Psychiatric pharmacy practice specialty certification process.
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Certification↗
Biomedical subjects
M W Jann
Publications and source records attributed to M W Jann.
Reversible metabolism of clozapine and clozapine N-oxide in schizophrenic patients.
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.
Adult↗
Increased lithium serum and red blood cell concentrations during ketorolac coadministration.
Case reports of a lithium-ketorolac drug interaction have been published, but no formal investigation of this interaction has been conducted. The objective of the study presented here was to determine significant changes in lithium serum and red blood cell (RBC) concentrations after lithium and ketorolac (oral formulation) coadministration at steady-state conditions. Five healthy men participated in the study and received lithium 900 mg/day (300 mg in the morning and 600 mg at bedtime) for 13 days. Ketorolac 40 mg/day (10 mg four times a day) was added on days 8 through 12. Ten blood samples were obtained on days 7 and 13 to determine area under the concentration-time curve (AUC) lithium serum and RBC concentrations. Serum and RBC lithium concentrations were assayed by atomic absorption spectrophotometry with an intra-assay coefficient of variation (CV) of 1.2% on day 1 (range 0-1.0 microg/mL) and 4.9% (range 0-1.0 microg/mL) on day 2 and an interassay CV of 2.9% (range 0-1.0 microg/mL) on days 1 and 2 of serum analysis and a CV of 5.3% (range 0-0.3 microg/mL) of RBC concentrations. Total serum AUC lithium and RBC AUC values significantly increased by 24% (p < 0.02) and by 27% (p < 0.05) with the ketorolac coadministration, respectively. An increased incidence and severity of lithium-associated side effects were reported during concomitant administration. A clinically significant drug interaction can occur when ketorolac is added to lithium therapy.
Adult↗
Elevated plasma clozapine concentrations after phenobarbital discontinuation.
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Adult↗
Dose-dependent reduced haloperidol/haloperidol ratios: influence of patient-related variables.
Plasma reduced haloperidol (RH) concentrations or RH to haloperidol (HL) ratios have been suggested to be important in determining the clinical efficacy and extrapyramidal side effects of HL. In this study, we measured the steady-state plasma HL and RH levels by high performance liquid chromatography and analyzed the effects of various variables (dose, gender, age, and body weight) on RH/HL ratios in four dose groups of Chinese schizophrenic inpatients: 10 mg/day (n = 84), 20 (n = 111), 30 (n = 29), and 60 (n = 55). In addition, the polymorphic distribution of RH/HL ratios, suggested by previous investigators, was further tested in each dosage group (for controlling the potential dosage effect on RH/HL ratios). As a result, both age and body weight could influence RH/HL ratios. Each year increase in age (after adjusting the effects of gender, body weight, and dosage) would elevate the RH/HL ratio by 0.0067 (P < 0.0001). On the other hand, after adjusting gender, age, and dosage effects, each kg increment in body weight would decrease the RH/HL ratio by 0.0044 (P < 0.01). Gender did not influence the ratio. Furthermore, the high dosage groups had higher RH/HL ratios (even with other variables being controlled). In comparison with the 10 mg group, the 60 mg group exhibited a higher mean RH/HL ratio by 0.84 (P < 0.0001) and the 30 mg group did by 0.31 (P < 0.0001). The 20 mg group was almost equal to the 10 mg group in RH/HL ratios. Besides, at each dosage group, the frequency distribution of RH/HL ratios seemed to be predominantly unimodal with a small proportion of extreme outliers. The results of this study clearly indicate that aging or a high dose (> or = 30 mg/day) of HL could raise the plasma RH/HL ratio, while an increasing body weight would reduce that. In contrast, gender does not affect the ratios.
Adult↗
Dextromethorphan phenotyping and haloperidol disposition in schizophrenic patients.
