PubMed Health⌕ Search

Biomedical subjects

B G Pollock

Publications and source records attributed to B G Pollock.

At least 91 records · Page 5Linked to original sources
PubMed1996

Antidepressants and drug-metabolizing enzymes--expert group report.

Antidepressant drugs are extensively metabolized. Consequently, the biotransformation pattern of antidepressants has an important influence on their clinical properties, i.e., pharmacokinetics, toxicity, drug-drug interactions, side-effect profile and last but not least therapeutic efficacy. It was against this background that a multidisciplinary group of experts discussed the clinical relevance of the rapidly increasing body of knowledge of antidepressant-metabolizing enzymes. The variability of the response of a given individual to an antidepressant is determined genetically and by the environment. Genetic polymorphism of drug-metabolizing enzymes and inhibition by other substrates may affect the enzymatic biotransformation of antidepressants. In vitro assay techniques allow an estimation of the potential variability in clinical response to antidepressants and a reasonable prediction of the drug-drug interaction patterns. The results of in vitro tests should therefore be considered early in the development of an antidepressant as a background for designing clinical studies (treatment schedules and dosing). Physicians should have an understanding of the relevance of genetic polymorphism for clinical practice. Education is needed in order to fill the existing gaps in knowledge about antidepressant-enzyme interactions and their application in daily treatment practice. The information on potential drug interactions determined by genetic polymorphism and based on studies with enzymes should be increasingly contained in drug compendia.

Antidepressive Agents↗
PubMed1996

Newer antidepressants and the cytochrome P450 system.

OBJECTIVE: This review evaluates the in vitro and in vivo evidence for inhibition of cytochrome P450 enzymes by the newer antidepressants and provides clinical recommendations for avoiding and managing drug interactions. METHOD: The international literature on the cytochrome P450 system and related drug interactions from 1966 to 1995 was reviewed. In vitro studies, pharmacokinetic trials in human subjects, and case reports were assessed. RESULTS: The newer antidepressants each inhibit a different cluster of cytochrome P450 enzymes, which are of relevance to the potential for drug interactions. Cytochrome P450 1A2 is inhibited by fluvoxamine and is implicated in drug interactions with theophylline, clozapine, and others. Fluoxetine, norfluoxetine, sertraline, and paroxetine are potent in vitro inhibitors of cytochrome P450 2D6 and are capable of causing marked elevations in plasma desipramine and nortriptyline concentrations. Fluoxetine, sertraline, and fluvoxamine are believed to inhibit cytochrome P450 2C because of observed interactions with phenytoin, diazepam, and other drugs metabolized by these enzymes. Cytochrome P450 3A4 metabolizes terfenadine, astemizole, carbamazepine, alprazolam, triazolam, and other benzodiazepines. Plasma concentrations of these drugs have increased when they are administered with fluvoxamine, nefazodone, fluoxetine, and sertraline. CONCLUSIONS: The majority of the newer antidepressants are associated with a risk for clinically significant drug interactions. A rapidly growing body of literature provides evidence for a distinct profile of cytochrome P450 inhibition and drug interaction risks by individual antidepressants. These findings underscore the need for definitive in vivo interaction studies of plasma from phenotyped patients treated with clinically effective antidepressant doses of medication, for direct comparative clinical studies, and for studies assessing the utility of phenotyping in clinical practice.

Antidepressive Agents↗
PubMed1996

Paroxetine is a novel nitric oxide synthase inhibitor.

The selective serotonin reuptake inhibitor, paroxetine, has been reported to inhibit cytochrome P450 activity. Nitric oxide synthase (NOS) is structurally homologous to cytochrome P450. Accordingly, in our study, we observed the effects of paroxetine on NOS activity. Seventeen ischemic heart disease (IHD) patients received paroxetine and fourteen received nortriptyline for treatment of clinical depression defined by a score of 17 or higher on the Hamilton Rating Scale for Depression (HAM-D). Serum nitrite and nitrate levels were significantly decreased following paroxetine treatment but not nortriptyline treatment. Paroxetine was also a more potent inhibitor of NOS enzyme activity than nortriptyline, as measured by the conversion of [14C] arginine to [14C] citrulline by hamster brain cytosols. In addition, paroxetine reversed the force-frequency relationship in isolated hamster papillary muscles in a manner analogous to that of known NOS inhibitors. Thus, paroxetine appears to be a novel NOS inhibitor in vitro and in vivo.

Animals↗
PubMed1995

Pharmacokinetics of single- and multiple-dose bupropion in elderly patients with depression.

