20 results on '"Chang, W. H."'
Search Results
2. Differences between in vitro and in vivo determinations of fluvoxamine-clozapine interaction.
- Author
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Lu ML, Lane HY, and Chang WH
- Subjects
- Clozapine antagonists & inhibitors, Cytochrome P-450 Enzyme Inhibitors, Drug Interactions physiology, Enzyme Inhibitors blood, Humans, Serotonin Antagonists blood, Selective Serotonin Reuptake Inhibitors blood, Clozapine blood, Fluvoxamine blood
- Published
- 2001
- Full Text
- View/download PDF
3. Repeated ingestion of grapefruit juice does not alter clozapine's steady-state plasma levels, effectiveness, and tolerability.
- Author
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Lane HY, Jann MW, Chang YC, Chiu CC, Huang MC, Lee SH, and Chang WH
- Subjects
- Adult, Clozapine adverse effects, Clozapine therapeutic use, Female, Humans, Male, Middle Aged, Prospective Studies, Psychiatric Status Rating Scales, Schizophrenia drug therapy, Beverages adverse effects, Citrus, Clozapine analogs & derivatives, Clozapine pharmacokinetics, Food-Drug Interactions, Schizophrenia blood
- Abstract
Background: Grapefruit juice can inhibit the gastrointestinal activity of cytochrome P450 (CYP) 3A4, while its effect on CYP1A2 remains controversial. Several grapefruit juice bioflavonoids also modulate the activity of the drug transporter P-glycoprotein in the gut and in the blood-brain barrier. Both CYP1A2 and CYP3A4 are involved in clozapine metabolism. This study investigated the effects of repeated ingestion of grapefruit juice on multiple-dose pharmacokinetics and pharmacodynamics of clozapine in schizophrenic patients., Method: Clozapine therapy was initiated for fifteen treatment-resistant schizophrenic inpatients (DSM-IV criteria). The doses were individually titrated from day -35 to day -15 and then kept unchanged from day -14 to day 49. Regular-strength grapefruit juice (250 mL) was coadministered b.i.d. with each clozapine dose from day 15 to day 28. Plasma levels of clozapine and its main metabolites (norclozapine and clozapine N-oxide) were obtained, and clinical efficacy and safety assessments were completed prior to juice administration (days 0, 7, and 14), during the coadministration (days 17, 21, and 28), and after cessation of the juice (days 35, 42, and 49)., Results: After reaching steady states, plasma concentrations of clozapine and its metabolites and Positive and Negative Syndrome Scale scores were not significantly altered by the effect of grapefruit juice ingestion. The Clinical Global Impressions scale scores, Calgary Depression Scale scores, and side effect profiles (by the Extrapyramidal Symptom Rating Scale, the UKU Side Effect Rating Scale, and thorough examinations including electrocardiography and electroencephalography) also remained constant during the study., Conclusion: Consumption of regular-strength grapefruit juice, 250 mL b.i.d., for 14 days did not significantly impact clozapine metabolism, clinical efficacy, or tolerability. One reason is that enzymes other than CYP3A4 also mediate clozapine disposition. Also, grapefruit juice inhibits CYP3A4 in the gut, but not in the liver. The preliminary results also suggest that clozapine is unlikely to be a P-glycoprotein substrate. Further rigorous studies are necessary to reconfirm these findings.