This study examined the relationship between the metabolic ratios of dextromethorphan/dextrorphan, haloperidol disposition, and the incidence of extrapyramidal side effects in schizophrenic patients. Eighteen schizophrenic patients were phenotyped with a test dose of dextromethorphan prior to the initiation of haloperidol treatment. The metabolic ratio of dextromethorphan/dextrorphan was determined in each patient. Patients were treated with oral haloperidol 10 mg/day for 2 weeks. Blood samples for haloperidol and reduced haloperidol were obtained at week 2 of haloperidol treatment. Haloperidol and reduced haloperidol plasma concentrations were assayed by HPLC with electrochemical detection. Significant correlations of dextromethorphan/dextrorphan metabolic ratios vs. plasma haloperidol concentrations, reduced haloperidol concentrations, and reduced haloperidol/haloperidol ratios were found (r = 0.726, P = 0.0007; r = 0.782, P = 0.0001; and r = 0.619, P = 0.006, respectively). Ten patients who experienced extrapyramidal side effects had higher reduced haloperidol concentrations and reduced haloperidol/haloperidol ratios than the other patients (2.49 +/- 1.42 [S.D.] ng/ml vs. 1.10 +/- 0.46 ng/ml, P = 0.014 and 0.287 +/- 0.102 vs. 0.192 +/- 0.065, P = 0.030). The former also had a trend to have higher haloperidol concentrations and dextromethorphan/dextrorphan ratios than the latter (8.04 +/- 2.91 ng/ml vs. 5.83 +/- 1.79 ng/ml, P = 0.066 and 0.023 +/- 0.017 vs. 0.011 +/- 0.010, P = 0.077). Phenotyping patients has the potential to assist clinicians in predicting plasma drug concentrations during the subsequent neuroleptic drug treatment. Further research with phenotyping and psychotropic drug metabolism in psychiatric patients is needed.
Adult↗
Blood levels of reduced haloperidol versus clinical efficacy and extrapyramidal side effects of haloperidol.
1. The studies of relationships between blood levels of reduced haloperidol HL (RH) and clinical efficacy in haloperidol (HL)-treated patients have yielded variable results. On the other hand, the contribution of RH upon HL's extrapyramidal side effects (EPS) had been suggested in animal models as well as in preliminary clinical studies with limited subjects. 2. This study explored the relationships between blood drug levels and clinical effects and EPS of HL in 48 Chinese acutely exacerbated schizophrenic inpatients. After a single-blind placebo period of one week, the patients were treated with a fixed dose 10 mg of HL for two weeks. Steady-state levels of HL and RH in plasma (n = 48) and in red blood cells (RBC) (n = 37) were measured by high performance liquid chromatography. 3. The mean RH/HL ratio in RBC in the Chinese (0.55) is lower than that in non-Chinese patients as reported in the literature (> 2), so is the RH/HL ratios in plasma. 4. No significant relationship emerged between percent improvement in BPRS total score and any of drug indices (HL, RH, sum of two compounds (HL+RH), and RH/HL ratio) in plasma and in RBC. Furthermore, the responders did not differ significantly from the nonresponders in each drug index. 5. Plasma RH levels were significantly higher in 30 patients experiencing EPS compared with the other 18 patients (mean 2.14 +/- 1.71 (S.D.) ng/ml vs. 1.38 +/- 0.37 ng/ml, p < 0.05). No significant differences in other drug indices were noted between subjects with or without EPS.
Adolescent↗
Plasma alpha-one acid glycoprotein and haloperidol concentrations in schizophrenic patients.
Thirty six schizophrenic patients were randomly assigned to placebo or haloperidol treatment for 6 weeks. Blood samples to measure plasma alpha-one acid glycoprotein (AAG), haloperidol and reduced haloperidol concentrations were obtained at baseline and weeks 2, 4, and 6. Blood samples were obtained 10-12 h after the evening dose and prior to the morning dose. Haloperidol and reduced haloperidol was assayed by HPLC with electrochemical detection. Plasma AAG levels were assayed by radial immunodiffusion. Patients were clinically assessed by the Brief Psychiatric Rating Scale (BPRS) and Abnormal Involuntary Movement Scale at baseline and weeks 2, 4, and 6. BPRS scores did not significantly decrease during placebo treatment, although a slight drop in plasma AAG levels was found. Haloperidol produced a significant decrease in BPRS scores and plasma AAG levels. Mean plasma haloperidol levels were 12.9 +/- 14.7 ng/ml at week 6. Significant correlations between decreasing BPRS scores and plasma AAG levels were not found with only a strong trend at week 2 (r = 0.445, p = 0.073). The role of AAG and psychotropic drug disposition in psychiatric patients requires further evaluation.
Adult↗
Clozapine dosages and plasma drug concentrations.
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.
Adult↗
Lack of pharmacokinetic interaction between buspirone and haloperidol in patients with schizophrenia.
