Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasma concentrations of clozapine at a given dose vary considerably between patients, but drug levels are not routinely monitored during the normal 4- to 8-week dose escalation period at the beginning of therapy. We hypothesized that the dose required to give a putative threshold therapeutic concentration of 350 micrograms/L could be individualized using pharmacokinetic predictions made at the beginning of normal dose escalation. Low-dose clozapine (25-75 mg every 12 h) was administered to 21 treatment-resistant patients with schizophrenia who had been split into three groups. In group A (six patients), individual target doses were predicted from area under the concentration-time curve data after a single 50-mg dose. In group B (five patients), predictions were made as in group A but at steady state. In group C (10 patients), predictions were based on trough clozapine levels obtained at steady state immediately before dose increase. Dosage was increased, if tolerated, by 25 mg twice daily three times a week for 4-8 weeks according to established clinical practice. Clozapine concentrations were measured weekly, and actual target doses were determined for each patient from dose-concentration plots. In groups A and B, the correlation between actual and predicted target dose was not significant (r = 0.18, p = 0.59). In group C, however, it was significant (r = 0.86, p = 0.0016). These results suggest that individualized doses of clozapine for treatment-resistant patients with schizophrenia can be conveniently predicted from trough drug levels at the start of therapy. Such information would facilitate a more rapid, individualized, and consistent attainment of therapeutic doses than is now the case in clinical practice.
Ther Drug Monit 1995 Apr
PMID:Can low-dose clozapine pharmacokinetics predict steady-state plasma concentration? 762 1

Plasma concentrations of clozapine and its metabolites desmethylclozapine and clozapine N-oxide were measured in 61 patients with refractory schizophrenia. Before the initiation of clozapine, each patient was given haloperidol (HL) up to 60 mg/day for at least 4 weeks without improvement. Patients were then given a fixed dose of clozapine 400 mg/day. Patients were assessed with the Brief Psychiatric Rating Scale (BPRS) at baseline before HL therapy, at the end of HL at 6 weeks, before clozapine, and after 6 weeks of clozapine therapy. Clozapine and its metabolites were measured by high-performance liquid chromatography with ultraviolet detection. The mean plasma concentrations of clozapine, desmethylclozapine, and clozapine N-oxide were 598 +/- 314, 281 +/- 140, and 90 +/- 29 ng/ml, respectively. The mean decrease in the total BPRS scores from baseline clozapine to the 6-week treatment period was 11 +/- 4. Clinical improvement was noted to occur in most patients with clozapine plasma levels > 300 ng/ml. Improvement diminished in patients with clozapine plasma levels > 700 ng/ml. The most common adverse effects were sedation and hypersalivation. Significant correlations between plasma clozapine concentrations and adverse side effects were not found.
Ther Drug Monit 1996 Apr
PMID:Monitoring of plasma clozapine levels and its metabolites in refractory schizophrenic patients. 872 Dec 85

Bromperidol is a close structural analog of haloperidol. The authors studied the effects of levomepromazine and thioridazine, which are frequently added to other neuroleptics as sedatives, on plasma concentrations of bromperidol and its reduced metabolite. The subjects were 26 inpatients with schizophrenia receiving bromperidol, 12 to 24 mg/day, for 1 to 19 weeks. In 10 cases, 50 mg levomepromazine per day and in nine cases, 50 mg thioridazine per day were coadministered for 1 week. In seven cases, both drugs were coadministered with > or = 2-week intervals. Plasma concentrations of bromperidol and reduced bromperidol were measured by a high-performance liquid chromatographic method. Levomepromazine (n = 17) significantly (p < 0.001) increased plasma concentrations of bromperidol (7.3 +/- 4.1 versus 10.2 +/- 4.8 ng/ml) and reduced bromperidol (1.8 +/- 1.4 versus 4.5 +/- 3.3 ng/ml). Thioridazine (n = 16) did not significantly change plasma concentrations of bromperidol (9.1 +/- 5.7 versus 8.6 +/- 5.5 ng/ml), while those of reduced bromperidol could not be measured because of interfering peaks. The current study suggests that levomepromazine, but not thioridazine, increases plasma concentrations of bromperidol and reduced bromperidol by inhibiting the metabolism of these compounds.
Ther Drug Monit 1997 Jun
PMID:Increased plasma concentrations of bromperidol and its reduced metabolite with levomepromazine, but not with thioridazine. 920 Jul 64

