period). Perceived sleep quality improved significantly during early continuation therapy with nortriptyline, but not to the level reported by a group of 30 age- and sex-matched healthy controls. The findings are consistent with the concept that anti-depressant drug efficacy may depend upon strengthening of the homeostatic regulation of sleep and upon changes in the REM-sleep regulation.

Aged↗
PubMed1990

Clinical pharmacokinetics of imipramine and desipramine.

The pharmacokinetics of imipramine and desipramine have been extensively investigated with recent studies designed to understand sources of intersubject variability and to study discrete clinical populations rather than healthy volunteers. Sources of intersubject variability in pharmacokinetics are both genetic (oxidative phenotype) and environmental. Oxidative phenotype has an important impact on first-pass metabolism. In individuals with poor metabolism, systemic availability for imipramine is increased. Intrinsic clearance of desipramine is reduced 4-fold in individuals with poor metabolism. Recent pharmacokinetic studies in diverse patient populations such as the depressed elderly, children and alcoholics have revealed decreased clearance of imipramine in the elderly and increased clearance of both imipramine and desipramine in chronic alcoholics. In at least a third of the population, nonlinear pharmacokinetics of desipramine may be observed at steady-state plasma concentrations above 150 micrograms/L. These nonlinear changes in desipramine pharmacokinetics are not associated with age or sex, but are associated with higher desipramine 2-hydroxydesipramine concentration ratios. Hydroxylated metabolites of imipramine and desipramine may possess both antidepressants and cardiotoxic activity but their formation is rate limited and plasma concentrations tend to follow the parent compound with little accumulation. The potent cardiovascular effects of the hydroxymetabolites may be particularly relevant for the elderly and in acute overdose.

Biological Availability↗
PubMed1990

The role of neuropharmacologic selectivity in antidepressant action: fluvoxamine versus desipramine.

Forty patients with a diagnosis of major depressive disorder were entered in a double-blind study to assess comparative clinical response and pharmacologic parameters of fluvoxamine, a highly selective blocker of serotonin reuptake, and desipramine, a noradrenergic agent. Eighteen patients receiving desipramine and 17 patients receiving fluvoxamine completed the study. Fluvoxamine was comparable to desipramine in its antidepressant efficacy and was better tolerated and caused minimal side effects. There was a direct linear relationship between plasma fluvoxamine levels and clinical response and a nonlinear relationship between plasma desipramine levels and clinical response. The pharmacologic specificity of the two drugs was assessed by determining uptake inhibition of serotonin and norepinephrine. The authors found a positive relationship between Hamilton Rating Scale for Depression scores and norepinephrine uptake inhibition for desipramine but found no such relationship between fluvoxamine and serotonin uptake inhibition. Although there was a clear-cut difference in the quality of pharmacologic specificity and a partial relationship to clinical response, the authors were unable to identify neuropharmacologic factors that would predict either treatment response or selective amelioration of symptomatologies in this patient population.

Adult↗
PubMed1989

Acute antidepressant effect following pulse loading with intravenous and oral clomipramine.

A double-blind, randomized trial of oral vs intravenous clomipramine hydrochloride pulse-loading dosing regimens was conducted. After a two-week drug-free assessment period, 22 inpatients with a diagnosis of major depressive disorder were given either an evening infusion of 150 mg of clomipramine hydrochloride and placebo tablets or 150 mg of oral clomipramine hydrochloride and an isotonic saline infusion. Twenty-four hours later, this procedure was repeated using a dose of 200 mg of clomipramine hydrochloride. Patients received no further medication over the next five days. The mean Hamilton Depression Rating Scale score for all patients, five days after pulse loading, had dropped by 35% (range, 13.3% to -82.4%). This improvement was significant, as was the amelioration in the Raskin Severity for Depression Scale and the Beck Depression Inventory scores. Although the bioavailability of parenteral clomipramine was greater, there were no significant differences in either efficacy or side effects between the two groups. Pronounced early improvements in severe depressive symptoms may be achieved via loading dose regimens with clomipramine in the absence of continuous treatment.

Administration, Oral↗
PubMed1989

Clomipramine and EEG sleep in depression.