The pharmacokinetic interaction between buspirone and haloperidol was evaluated in schizophrenic patients in two different groups. In both groups, haloperidol doses (10-40 mg/day) remained constant for 6 weeks before the addition of buspirone 10 mg three times daily. Serial blood samples were obtained from the 11 patients in group I at baseline (before addition of buspirone) and after administration for 24 hours. The pharmacokinetic parameters of haloperidol were determined alone and with coadministration of buspirone. In group II, buspirone 10 mg three times daily was added to treatment with haloperidol in 27 patients. Blood samples were obtained before addition of buspirone and at weeks 2 and 6 of treatment with buspirone. Samples were obtained 10 to 12 hours after administration of the evening dose and before the morning dose. Haloperidol and its metabolite, reduced haloperidol (RH), were assayed by means of high-performance liquid chromatography with electrochemical detection. Significant changes in the pharmacokinetic parameters of haloperidol were not found in group I; a mean increase in the half-life (t1/2) of haloperidol from 21.5 to 28.1 hours was observed, but this finding was not statistically significant. Under steady-state conditions, plasma levels of haloperidol in the patients in group II did not change significantly from baseline to week 6. Plasma concentrations of RH remained unaltered in both groups. The results indicate that coadministration of buspirone does not markedly affect the pharmacokinetics or plasma concentrations of haloperidol.
Adult↗
Haloperidol and reduced haloperidol plasma concentrations after a loading dose regimen with haloperidol decanoate.
1. Haloperidol and reduced haloperidol plasma levels were measured in schizophrenic patients who received both oral (10 mg, N=16 and 20 mg, N=4) and depot haloperidol treatment 2. Patients were of Asian ethnicity and were safely and effectively converted from oral to depot therapy using a loading dose regimen using a 100 mg weekly injection interval for 4 weeks, biweekly for one month and then monthly. 3. Significant correlations were found for plasma haloperidol and reduced haloperidol levels and reduced haloperidol/haloperidol ratios between oral and depot therapy in these non-smoking patients. 4. A loading dose regimen is needed due to the long elimination half-life of decanoate of 26 days otherwise steady-state condition will not occur until 34 months of therapy. 5. Patients were maintained on monthly depot treatment for 40 weeks after the loading dose regimen and only one patient relapsed during treatment despite dosage increases. 6. The formation of reduced haloperidol remained consistent for oral and depot haloperidol treatment.
Adult↗
Monitoring of plasma clozapine levels and its metabolites in refractory schizophrenic patients.
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.
Adult↗
Plasma haloperidol and reduced haloperidol concentrations in a geriatric population.
Haloperidol (HL) and reduced haloperidol (RH) plasma concentrations were measured in geriatric patients (n = 45) and schizophrenic patients (n = 8). In the elderly patients, HL doses were 1-4 mg/day while only 2 mg/day was used in the schizophrenics. At HL 2 mg/day dose in both age groups, mean plasma HL levels were approximately twice as high in the elderly patients compared to the schizophrenics (1.39 +/- 0.82 vs. 0.56 +/- 0.23 ng/ml, p < 0.02). RH plasma concentrations were almost 5 times greater in the elderly patients (0.54 +/- 0.35 vs. 0.09 +/- 0.05 ng/ml, p < 0.0001). These results suggest that HL plasma concentrations in the elderly are greater than in adult schizophrenic patients treated with similar HL doses.
Adult↗
A practical loading dose method for converting schizophrenic patients from oral to depot haloperidol therapy.
BACKGROUND: Haloperidol decanoate is a long-acting depot antipsychotic agent used for the treatment of schizophrenic patients. The decanoate formulation was developed to treat schizophrenics who have a history of noncompliance with oral medication. Studies of techniques to convert from oral to depot therapy have not utilized the pharmacokinetics of the decanoate formulation. This study is a prospective evaluation for converting patients from oral to depot treatment. METHOD: Twenty-one patients meeting DSM-III-R criteria for schizophrenia participated in the study. Patients were treated with oral haloperidol for 6 weeks and then were switched to decanoate. Haloperidol decanoate 100 mg was administered on a weekly basis for the first 4 weeks. Afterward, injection intervals were increased to every 2 weeks and then to every 4 weeks. Plasma haloperidol concentrations were obtained prior to the next injection and assayed by HPLC with electrochemical detection. Patients were monitored by the psychiatrists and nursing staff for symptoms of clinical deterioration. RESULTS: All patients completed the conversion trial during the first 4 weeks without any problems or adverse side effects. By the third week, mean plasma haloperidol concentrations from the decanoate injections were comparable with those of the 10-mg oral haloperidol treatment (7.95 +/- 4.94 ng/mL vs. 7.79 +/- 4.79 ng/mL). Steady-state conditions for the decanoate therapy were achieved by the fourth week. CONCLUSION: These findings suggest that schizophrenic patients can be easily converted from oral to depot therapy without problems. Further studies with haloperidol decanoate and its conversion from oral treatment utilizing plasma concentrations are needed.