- Published
- 2001
- Full Text
- View/download PDF
4. Lack of CYP3A4 inhibition by grapefruit juice and ketoconazole upon clozapine administration in vivo.
- Author
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Lane HY, Chiu CC, Kazmi Y, Desai H, Lam YW, Jann MW, and Chang WH
- Subjects
- Adult, Antifungal Agents pharmacology, Antipsychotic Agents therapeutic use, Clozapine therapeutic use, Cross-Over Studies, Cytochrome P-450 CYP3A, Cytochrome P-450 Enzyme System physiology, Drug Interactions, Enzyme Inhibitors pharmacology, Food-Drug Interactions, Humans, Ketoconazole pharmacology, Male, Mixed Function Oxygenases physiology, Schizophrenia drug therapy, Antipsychotic Agents blood, Beverages, Citrus, Clozapine blood, Cytochrome P-450 Enzyme Inhibitors, Mixed Function Oxygenases antagonists & inhibitors, Schizophrenia blood
- Abstract
The drug-food and drug-drug interaction between grapefruit juice (GFJ) and ketoconazole (KETO) was evaluated in schizophrenic patients given a single dose of clozapine (CLZ). CLZ is metabolized primarily by CYP isozymes 3A4 and 1A2 to two principal metabolites, desmethylclozapine (DCLZ) and clozapine N-oxide (CNO). GFJ and KETO are well known potent CYP 3A4 inhibitors in the gastrointestinal tract and hepatic isozymes, respectively. Twenty-one schizophrenic patients participated in the co-administration of CLZ 50 mg and GFJ. After a one-week washout, five patients were given double the GFJ (HGFJ) dose for 7 consecutive days. In another group of five patients, ketoconazole (KETO) 400 mg was given for 7 consecutive days. At the end of the 7-day period for both groups, CLZ was coadministered with the HGFJ and KETO groups. CLZ, DCLZ and CNO were assayed by HPLC. GFJ, HGJF and ketoconazole failed to significantly change CLZ disposition. Metabolites DCLZ and CNO concentrations remained unchanged during the study. The only exception was decreased Cmax in DCLZ and CNO concentrations. These results indicate that CYP 3A4 inhibition may not be clinically significant compared to CYP 1A2, as previous studies show a dramatic increase in CLZ plasma concentrations with fluvoxamine (CYP 1A2 inhibitor). The reasons for the lack of drug-food and drug-drug interactions with CLZ and CYP 3A4 inhibitors can be explained by the higher Ki values for gastrointestinal and hepatic CYP 3A4 isozymes.
- Published
- 2001
- Full Text
- View/download PDF
5. Fluvoxamine reduces the clozapine dosage needed in refractory schizophrenic patients.
- Author
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Lu ML, Lane HY, Chen KP, Jann MW, Su MH, and Chang WH
- Subjects
- Adult, Antipsychotic Agents administration & dosage, Antipsychotic Agents blood, Chronic Disease, Clozapine administration & dosage, Clozapine blood, Comorbidity, Drug Administration Schedule, Drug Therapy, Combination, Female, Humans, Male, Prospective Studies, Psychiatric Status Rating Scales statistics & numerical data, Schizophrenia epidemiology, Smoking epidemiology, Treatment Outcome, Antipsychotic Agents therapeutic use, Clozapine therapeutic use, Fluvoxamine therapeutic use, Schizophrenia drug therapy, Selective Serotonin Reuptake Inhibitors therapeutic use
- Abstract
Background: Concomitant fluvoxamine use can potentially reduce the dosage of clozapine needed in treatment-refractory patients with schizophrenia. Previous reports have shown that fluvoxamine can increase plasma clozapine concentrations by inhibition of cytochrome P450 (CYP) 1A2. We evaluated the safety and efficacy of fluvoxamine, 50 mg/day, coadministration with clozapine, 100 mg/day, in refractory schizophrenic patients., Method: In this prospective study, 18 treatment-refractory patients with DSM-IV schizophrenia (10 nonsmokers and 8 smokers) were treated with clozapine at a target dose of 100 mg h.s. After steady-state conditions of clozapine had been reached, 50 mg/day of fluvoxamine was then added. Plasma levels of clozapine, norclozapine, and clozapine N-oxide were measured prior to fluvoxamine addition and on days 14 and 28 during combined treatment. Side effects and efficacy were monitored with standardized rating instruments., Results: After 14 days of combined treatment, the mean +/- SD plasma clozapine level increased 2.3-fold to 432.4+/-190.9 ng/mL without further elevation on day 28. All patients completed the study without significant adverse side effects. Twelve of the 18 patients achieved plasma clozapine concentrations of at least 350 ng/mL. While plasma norclozapine levels also rose (but to a smaller extent), plasma clozapine N-oxide levels remained unchanged after the add-on therapy. Patients who smoked had 34% lower plasma clozapine concentrations than nonsmokers (NS). Three of the 4 patients who did not reach clozapine plasma levels of at least 300 ng/mL were smokers. Plasma norclozapine/clozapine ratios, especially in smokers, declined significantly with fluvoxamine addition., Conclusion: The addition of fluvoxamine, 50 mg/day, to low-dose clozapine, 100 mg/day, can raise plasma clozapine levels to at least 300 ng/mL in most patients. Only slight dosage adjustments with clozapine may be needed after fluvoxamine coadministration in some patients who smoke. Plasma clozapine levels remained stable after 14 days of fluvoxamine addition. The combined treatment was well tolerated, and clinical improvement was observed in our patients. Further long-term studies with this drug combination are needed to determine its economic impact.
