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Biomedical subjects

R A Lucas

Publications and source records attributed to R A Lucas.

14 recordsLinked to original sources
PubMed1998

A pharmacokinetic interaction between carbamazepine and olanzapine: observations on possible mechanism.

OBJECTIVE: Olanzapine is a novel antipsychotic, which is effective against both the positive and negative symptoms of schizophrenia and causes fewer extrapyramidal adverse effects than conventional antipsychotics. The purpose of the present study was to assess the potential for a pharmacokinetic interaction between olanzapine and carbamazepine, since these agents are likely to be used concomitantly in the treatment of manic psychotic disorder. METHOD: The pharmacokinetics of two single therapeutic doses of olanzapine were determined in 11 healthy volunteers. The first dose of olanzapine (10 mg) was taken alone and the second dose (10 mg) after 2 weeks of treatment with carbamazepine (200 mg BID). Measurement of urinary 6beta-hydroxycortisol/cortisol excretion was used as an endogenous marker to confirm that induction of CYP3A4 by carbamazepine had occurred. RESULTS: The dose of olanzapine given after a 2-week pretreatment with carbamazepine was cleared more rapidly than olanzapine given alone. Olanzapine pharmacokinetic values for Cmax and AUC were significantly lower after the second dose, the elimination half-life was significantly shorter, and the clearance and volume of distribution were significantly increased. CONCLUSION: Carbamazepine has been shown to induce several P450 cytochromes including CYP3A4 and CYP1A2. Since CYP1A2 plays a role in the metabolic clearance of olanzapine, the interaction may be attributed to induction of CYP1A2 by carbamazepine, leading to increased first-pass and systemic metabolism of olanzapine. The interaction is not considered to be of clinical significance because olanzapine has a wide therapeutic index, and the changes in plasma concentration of olanzapine are within the fourfold variation that occurs without concern for safety in a patient population.

Administration, Oral↗
PubMed1996

Inhibition of ex vivo neutrophil activation by oral LY293111, a novel leukotriene B4 receptor antagonist.

1. The effects of orally administered LY293111 on ex vivo neutrophil Mac-1 upregulation were determined in a total of 24 healthy male subjects within three study periods. 2. In the first period, eight volunteers received 60 mg LY293111 or placebo three times daily in 22 total doses over 8 days followed by a 1 week follow-up. The average ex vivo Mac-1 response of the LY293111 group was 56% of the predose control (95% confidence interval (CI) 44.3 to 67.9%; P < 0.01). The inhibitory effect was maximum at the end of dosing and had disappeared by day 14. 3. In the second period, eight subjects received 120 mg LY293111 or placebo three times daily in 22 total doses over 8 days followed by a 1 week follow-up. The average response of the LY293111 group was 70% of the pre-dose control (95% CI 59.7 to 81.0%; P < 0.01). The inhibitory effect was maximum the day following the initial dose and continued throughout the dosing period. 4. In the third period, eight subjects received 200 mg LY293111 or placebo twice daily in 15 total doses over 8 days followed by a 1 week follow-up. Mac-1 upregulation was 64% of pre-dose levels (95% CI 53.8 to 75.1%; P < 0.01) over the course of the study period. The inhibition had disappeared 2 days following the final dose. Alternate neutrophil stimulation by fMLP was not inhibited. 5. No statistically significant inhibition was observed for placebo-treated subjects. 6. No statistically significant differences were apparent between the active dose regimens. 7. The results indicate that orally administered LY293111 is pharmacologically active in humans. Results from this study may be useful in determining dose selection for efficacy trials.

Administration, Oral↗
PubMed1995

Antipsychotic drug-induced dysphoria.

BACKGROUND: Dysphoric reactions to antipsychotic medication are well recognised in association with akathisia, but can also occur independently. METHOD: Fifty-one healthy volunteers were given haloperidol 5 mg in two consecutive pharmacokinetic studies. RESULTS: Dysphoria occurred in about 40% of the subjects on both occasions, but akathisia was only detected in 8% (first study) and 16% (second study). All adverse effects were transient and were abolished in nine of the ten subjects given procyclidine. CONCLUSIONS: While dysphoria is a well-recognized reaction in healthy volunteers, it is probably insufficiently recognised in patients, particularly if it occurs in the absence of akathisia. Better detection could improve compliance in patients.

Adult↗
PubMed1993

Group cognitive-behavioral treatment of panic disorder.

The present study examined the efficacy of an 8-wk, cognitive-behavioral group treatment for panic disorder. Patients meeting DSM-III-R criteria for panic disorder with or without agoraphobia were randomly assigned to treatment (N = 34) or delayed treatment control (N = 33). The treatment consisted of: (a) education and corrective information; (b) cognitive therapy; (c) training in diaphragmatic breathing; and (d) interoceptive exposure. At posttreatment, 85% of treated Ss were panic free, compared to 30% of controls. Treated Ss also showed clinically significant improvement on indices of anxiety, agoraphobia, depression and fear of fear. Recovery, as estimated conservatively by the attainment of normal levels of functioning on each of the major clinical dimensions of the disorder (i.e. panic, anxiety and avoidance), was achieved in 64% of the treated Ss and 9% of the controls. At the 6 month follow-up, 63% of the treated patients met criteria for recovery. These findings mirror those from recently-completed trials of individually-administered cognitive-behavioral treatment, and suggest that CBT is a viable alternative to pharmacotherapy in the treatment of panic disorder.

Adult↗
PubMed1992

The human pharmacology of fluoxetine.

Fluoxetine is a potent and specific inhibitor of 5-HT uptake even after prolonged dosing. Both fluoxetine and norfluoxetine, an active metabolite, have a long plasma half life. The drug is extensively metabolized and undergoes renal elimination. Impairment of renal function, increasing age or obesity do not appear to alter the disposition of fluoxetine, although hepatic impairment predictably decreases the clearance of the drug. Recent data suggests that fluoxetine is an inhibitor of cytochrome P450-II-D6 in man and has been shown to inhibit the metabolism of a number of drugs which are substrates for this isoenzyme. It does not, however, affect the elimination of ethanol and does not enhance the effect of ethanol on psychometric testing. Fluoxetine has no effect on normal blood pressure although mean heart rate is slightly reduced. It does not appear to have a clinically significant effect on pituitary function. Although there is psychometric and EEG evidence to suggest a vigilance enhancing property, fluoxetine does not exhibit stimulant activity of the amphetamine type and has been shown to be well tolerated at doses clinically useful for appetite suppression in extensive clinical trials and widespread clinical use since marketed in 1987 for depressive illness.

Blood Platelets↗