A sensitive high-performance liquid chromatography method with electrochemical detection for the determination of olanzapine in human plasma is described. Olanzapine from plasma samples was isolated by a simple one-step liquid--liquid extraction with 15% methylene chloride in pentane with an extraction recovery of approximately 94% of the total olanzapine in plasma. The compound was separated on a cyano column. Under the conditions described, commonly coadministered drugs and other common antipsychotic drugs did not interfere with the analysis of olanzapine. The lower limit of determination of the assay was 0.25 ng of olanzapine per ml when 1 ml of plasma was used for the analysis. The interaassay and intraassay variance was (CV%) less than 10%. The standard curve was linear within the range of 0.25 to 50 ng/ml of olanzapine. This method has been used for the determination of plasma levels of olanzapine in patients with schizophrenia who were treated with daily oral doses of 10, 15, and 20 mg of olanzapine. The results indicate that the plasma level of olanzapine increases linearly with the administered daily oral dose (r = 0.6889, p = 0.01).
Ther Drug Monit 1997 Jun
PMID:Plasma level monitoring of olanzapine in patients with schizophrenia: determination by high-performance liquid chromatography with electrochemical detection. 920 Jul 72

Clozapine is an atypical neuroleptic that is increasingly used for the treatment of schizophrenia. An automated method was developed for the routine quantification of clozapine and its major metabolites, N-desmethylclozapine and clozapine N-oxide, in human serum and urine by column switching and online high-performance liquid chromatography with ultraviolet detection. The method included adsorption of clozapine and its metabolites on a cyanopropyl-coated clean-up column (10 microns; 10 mm x 4.0 mm ID), washing interfering serum constituents to waste by deionized water, and, after column switching, separation on C18 ODS Hypersil reversed-phase material (5 microns; 250 mm x 4.6 mm ID). The compounds of interest were separated and eluted in fewer than 20 minutes, using a mobile phase consisting of 37.5 acetonitril:62.5 water, containing 0.4% (vol/vol) tetramethylethylenediamine and adjusted to pH 6.5 with concentrated acetic acid. Ultraviolet-detection was performed at 254 nm. The determinations exhibited linearity between detector signal and drug concentrations in a range from 5 ng/ml to 50 micrograms/ml. As little as 10 ng/ml of clozapine and 20 or 30 ng/ml of the metabolites was quantifiable. Interferences with other psychotropic drugs, serum, or urine constituents were negligible. The automated procedure enables the analysis of clozapine and metabolites in serum or urine in less than 1 hour.
Ther Drug Monit 1997 Aug
PMID:Automated determination of clozapine and major metabolites in serum and urine. 926 93

The steady state plasma concentrations of clozapine and its two major metabolites, norclozapine and clozapine N-oxide, were compared in patients with schizophrenia treated with clozapine in combination with phenobarbital (n=7), and in control patients treated with clozapine alone (n=15). Patients were matched for sex, age, body weight, and antipsychotic dosage. Patients comedicated with phenobarbital had significantly lower plasma clozapine levels than those of the controls (232+/-104 versus 356+/-138 ng/ml; mean, SD, p < 0.05). Plasma norclozapine levels did not differ between the two groups (195+/-91 versus 172+/-61 ng/ml, NS), whereas clozapine N-oxide levels were significantly higher in the phenobarbital group (115+/-49 versus 53+/-31 ng/ml, p < 0.01). Norclozapine/clozapine and clozapine N-oxide/ clozapine ratios were also significantly higher (p < 0.001) in patients comedicated with phenobarbital. These findings suggest that phenobarbital stimulates the metabolism of clozapine, probably by inducing its N-oxidation and demethylation pathways.
Ther Drug Monit 1998 Dec
PMID:Inducing effect of phenobarbital on clozapine metabolism in patients with chronic schizophrenia. 985 78