- Published
- 2000
- Full Text
- View/download PDF
6. Selective serotonin reuptake inhibitor syndrome: precipitated by concomitant clozapine?
- Author
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Lu ML, Lane HY, and Chang WH
- Subjects
- Antipsychotic Agents therapeutic use, Clozapine therapeutic use, Dose-Response Relationship, Drug, Drug Therapy, Combination, Fluoxetine therapeutic use, Humans, Male, Middle Aged, Serotonin Syndrome diagnosis, Selective Serotonin Reuptake Inhibitors therapeutic use, Antipsychotic Agents adverse effects, Clozapine adverse effects, Fluoxetine adverse effects, Schizophrenia drug therapy, Serotonin Syndrome chemically induced, Selective Serotonin Reuptake Inhibitors adverse effects, Substance Withdrawal Syndrome diagnosis
- Published
- 1999
- Full Text
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7. Clozapine versus risperidone in treatment-refractory schizophrenia: possible impact of dosing strategies.
- Author
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Lane HY and Chang WH
- Subjects
- Antipsychotic Agents administration & dosage, Clinical Trials as Topic, Clozapine administration & dosage, Dose-Response Relationship, Drug, Drug Administration Schedule, Humans, Risperidone administration & dosage, Schizophrenic Psychology, Treatment Outcome, Antipsychotic Agents therapeutic use, Clozapine therapeutic use, Risperidone therapeutic use, Schizophrenia drug therapy
- Published
- 1999
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8. In-vitro and in-vivo evaluation of the drug-drug interaction between fluvoxamine and clozapine.
- Author
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Chang WH, Augustin B, Lane HY, ZumBrunnen T, Liu HC, Kazmi Y, and Jann MW
- Subjects
- Adult, Anti-Anxiety Agents blood, Antipsychotic Agents blood, Area Under Curve, Clozapine blood, Drug Interactions, Fluvoxamine blood, Humans, Male, Microsomes, Liver drug effects, Microsomes, Liver metabolism, Middle Aged, Anti-Anxiety Agents pharmacokinetics, Antipsychotic Agents pharmacokinetics, Clozapine pharmacokinetics, Fluvoxamine pharmacokinetics, Schizophrenia blood
- Abstract
The drug-drug interaction between fluvoxamine (FLV) and clozapine (CLZ) was evaluated by in-vitro and in-vivo methods. In-vitro studies were conducted using human hepatic microsomal preparations with standard chemical inhibitors of the cytochrome P450 (CYP 450) isozyme system. Furafyline, FLV, troleandomycin (TAO) and erythromycin were used as the chemical inhibitors. For the in-vivo study, nine male schizophrenic patients were administered a single dose of CLZ 50 mg on two separate occasions with a 2-week FLV treatment of 50 mg twice a day in between each CLZ dose. Blood samples were obtained over 48 h following CLZ administration. CLZ and its two principle metabolites, clozapine N-oxide (CNO) and desmethylclozapine (DCLZ), were measured by high performance liquid chromatography with ultraviolet detection for both in-vitro and in-vivo studies. The in-vitro formation of DCLZ was inhibited by furafyline and FLV by 42.0% and 48.5% (P<0.01), respectively. TAO and erythromycin had only modest inhibition effects on DCLZ formation of 18.3% and 21.0% (P = NS), respectively. CNO in-vitro formation was significantly reduced by TAO and erythromycin by 44.5% and 45.0% (P<0.01), respectively. Furafyline and FLV had only modest effects of 19.2% and 8.5% (P = NS), respectively. In schizophrenic patients, FLV resulted in a pronounced increased in CLZ plasma concentrations with the total mean CLZ AUC increased by a factor of 2.58 from 780.8 ng/ml per hour to 2218.0 ng/ml per hour (P<0.001). All patients were sedated during combined FLV and CLZ use. During FLV treatment, CNO and DCLZ AUC both decreased by 18.8% (P = 0.07) and 9.0% (P = NS), respectively. These results indicate that in-vitro evaluations may not always accurately reflect changes in drug-drug interaction observed in-vivo. Careful patient monitoring is recommended during FLV/CLZ co-administration.