A study of a dopaminergic antidepressant that may have an advantageous profile for use in elderly patients, bupropion, was conducted to determine the pharmacokinetics of bupropion in the elderly. Pharmacokinetics of single- and multiple-dose bupropion were examined in six elderly patients (five women and one man) diagnosed with depression. Mean (+/- SD) CL app of bupropion was 1.6 +/- 0.4 L/hr/kg, approximately 80% of the corresponding value reported for younger patients. Mean bupropion t1/2 was 34.2 +/- 8.7 hours, and average apparent Vd (Vd app) was 79.3 +/- 29.4 L/kg. Apparent half-lives (t1/2 app) of the metabolites hydroxybupropion, erythrobupropion, and threohydrobupropion were 34.2 +/- 4.6 hours, 61.4 +/- 21.6 hours, and 38.8 +/- 7.6 hours, respectively. After multiple dosing, the mean t1/2 for bupropion and its metabolites did not change significantly, although in some patients the t1/2 app of the metabolites was substantially prolonged. There was also evidence of inordinate accumulation of metabolites. The elderly are at risk for accumulation of bupropion and its metabolites. Specification of therapeutic drug monitoring parameters for bupropion treatment of the elderly is needed.

Administration, Oral↗
PubMed1995

Antipsychotics in older patients. A safety perspective.

Age is a major source of variation in drug response. Social, medical and physiological heterogeneity intertwines to complicate geriatric pharmacotherapy. Inappropriate and excessive use of medication may be the most significant treatable health problem in the elderly. Older people are especially sensitive to antipsychotics, which are disproportionately prescribed to them. Antipsychotic side effects and adverse reactions are intensified and protean in an older population, ranging from disabling to deadly. It is therefore essential that the use of antipsychotics be based on clear indications, guided by knowledge of both age-related and individual determinants of drug clearance and action. Prospective and frequent assessments for adverse effects are also essential.

Absorption↗
PubMed1995

Prospective cytochrome P450 phenotyping for neuroleptic treatment in dementia.

Older patients have more adverse experiences when treated with psychotropics than younger patients. Age-associated physiological changes, such as reductions in hepatic mass and blood flow, magnify genetic and acquired variations in drug metabolism. Cytochrome P450 2D6 (debrisoquine hydroxylase), which is responsible for the metabolism of several antidepressants and neuroleptics, is constitutionally deficient in up to 10 percent of the population. In this study of 45 elderly patients suffering from dementia and treated with perphenazine, 5 patients who were prospectively identified as poor P450 2D6 metabolizers had significantly greater side effects than the 40 extensive metabolizers.

Aged↗
PubMed1995

Prolactin response to neuroleptic challenge in late-life psychosis.

Psychosis in the elderly is superimposed on both age-related and disease-specific declines in dopaminergic function. Though the prolactin (PRL) response to neuroleptic challenge has been used as an in vivo measure of dopaminergic function in midlife adults, it remains uninvestigated in late-life psychoses. We examined the PRL response to intravenous perphenazine (PZ) in 11 elderly patients with psychotic symptoms complicating either a major depression (MD-P) or a dementia. The magnitude of increase in prolactin after PZ divided patients into three non-overlapping groups: dementia patients had a bimodal response and MD-P patients fell between the dementia groups. Our findings suggest that the PRL response to PZ may provide an in vivo measure of dopaminergic function in elderly patients. This finding must be confirmed through correlation with other measures of dopaminergic function in late-life psychoses and with measures of neuroleptic response and neuroleptic-induced extrapyramidal effects.

Aged↗
PubMed1995

Double-blind comparison of paroxetine and nortriptyline on the postural stability of late-life depressed patients.

This article describes a 6-week study evaluating body sway during double-blind therapy with nortriptyline versus paroxetine in geriatric patients. Body sway was measured with patients' eyes open, then closed, using a stable force platform at 4 timepoints: before starting antidepressant medication, and after 1, 2, and 6 weeks of treatment. Measures such as the length (L) of path of the center of pressure (COP) and the area included within the COP path were selected for quantitative assessment of stability. A repeated measures analysis of variance (ANOVA) model with planned comparisons was used to examine the pair-wise difference at baseline and Weeks 1, 2, and 6 of treatment. No significant difference was found in body sway parameters over the 6 weeks of study for patients treated with either nortriptyline or paroxetine.

Aged↗
PubMed1994

Effect of pulse loading with clomipramine on EEG sleep.