Administration, Oral↗
Disposition of remoxipride in Chinese schizophrenic patients.
The disposition of remoxipride was evaluated in 13 male chronic schizophrenic patients. A single 150 mg dose of remoxipride was administered and blood sampling performed over the following 48 hours. The mean (SD) oral clearance and half-life of remoxipride were 74.46 (25.9) ml/min and 5.46 (0.87) hours, respectively. The mean (SD) AUC for remoxipride was 25,320 (9,820) ng.h/ml. A wide interpatient variability was observed. Compared to Caucasian studies there were no significant differences in the disposition of remoxipride.
Adult↗
Ketone reductase activity and reduced haloperidol/haloperidol ratios in haloperidol-treated schizophrenic patients.
Twenty schizophrenic patients were treated with a fixed haloperidol (HL) dose of 20 mg/day for 4 weeks. The conversion of HL to its reduced metabolite (reduced haloperidol, RH) occurs via the ketone reductase enzyme. RH is also converted back to HL by the cytochrome P450 2D6 isozyme. Ketone reductase activity can be measured in red blood cells. Plasma HL and RH levels were assayed by high performance liquid chromatography. Blood samples were obtained at baseline and during weeks 2 and 4 of HL therapy. Seventeen of 20 patients had ketone reductase values < 3. A significant correlation between ketone reductase and RH/HL plasma ratios was observed at week 4 in these 17 patients. Patients with ketone reductase activity < 3 could represent a subgroup of patients that metabolize HL differently. The wide interpatient variability observed with HL and RH plasma levels in HL-treated patients could reflect differences in ketone reductase activity and the metabolic status of debrisoquin hydroxylase (cytochrome P450IID6) in psychiatric patients.
Adult↗
Intra- and interethnic variability in reduced haloperidol to haloperidol ratios.
Steady-state haloperidol and reduced haloperidol concentrations were measured in 250 schizophrenic patients from 4 ethnic groups: 39 Blacks, 66 Caucasians, 82 Chinese, and 63 Mexican Americans. The distribution of the reduced haloperidol to haloperidol concentration (RH/HL) ratios was bimodal in all ethnic groups, with the antimode determined by probit plot as 0.46, 0.51, 0.36, and 0.76, respectively. With these antimodes, the proportion of patients with low RH/HL ratios were 41%, 42%, 73%, and 57% in the four ethnic groups, respectively. Compared with the other three ethnic groups, in the Chinese patients the ratio was lower. The mean RH/HL ratio in the Chinese was 0.34 compared with 0.81 to 0.87 in the non-Chinese groups. In 53 patients who were treated with two or more haloperidol dosage regimens, steady-state haloperidol and reduced haloperidol drug concentrations obtained from the different regimens were positively correlated with the haloperidol dose (R = .79 and R = .62, respectively). Our data suggest not only the existence of a bimodal distribution in the RH/HL ratio, but also that the antimode separating the low and high ratio subgroups is different among the various ethnic groups.
Adult↗
Flash P2 delay in primary degenerative dementia of the Alzheimer type.
1. Flash visual evoked responses of 31 patients meeting DSM-III-R criteria for primary degenerative dementia of the Alzheimer type were compared with 31 healthy controls. 2. P1 latency was normal (75 +/- 6 msec Alzheimer's; 75 +/- 6 msec controls). 3. P2 was significantly delayed (162 +/- 32 msec, 147 +/- 20 msec, p < 0.03) among patients. 4. P1-P2 interpeak latency was significantly increased (87 +/- 32 msec, 71 +/- 21 msec, p < 0.03) among patients.
Aged↗