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H Y Lane

Publications and source records attributed to H Y Lane.

At least 19 recordsLinked to original sources
PubMed2001

Lack of CYP3A4 inhibition by grapefruit juice and ketoconazole upon clozapine administration in vivo.

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.

Adult↗
PubMed2001

Repeated ingestion of grapefruit juice does not alter clozapine's steady-state plasma levels, effectiveness, and tolerability.

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.

Adult↗
PubMed2000

Pretreatment plasma HVA and haloperidol response in acute mania.

INTRODUCTION: Pretreatment plasma homovanillic acid (HVA) levels have been reported to be a correlate of clinical response to typical antipsychotics for schizophrenic, bipolar manic, and mixed groups of psychotic patients. Biological markers of clinical response to antipsychotics could be useful for optimizing drug treatment. METHOD: Thirty-one consenting acute inpatient subjects between ages 19 and 66 years with a DSM-III-R clinical diagnosis of bipolar disorder, manic with psychotic features were entered into this double-blind study and were randomly assigned to receive either haloperidol 25 mg/day or haloperidol 5 mg for the 3-week study. Subjects also received one of the following concomitant medications: standard lithium, lorazepam 4 mg/day, or placebo. RESULTS: The primary multiple regression analysis, including all subjects on both haloperidol doses, yielded a significant main effect for pretreatment plasma HVA (n=31, F=5.7, P=0.025), indicating that higher pretreatment plasma HVA was predictive of better clinical response. In addition, the interaction between haloperidol dose and pretreatment plasma HVA was also significantly associated with clinical response (F=12.59, P=0.0015). When the two haloperidol doses were analyzed separately, we found that pretreatment plasma HVA was only correlated with clinical response in the low haloperidol 5 mg/day group (n=18, F=11.73, P=0.0038) and was unrelated to clinical response to the high haloperidol 25 mg/day group. LIMITATIONS: The sample size was small. Results may have been confounded by prior antipsychotic treatment and concomitant use of lithium or lorazepam. DISCUSSION: These results suggest that pretreatment plasma HVA could be useful for dosing antipsychotics. Patients with high plasma HVA levels would be good candidates for low-dose treatment because they are more likely to improve on such a dose, while patients with low plasma HVA levels might warrant more rapid dosage escalation.

Acute Disease↗
PubMed2000

Risperidone in acutely exacerbated schizophrenia: dosing strategies and plasma levels.

BACKGROUND: The optimal risperidone dosing strategy for acute schizophrenia requires elucidation. Furthermore, plasma levels of risperidone and its active metabolite (9-hydroxyrisperidone) at a given dose vary greatly among different individuals. For patients who metabolize risperidone slowly, a medium dose results in excessively high plasma levels, which might be related to adverse events and perhaps poor response. We thus investigated whether dose reduction to diminish adverse reactions associated with ordinary risperidone doses could still yield efficacy for acutely exacerbated schizophrenia. METHOD: Thirty-one newly hospitalized Chinese patients with acute exacerbation of schizophrenia (DSM-IV) entered this prospective, 6-week open trial. Risperidone doses were titrated to 6 mg/day (if tolerable) over 3 days, but were lowered thereafter if side effects appeared. Efficacy and side effect assessments were conducted on days 0, 4, 14, 28, and 42. Endpoint steady-state plasma levels of risperidone and 9-hydroxyrisperidone were analyzed by high performance liquid chromatography with ultraviolet detection. RESULTS: Thirty patients completed the trial. Of them, 17 tolerated the 6-mg target dose well, while the other 13 received lower final doses (mean +/- SD = 3.6 +/- 0.9 mg, p = .0001) for curtailing treatment-emergent side effects. At endpoint, 92.3% of the 13 low-dose individuals responded to treatment (20% or more reduction in the total Positive and Negative Syndrome Scale score), compared with 52.9% of the 17 high-dose subjects (p < .05). No significant between-group differences were revealed in other minor efficacy measures. Of note, endpoint plasma levels of the active moiety (risperidone plus 9-hydroxyrisperidone) were similar between the low- and high-dose groups (40.4 +/- 31.1 ng/mL vs. 49.7 +/- 13.4 ng/mL, NS). CONCLUSION: The results of this preliminary trial suggest that up to 6 mg of risperidone is efficacious in treating patients with acute exacerbation of schizophrenia. Nearly 60% of the patients could tolerate a 6-mg dose. For the other 40%, reducing dosages to 3.6 +/- 0.9 mg for relieving side effects still yielded efficacy. The 2 dose groups were comparable in the endpoint steady-state plasma drug concentrations.

Acute Disease↗
PubMed2000

Fluvoxamine reduces the clozapine dosage needed in refractory schizophrenic patients.

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.

Adult↗
PubMed2000

Disposition of olanzapine in Chinese schizophrenic patients.

The disposition of olanzapine was evaluated in 21 male chronic schizophrenic patients. A single 10 mg dose of olanzapine was administered and blood sampling performed over the following 120 hours. The mean (+/- SD) oral clearance and elimination half-life of olanzapine were 51.5+/-61.6 l/h and 30.9+/-4.3 hours, respectively. A wide interpatient variability was found. Compared to the population norms, no significant differences were observed between different populations and Chinese patients in olanzapine disposition.

Adult↗
PubMed1999

In-vitro and in-vivo evaluation of the drug-drug interaction between fluvoxamine and clozapine.

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.

Adult↗
PubMed1999

Effects of gender and age on plasma levels of clozapine and its metabolites: analyzed by critical statistics.

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.

Adult↗