Two different initial dosing regimens with clomipramine (CMI) were used to compare early response indicators and dose strategies. Thirty-two inpatients with major depressive disorder were randomized in a double-blind protocol. The pulse-loading group received 150 and 200 mg of CMI on 2 consecutive evenings and then received a placebo for 8 days. The traditional dosing group began at 50 mg of CMI followed by gradual increases every second day until 200 mg was reached. After 10 days, both groups were placed on an adjustable dosing schedule of CMI, initially set at 200 mg, for an additional 2 weeks. Significant drug effects were noted on several sleep parameters demonstrating suppression of rapid eye movement (REM) sleep. In the pulse-loading group, drug responders were found to have a significantly faster and more robust rebound in REM sleep than nonresponders. Both measures of REM activity and REM sleep time showed a significant difference between the groups. In addition, a significant correlation was found between falling levels of the desmethylclomipramine metabolite of CMI and REM sleep activity during the rebound phase. The clinical and theoretical implications of these findings are discussed.

Adult↗
PubMed1994

Treatment of consecutive episodes of major depression in the elderly.

OBJECTIVE: The purpose of this study was to determine treatment outcome in elderly patients with consecutively treated episodes of recurrent unipolar major depression. METHOD: Subjects were 32 "young" elderly patients with recurrent unipolar depression (mean age = 66.8 years, SD = 5.1) and with two consecutively treated episodes of major depression. Both index and subsequent episodes of major depression were treated in open trial with combined nortriptyline and interpersonal psychotherapy. Rates of remission in index and subsequent episodes were compared by using nonparametric statistics and survival analysis with proportional hazards modeling. RESULTS: Of 30 patients who completed treatment of the subsequent episode, 27 (90%) achieved stable remission of symptoms in both consecutively treated episodes, whereas three patients (10%) did not. Twenty-two (81%) of 27 patients who responded to treatment had a shorter time to remission in treatment of the subsequent episode than in the index episode. Survival analysis with proportional hazards modeling detected a significant difference in time to remission of the index and subsequent episodes (32 paired observations). CONCLUSIONS: In this research study group, recurrent episodes of unipolar major depression in the young elderly were successfully treated to remission in over 80% of patients by using combined pharmacotherapy and psychotherapy similar to that employed in treatment of the index episode. Remission rate and time to remission in consecutively treated episodes were comparable to those in a group of midlife patients with recurrent depression reported by Kupfer et al. in 1989. Thus, recurrent depressive disorder appears to be as treatable in the young elderly as it is in midlife patients.

Age Factors↗
PubMed1994

Metabolic and physiologic consequences of nortriptyline treatment in the elderly.

The challenge in the pharmacotherapy of affective disorders is shifting to maintenance treatment. Hence, there is a need for systematic data on the somatic effects of long-term medication use. Twenty-six depressed patients (age > 60 yr) treated with therapeutic concentrations of nortriptyline were evaluated after an average of 7 months for changes in lipoproteins and cardiovascular parameters. Twelve patients were tested for debrisoquine (P450 2D6) metabolic status and creatinine clearance at these same intervals. There was no significant change in cholesterol levels, but triglycerides and very-low-density lipoproteins (VLDL) were significantly increased. Heart rate was also elevated by a mean of 15 beats per minute, and there were modest but significant increases in cardiac conduction parameters. Creatinine clearance declined significantly (by 34%), and blood pressure was unchanged. Small decrements in P450 2D6 could be quantitated. Older patients treated with maintenance psychotropic medications should be evaluated at the regular intervals, particularly with regard to the age-related complications of multiple illness and medications.

Aged↗
PubMed1993

Treatment of nortriptyline's side effects in elderly patients: a double-blind study of bethanechol.

A double-blind, placebo-controlled study of bethanechol was conducted in 26 elderly depressed patients being treated with nortriptyline. Patients receiving bethanechol had reduced subjective complaints of anticholinergic side effects and showed a trend toward improvement on an objective measure of salivary flow. The potential use of bethanechol in older patients to reduce morbidity and improve compliance with medication regimens is discussed.

Aged↗
PubMed1993

Early response patterns associated with successful clomipramine treatment.