Recent studies with clomipramine (CMI) have demonstrated that a pulse-loading approach is associated with a rapid improvement in symptomatology in the absence of continuous treatment. In the present study, sleep changes were evaluated to ascertain the rapidity of clomipramine's effect on electroencephalographic sleep, especially rapid eye movement (REM) and delta wave sleep measures. Clomipramine produced rapid changes in sleep with reduced sleep continuity and almost complete suppression of REM sleep as well as a redistribution of slow wave sleep. Delta waves during sleep were also found to be shifted to the earlier part of the night and increased in intensity. Spectral analysis revealed an increase in power in the delta frequency range that was correlated with clinical responsiveness. These studies point toward a role for clomipramine in the rapid treatment of depression and confirm that sleep physiology may be a good predictor of antidepressant action.

Administration, Oral↗
PubMed1989

Tricyclic antidepressants: contemporary issues for therapeutic practice.

The clinical pharmacology of tricyclic antidepressants is reviewed, with an emphasis on recent findings. These medications have become the treatment of choice for the majority of depressed patients. Their efficacy is limited by lack of vigor and precision in dosage. Pharmacokinetic aspects are addressed which affect the rationale for selective use and interpretation of plasma concentration monitoring. These include nonlinearity, active metabolites, plasma protein binding and age effects. Specific indications for therapeutic drug monitoring occur with patients who fail to respond, those at risk because of age, medical condition or polypharmacy, and to check compliance. Integration of knowledge concerning pharmacokinetics and plasma levels with clinical response will aid in making appropriate pharmacotherapeutic decisions.

Antidepressive Agents, Tricyclic↗
PubMed1988

Regression models in clinical studies: determining relationships between predictors and response.

Multiple regression models are increasingly being applied to clinical studies. Such models are powerful analytic tools that yield valid statistical inferences and make reliable predictions if various assumptions are satisfied. Two types of assumptions made by regression models concern the distribution of the response variable and the nature or shape of the relationship between the predictors and the response. This paper addresses the latter assumption by applying a direct and flexible approach, cubic spline functions, to two widely used models: the logistic regression model for binary responses and the Cox proportional hazards regression model for survival time data.

Humans↗
PubMed1988

Surgical survival benefits for coronary disease patients with left ventricular dysfunction.

Controversy still exists about the proper selection of patients with coronary artery disease and left ventricular dysfunction for coronary bypass surgery. To examine this issue, we studied 710 patients with significant coronary artery disease and left ventricular dysfunction (ejection fraction less than or equal to 40%). Of 301 patients treated surgically, 232 had bypass grafts; 17, left ventricular surgery; and 52, both procedures. At 3 years after treatment, unadjusted survival was 84% for surgical patients and 64% for medical patients. At baseline, medical patients had more left ventricular dysfunction than surgical patients, but surgical patients had more coronary artery disease and angina than medical patients. In Cox survival models, two invasive factors (ejection fraction and extent of coronary artery disease) and three noninvasive indexes (assessment of myocardial infarction, angina, and conduction disturbances) were the five best predictors of survival (p less than 0.001). After adjustment for these factors between the two treatment groups, overall surgical survival at 3 years after treatment was 86%, and medical survival was 68%. Long-term surgical survival benefits appeared greatest in patients with the most severe left ventricular dysfunction, most extensive coronary artery disease, and most severe anginal symptoms. We conclude that surgery provides significant survival benefits for coronary disease patients with left ventricular dysfunction; in general, the sicker the patient, the greater the benefit.

Angina Pectoris↗
PubMed1987

Pharmacokinetics of pimozide in adults and children with Tourette's syndrome.

Pimozide is a neuroleptic drug with dopamine receptor and calcium channel blocking activity that is used in the treatment of Tourette's syndrome. A comparison of the pharmacokinetics of pimozide was made in children and adults with Tourette's syndrome. Seven adults (ages 23-39) and four children (ages 6-13) received a single 2-mg oral dose of pimozide and a minimum of nine blood samples were collected over a four-day period. Mean elimination half-life of pimozide in children was 66 hours compared with 111 hours in adults with Tourette's syndrome. Significant interindividual variability of pimozide pharmacokinetics was found in both adults and children with Tourette's syndrome. The pharmacokinetics of pimozide in patients with Tourette's syndrome differs from that reported in adult populations with chronic schizophrenia.

Administration, Oral↗