- Published
- 1999
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9. Seizures after discontinuation of low-dose lorazepam from originally seizure-free clozapine regimen: combined effects?
- Author
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Lane HY, Su KP, and Chang WH
- Subjects
- Adult, Anti-Anxiety Agents administration & dosage, Anti-Anxiety Agents therapeutic use, Clozapine administration & dosage, Clozapine adverse effects, Dose-Response Relationship, Drug, Drug Administration Schedule, Drug Therapy, Combination, Electroencephalography drug effects, Humans, Lorazepam administration & dosage, Lorazepam therapeutic use, Male, Risperidone therapeutic use, Anti-Anxiety Agents adverse effects, Clozapine therapeutic use, Lorazepam adverse effects, Schizophrenia drug therapy, Seizures chemically induced, Substance Withdrawal Syndrome etiology
- Published
- 1999
- Full Text
- View/download PDF
10. Effects of gender and age on plasma levels of clozapine and its metabolites: analyzed by critical statistics.
- Author
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Lane HY, Chang YC, Chang WH, Lin SK, Tseng YT, and Jann MW
- Subjects
- Adult, Age Factors, Body Weight, Chromatography, High Pressure Liquid, Clozapine analogs & derivatives, Clozapine metabolism, Dose-Response Relationship, Drug, Drug Administration Schedule, Female, Humans, Linear Models, Male, Retrospective Studies, Sex Factors, Clozapine blood, Clozapine pharmacokinetics, Schizophrenia blood, Schizophrenia drug therapy
- Abstract
Background: Previous reports concerning the effects of gender and age on steady-state plasma concentrations of clozapine and its major metabolites, norclozapine and clozapine-N-oxide, have been controversial. Since the frequency distribution of the plasma levels is asymmetrical and skewed to the right, the statistical methods (such as analysis of variance and regression analysis) used earlier are actually inappropriate for analyzing the effects of the variables on the concentrations and might contribute to the inconsistent results. The goal of the present study, with befitting statistics, is to measure the potential effect of dose, gender, age, and body weight on plasma levels of clozapine and its 2 major metabolites., Method: We retrospectively analyzed data from a therapeutic drug monitoring study for steady-state plasma clozapine, norclozapine, and clozapine-N-oxide levels that was conducted in a large group of Chinese schizophrenic inpatients (male:female ratio = 83:79; age range, 33.8 +/- 9.3 years). The daily doses of clozapine had ranged from 100 to 900 mg, with a mean +/- SD value of 379.5 +/- 142.2 mg. Plasma concentrations had been measured using high-performance liquid chromatography with ultraviolet detection. Multiple linear regression was adopted to quantify the effects of various factors on the plasma levels. The natural logarithm of the plasma level was used as the dependent variable to overcome the skewness problem., Results: After adjusting the effects of gender, age, and body weight by multiple linear regression, each 1-mg increment in the daily dose could raise the clozapine level by 0.31%, norclozapine by 0.27%, and clozapine-N-oxide by 0.16%. Female patients had 34.9% higher clozapine levels and 36.3% higher norclozapine, with other variables being controlled. No sex differences were demonstrated for clozapine-N-oxide levels. Each 1-year increment in age would elevate the clozapine level by 1.1%, norclozapine by 1.0%, and clozapine-N-oxide by 1.0%. Body weight could not influence the levels of these compounds., Conclusion: The present results suggest that women possess higher plasma levels (about one third higher) of clozapine and norclozapine, but not the N-oxide metabolite. Each addition of 1 year in age elevated clozapine and either metabolite's levels by about 1%. Furthermore, every 1-mg increase in the daily dose raised clozapine and norclozapine concentrations by approximately 0.3%. These findings could assist clinicians in optimizing clozapine dosing strategies.
- Published
- 1999
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11. Extrapyramidal symptoms after addition of fluvoxamine to clozapine.