Two separate studies were carried out to assess the effect of valproic acid on the steady-state plasma concentrations of clozapine and its major metabolites norclozapine and clozapine N-oxide in psychotic patients. In the first study, concentrations of clozapine and metabolites were compared between patients treated with clozapine in combination with sodium valproate (n = 15) and control patients treated with clozapine alone (n = 22) and matched for sex, age, body weight, and antipsychotic dosage. Patients comedicated with valproate tended to have higher clozapine levels and lower norclozapine levels, but the differences did not reach statistical significance. In a subsequent study, plasma concentrations of clozapine and its metabolites were determined in 6 patients with schizophrenia stabilized on clozapine therapy (200-400 mg/d) before and after treatment with sodium valproate (900-1200 mg/d) for 4 weeks. Mean plasma concentrations of clozapine and its metabolites did not change significantly throughout the study, but there was a trend for clozapine levels to be higher and for norclozapine levels to be lower after valproate. Overall, these findings suggest that valproic acid may have an inhibiting effect on the CYP1A2- or CYP3A4-mediated conversion of clozapine to norclozapine. However, the interaction is unlikely to be clinically significant.
Ther Drug Monit 1999 Jun
PMID:Small effects of valproic acid on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenic or affective disorders. 1036 50

A 35-year-old man with schizophrenia was successfully treated with clozapine at a daily oral dose of 700-725 mg for more than 7 consecutive years. Two weeks after abrupt cessation of chronic heavy cigarette smoking, he suddenly developed tonic clonic seizures followed by stupor and coma. After 2 days of intensive care, the patient recovered completely but could not recall the episode. Clozapine therapy was reinstituted and could be carried out successfully at 425 mg daily, i.e., at an approximately 40% reduction of the daily dose before he stopped smoking. The sudden cessation of smoking most likely caused a rise in plasma concentrations of clozapine and/or clozapine metabolites resulting in the seizure episode. A likely mechanism is that the heavy smoking had induced cytochrome P450-1A2, the main enzyme involved in the metabolism of clozapine.
Ther Drug Monit 1999 Oct
PMID:Could discontinuing smoking be hazardous for patients administered clozapine medication? A case report. 1051 59

The authors we investigated the relationship between plasma levels of haloperidol (HAL) and the number of CYP2D6*10 (*10) alleles in 66 Japanese inpatients with schizophrenia (male = 61, female = 5) on HAL. Plasma HAL level was determined by an enzyme immunoassay method. Daily dose of HAL was 1.5-36 (mean +/- SD = 12.3 +/- 7.6) mg or 0.02-0.49 (0.21 +/- 0.13) mg/kg body weight. Plasma HAL levels ranged from 1.4 to 47.4 (12.4 +/- 9.5) ng/mL. No significant difference in the plasma HAL levels was observed between the subjects with no, one, and two *10 alleles (one-way analysis of variance: 56.1 +/- 20.3, 61.0 +/- 20.3, and 63.3 +/- 20.3 ng/mL/mg/kg, respectively, F(2,63) = 0.65, p = 0.52). These results are not supportive of the previous report that plasma HAL levels can be predicted by the number of *10 alleles in Asian patients.
Ther Drug Monit 2000 Aug
PMID:CYP2D6*10 alleles are not the determinant of the plasma haloperidol concentrations in Asian patients. 1094 77

The effect of reboxetine on steady-state plasma concentrations of the atypical antipsychotics clozapine and risperidone was studied in 14 patients with schizophrenia or schizoaffective disorder with associated depressive symptoms. Seven patients stabilized on clozapine therapy (250-500 mg/day) and seven receiving risperidone (4-6 mg/day) were given additional reboxetine (8 mg/day). After 4 weeks of reboxetine therapy, mean plasma concentrations of clozapine, norclozapine, and risperidone active moiety (sum of concentrations of risperidone and 9-hydroxyrisperidone) increased slightly but not significantly by 5%, 2%, and 10%, respectively. The mean plasma clozapine/norclozapine and risperidone/9-hydroxyrisperidone ratios were not modified during reboxetine treatment. Reboxetine coadministration with either clozapine or risperidone was well tolerated. These findings indicate that reboxetine has minimal effects on the metabolism of clozapine and risperidone and may be added safely to patients receiving maintenance treatment with these two antipsychotics.
Ther Drug Monit 2001 Dec
PMID:No effect of reboxetine on plasma concentrations of clozapine, risperidone, and their active metabolites. 1180 3


1 2 3 4 5 Next >>