Two different initial dosing regimens with clomipramine (CMI) were compared with particular attention to early response indicators. Thirty-two inpatients with major depressive disorder were randomized in a double-blind protocol. The pulse-loading (P-L) group received 150 and 200 mg of CMI on two consecutive evenings, then placebo for 8 days; the traditional group began at 50 mg, followed by gradual increases every second day until 200 mg was reached. Both groups were then placed on an adjustable dosing schedule of CMI, initially set at 200 mg for an additional 2 weeks. After the completion of P-L, the improvement in scores on the Hamilton Rating Scale for Depression across protocol days 7 to 13 (the P-L placebo period) was equivalent for both dosage regimens and was significantly associated with therapeutic response at the end of the study (p = 0.0186). Desmethylclomipramine levels were significantly greater in P-L nonresponders (p = 0.0039), and a ratio of desmethylclomipramine/CMI of 2 or more after P-L was strongly associated with failure to respond to CMI (p = 0.02). Early, acute responses and assessments of metabolism observed with targeted doses of CMI may be predictive of later successful treatment.

Adult↗
PubMed1993

Nortriptyline in the hospitalized elderly: tolerance and side effect reduction.

This article describes two separate but related studies regarding the use of nortriptyline (NT) in the treatment of depressed elderly inpatients. The first study assesses medication tolerance to NT during the acute treatment of late-life depression. The second describes a placebo-controlled study of the effect of bethanechol in reducing antimuscarinic side effects of NT. Antidepressant pharmacotherapy was considered for 72 patients with late-life depression; 17 (24%) did not receive NT; 5 (7%) because of absolute or relative medical contraindications. Of the 55 patients who started on NT, 9 percent had side effects that necessitated medication discontinuation. A separate sample of 26 elderly depressed patients being treated with NT participated in a double-blind, placebo-controlled trial of bethanechol. Patients receiving bethanechol had reduced subjective complaints of anticholinergic side effects and showed improvement on an objective measure of salivary flow.

Aged↗
PubMed1992

Imipramine and 2-hydroxyimipramine: comparative cardiotoxicity and pharmacokinetics in swine.

The hemodynamic, cardiographic, and initial pharmacokinetic characteristics of the de novo administration of the 2-hydroxymetabolite (2-OH-IMI) of imipramine (IMI), compared with its parent was studied in a swine preparation. Cardiac output, arterial pressure, and the continuous electrocardiogram were assessed after the intravenous administration of the drug or its metabolite. Plasma, sampled over 120 min and CSF sampled at 60 min were analyzed by reverse phase HPLC with spectroflurometric detection. Equilibrium dialyses were performed on plasma sampled at 60 min. 2-OH-IMI, in doses of 5-6 mg/kg, compared to dosages of IMI up to 8.5 mg/kg, produced a significantly greater incidence of life-threatening arrhythmias, and caused profound and significant decreases in blood pressure and cardiac output. 2-OH-IMI had a smaller volume of distribution (Vd) and shorter half-life. CNS penetration, as estimated by CSF/plasma ratios, was significantly greater for 2-OH-IMI. These phenomena were partly accounted for by significantly less protein binding for the hydroxymetabolite. It is concluded that 2-OH-IMI has increased penetrance into the CNS despite a smaller Vd and that it is significantly more cardiotoxic than its parent.

Animals↗
PubMed1992

Combined pharmacotherapy and psychotherapy in the acute and continuation treatment of elderly patients with recurrent major depression: a preliminary report.

OBJECTIVE: The authors examined the rate of response to the combination of nortriptyline and interpersonal psychotherapy for acute and continuation treatment of elderly patients with recurrent major depression. METHOD: The subjects were 73 elderly patients, 61 of whom completed treatment. Nortriptyline steady-state blood levels were maintained at 80-120 ng/ml, and interpersonal psychotherapy was administered weekly for 9.1 weeks (medium) of acute therapy and was decreased from biweekly to triweekly during 16 weeks of continuation therapy. During acute treatment nonresponding patients also received brief adjunctive pharmacotherapy with lithium or perphenazine. RESULTS: Of the 61 subjects given adequate trials of nortriptyline and interpersonal psychotherapy, 48 (78.7%) achieved full remission (Hamilton depression rating of 10 or lower over 16 weeks of continuation therapy), 10 patients (16.4%) did not respond (Hamilton rating never below 15), and three achieved only partial remission (Hamilton rating of 11-14). Early versus late onset was not associated with a difference in response rate. During the placebo-controlled, double-blind transition to maintenance therapy, 19 (76.0%) of the 25 patients randomly assigned to placebo maintenance conditions showed continued recovery and six relapsed. None of the 24 patients assigned to nortriptyline conditions relapsed. CONCLUSIONS: Use of nortriptyline plus interpersonal psychotherapy for 9.1 weeks (median) of acute and 16 weeks of continuation therapy appears to be associated with good response and relatively low attrition but about a 25% chance of relapse during double-blind discontinuation of nortriptyline. These data require confirmation in a controlled clinical trial of acute and continuation therapy.

Age Factors↗