- Author
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Kuo FJ, Lane HY, and Chang WH
- Subjects
- Antidepressive Agents, Second-Generation therapeutic use, Antipsychotic Agents therapeutic use, Clozapine therapeutic use, Drug Interactions, Female, Fluvoxamine therapeutic use, Humans, Male, Middle Aged, Schizophrenia drug therapy, Antidepressive Agents, Second-Generation adverse effects, Antipsychotic Agents adverse effects, Basal Ganglia Diseases chemically induced, Clozapine adverse effects, Fluvoxamine adverse effects
- Published
- 1998
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12. Reversible metabolism of clozapine and clozapine N-oxide in schizophrenic patients.
- Author
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Chang WH, Lin SK, Lane HY, Wei FC, Hu WH, Lam YW, and Jann MW
- Subjects
- Adult, Area Under Curve, Biotransformation, Chromatography, High Pressure Liquid, Clozapine pharmacokinetics, Cross-Over Studies, Humans, Male, Middle Aged, Models, Biological, Spectrophotometry, Ultraviolet, Antipsychotic Agents pharmacokinetics, Clozapine analogs & derivatives, Schizophrenia metabolism
- Abstract
1. To characterize the interconversion process between clozapine and its metabolite clozapine N-oxide (CNO), eight healthy male schizophrenics were administered a single dose of clozapine or CNO in a randomized crossover manner. 2. Using a general pharmacokinetic model for the interconversion process, the mean total clearances of clozapine and CNO were 28.45 L/hr and 45.30 L/hr, respectively. These values were similar to the values obtained by the usual model-independent method of pharmacokinetic analysis. 3. When administered clozapine, mean CNO plasma concentrations of 17.7 +/- 16.4 ng/ml were slightly lower than the other clozapine metabolite-desmethylclozapine (DCLOZ) plasma levels of 24.4 +/- 8.6 ng/ml at the 12 hour time point. When CNO was administered, plasma concentrations at the 12 hour time point of clozapine were twice the amount of CNO (28.1 +/- 8.9 ng/ml vs 14.4 +/- 8.8 ng/ml). 4. DCLOZ plasma concentrations were detected in all patients upon clozapine administration. Upon CNO administration, only one patient had detectable plasma DCLOZ levels. 5. The interconversion process of clozapine and CNO could partially account for the wide interpatient variability reported for clozapine plasma concentrations in schizophrenic patients.
- Published
- 1998
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13. Elevated plasma clozapine concentrations after phenobarbital discontinuation.
- Author
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Lane HY, Su KP, Chang WH, and Jann MW
- Subjects
- Adult, Drug Therapy, Combination, Humans, Male, Phenobarbital therapeutic use, Antipsychotic Agents blood, Clozapine blood, Phenobarbital adverse effects, Substance Withdrawal Syndrome etiology
- Published
- 1998
- Full Text
- View/download PDF
14. Clozapine dosages and plasma drug concentrations.
- Author
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Chang WH, Lin SK, Lane HY, Hu WH, Jann MW, and Lin HN
- Subjects
- Adult, Aged, Clozapine administration & dosage, Dose-Response Relationship, Drug, Female, Humans, Male, Middle Aged, Antipsychotic Agents blood, Clozapine blood
- Abstract
Steady-state plasma concentrations of clozapine and its metabolites, desmethylclozapine and clozapine-N-oxide, were measured in 162 Taiwanese patients with refractory schizophrenia. The daily doses of clozapine ranged from 100 to 900 mg, with a mean value of 379.5 +/- 142.2 mg. A dosage of 400 mg/day or lower was used for most patients (n = 131, 81%). Plasma concentrations of clozapine and its two major metabolites were measured using high performance liquid chromatography with ultraviolet detection. The mean plasma clozapine concentration was 566.9 +/- 398.8 ng/mL. The plasma concentrations of desmethylclozapine and clozapine-N-oxide were 46% and 16% of the concentration of the parent drug, respectively. We used an approximate rule that each 100 mg/day dose results in about 150 ng/mL plasma clozapine. This value is about 30% to 50% higher than that reported in Caucasians. The suggested therapeutic plasma clozapine concentration range of 300 to 700 ng/mL can be achieved with a dose range of 200 to 500 mg/day in most Taiwanese patients. Dose-dependent plasma clozapine concentrations were found. The interpatient variation was up to 12-fold in patients receiving the same dose, eg, 400 mg/day (n = 62). In four of these patients, the plasma drug concentrations were very high (1,446 +/- 114 ng/mL). The application of therapeutic drug monitoring in clozapine-treated patients with refractory schizophrenia is important, not only in dose adjustment, prediction of severe side effects such as seizures, and exploration of drug interactions, but also in the effective use of this expensive drug.
- Published
- 1997
15. Monitoring of plasma clozapine levels and its metabolites in refractory schizophrenic patients.
- Author
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Liu HC, Chang WH, Wei FC, Lin SK, Lin SK, and Jann MW
- Subjects
- Adult, Antipsychotic Agents adverse effects, Antipsychotic Agents therapeutic use, Chromatography, High Pressure Liquid methods, Clozapine adverse effects, Clozapine therapeutic use, Female, Haloperidol adverse effects, Haloperidol blood, Haloperidol therapeutic use, Humans, Male, Schizophrenia drug therapy, Antipsychotic Agents blood, Clozapine analogs & derivatives, Clozapine blood, Schizophrenia blood
- Abstract
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.
- Published
- 1996
- Full Text
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16. Rapid formation of clozapine in guinea-pigs and man following clozapine-N-oxide administration.
- Author
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Jann MW, Lam YW, and Chang WH
- Subjects
- Animals, Caudate Nucleus metabolism, Clozapine administration & dosage, Clozapine blood, Guinea Pigs, Humans, Liver metabolism, Prefrontal Cortex metabolism, Rats, Rats, Wistar, Schizophrenia blood, Schizophrenia drug therapy, Clozapine analogs & derivatives, Clozapine metabolism
- Abstract
Clozapine and its metabolite clozapine-N-oxide (0.5 mg/kg) were administered intraperitoneally to guinea-pigs. Significant amounts of clozapine were detected in plasma, liver, frontal cortex and caudate after clozapine-N-oxide administration. The amount of clozapine detected in plasma two hours post-administration of N-oxide was approximately 40% of the amount of clozapine after clozapine injection. Tissue concentrations of clozapine in liver, frontal cortex and caudate were greater than plasma concentrations. Clozapine concentrations were almost equivalent in the liver. Clozapine concentrations after N-oxide injection were approximately 40-50% lower compared to clozapine concentrations after clozapine administration in the frontal cortex and caudate. A single dose of clozapine-N-oxide was given to a schizophrenic patient. Clozapine plasma concentrations were detected after N-oxide administration. This study shows that clozapine is formed from its N-oxide metabolite and that a reversible metabolic pathway exists for clozapine and clozapine-N-oxide.
- Published
- 1994
17. Disposition of clozapine and desmethylclozapine in schizophrenic patients.
- Author
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Lin SK, Chang WH, Chung MC, Lam YW, and Jann MW
- Subjects
- Adult, Chronic Disease, Clozapine administration & dosage, Dextromethorphan urine, Half-Life, Homovanillic Acid blood, Humans, Male, Metabolic Clearance Rate, Middle Aged, Phenotype, Clozapine analogs & derivatives, Clozapine pharmacokinetics, Schizophrenia metabolism
- Abstract
The disposition of the atypical clozapine and its desmethyl metabolite were evaluated in fourteen male chronic patients. A single 100 mg dose of clozapine was administered and blood sampling performed over the following 72 hours. The mean (SD) oral clearance and half-life of clozapine were 55.4 (29.7) L/hr and 13.7 (9.9) hours, respectively. The mean (SD) AUC for clozapine and desmethylclozapine was 2389.9 (1406) and 751.1 (622.9) ng.hr/mL, respectively. The elimination of the metabolite is rate limited by its formation from cloza-pine. A wide interpatient variability in clozapine and desmethylclozapine pharmacokinetics was observed.
- Published
- 1994
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18. Determination of clozapine and desmethylclozapine in human plasma by high-performance liquid chromatography with ultraviolet detection.
- Author
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Chung MC, Lin SK, Chang WH, and Jann MW
- Subjects
- Adult, Humans, Male, Schizophrenia blood, Spectrophotometry, Ultraviolet, Chromatography, High Pressure Liquid methods, Clozapine analogs & derivatives, Clozapine blood
- Abstract
A method using reversed-phase high-performance liquid chromatography for the simultaneous determination of clozapine and its desmethyl metabolite in human plasma has been established. Clozapine and N-desmethylclozapine were extracted with n-hexane-isoamyl alcohol (98.5:1.5, v/v). Protriptyline served as the internal standard. The limits of detection for clozapine and desmethylclozapine are 2 and 1 ng/ml, respectively. The sensitivity and precision of this method can be utilized for pharmacokinetic studies and therapeutic drug monitoring regimens.
- Published
- 1993
- Full Text
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19. Pharmacokinetics and pharmacodynamics of clozapine.
- Author
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Jann MW, Grimsley SR, Gray EC, and Chang WH
- Subjects
- Clozapine administration & dosage, Clozapine therapeutic use, Humans, Schizophrenia drug therapy, Clozapine pharmacokinetics, Clozapine pharmacology
- Abstract
The introduction of clozapine has given clinicians a unique agent for treating patients with schizophrenia that is refractory to other neuroleptics. Despite its efficacy, the drug continues to be prescribed with trepidation due to the incidence of agranulocytosis. This article reviews the pharmacokinetic and pharmacological properties of clozapine and the clinical implications for monitoring plasma concentrations. Various assays have been developed for clozapine that include gas-liquid chromatography, radioimmunoassay and high performance liquid chromatography. Only a few studies have examined the pharmacokinetics of clozapine in patients with schizophrenia. These studies have revealed a wide interpatient variability in pharmacokinetic parameters that include: time to reach peak plasma concentrations 1.1 to 3.6h; elimination half-life 9.1 to 17.4h; clearance 8.7 to 53.3 L/h; and a volume of distribution of 1.6 to 7.3 L/kg. Clozapine is metabolised via the hepatic microsomal enzyme system into 2 principle metabolites: demethyl-clozapine and clozapine N-oxide. Urine samples have reported the ratio of clozapine:demethyl:N-oxide to be 1:1:2. The clozapine N-oxide binding affinity with 3H-haloperidol was 4 times lower than clozapine and its conversion back to clozapine is hypothesised. Although the exact pharmacological mechanism of action of clozapine is not fully understood, the drug does possess significant binding affinity for different dopamine receptors, with recent evidence supporting binding to the D4 receptor subtype. Clozapine transiently increases serum prolactin levels with minimal changes in homovanillic acid plasma levels. Limited studies investigating the relationship between clinical response and plasma clozapine concentrations have investigated the range between 100 and 800 micrograms/L. In the treatment of patients with refractory schizophrenia, a minimum concentration of 350 micrograms/L was suggested as needed. The occurrence of agranulocytosis could have a genetic basis and patients should be rigorously monitored during treatment. The incidence of tardive dyskinesia and extrapyramidal side effects is minimal. Clozapine can lower the seizure threshold in a dose- and time-dependent manner. Careful patient selection and monitoring are required when clozapine therapy is used in patients with schizophrenia.
- Published
- 1993
- Full Text
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20. Risk of Extrapyramidal Syndrome in Schizophrenic Patients Treated with Antipsychotics: A Population-based Study.
- Author
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Yang, S.-Y., Yang, Y.-H. Kao, Chong, M.-Y., Yang, Y.-H., Chang, W.-H., and Lai, C.-S.
- Subjects
ANTIPSYCHOTIC agents ,SEROTONIN antagonists ,RISPERIDONE ,CLOZAPINE ,DOPAMINE antagonists - Abstract
To compare the prevalence of extrapyramidal syndrome (EPS) between the first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs), the co-prescribing rate of anti-Parkinson drugs (APDs) of each antipsychotic drug was analyzed using population database. Fourteen antipsychotics had been prescribed during the 5-year study period. Among the SGAs, quetiapine had the lowest crude co-prescribing rate of APDs (27.09%), whereas risperidone had the highest rate (66.50%). Among the FGAs, thioridazine and loxapine had the lowest (60.99%) and highest rates (96.35%), respectively. The rankings of the co-prescribing rate of APDs among antipsychotics, in increasing order, were quetiapine, clozapine, olanzapine, thioridazine, zotepine, chlorpromazine, risperidone, sulpiride, clotiapine, flupentixol, haloperidol, zuclopentixol, trifluoperazine, and loxapine. The results indicate that the risk of EPS appears to be lower in SGAs than in FGAs; however, the considerably high rate of EPS in some of the newer generation of antipsychotics warrants clinical attention.Clinical Pharmacology & Therapeutics (2007) 81, 586–594. doi:10.1038/sj.clpt.6100069; published online 18 January 2007 [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
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