Relationship between clinical efficacy and clozapine concentrations in plasma in schizophrenia: effect of smoking

Concentrations in plasma of clozapine and norclozapine, the major metabolite of clozapine, were measured in 59 treatment-resistant schizophrenic patients at a random time period during the course of treatment. A lower sum of the concentrations of clozapine and norclozapine or either alone predicted less improvement in the Brief Psychiatric Rating Scale (BPRS) Total and Positive symptoms in a multivariate analysis that controlled for baseline BPRS rating and dose. The mean doses of clozapine after 6 months of treatment and at the time of blood sampling were not significantly different in 30 responders and 29 nonresponders to clozapine, on the basis of the decrease in BPRS Total scores, whereas the concentrations in plasma in clozapine of norclozapine and the sum of their concentrations were significantly higher in responders. Clozapine and norclozapine concentrations in plasma correlated both with dose at the time of sampling and with dose at 6 months. A clozapine concentration of 370 ng/ml was the optimal cutoff for distinguishing responders from nonresponders. Clozapine and norclozapine concentrations did not differ in male smokers and nonsmokers.     

Effect of scopolamine on the efflux of dopamine and its metabolites after clozapine, haloperidol or thioridazine

The extracellular concentrations of dopamine (DA) and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum and the nucleus accumbens were measured in awake, freely-moving rats. Clozapine (20 mg/kg, i.p.) increased extracellular DA and HVA in both regions but increased DOPAC only in the striatum. Scopolamine (1 mg/kg), although it had no effect by itself in the striatum or nucleus accumbens, inhibited the ability of clozapine to increase extracellular DA, DOPAC and HVA concentrations in the striatum. The clozapine-induced increase in DA in the frontal cortex was not blocked by scopolamine. Haloperidol (1 mg/kg, i.p.) and thioridazine (10 mg/kg, i.p.) also increased extracellular DA, DOPAC and HVA in the striatum, but scopolamine pretreatment did not inhibit these increases. The results suggest that clozapine differs from haloperidol and thioridazine in that the effect of clozapine, but not that of the two neuroleptic drugs, to increase DA release in the striatum acutely depends on muscarinic receptor stimulation. These results suggest that clozapine, despite its strong muscarinic antagonist properties, does not produce full blockade of muscarinic receptors in vivo in the striatum. The interaction of clozapine with the cholinergic system in the striatum could be relevant to its lack of ability to produce extrapyramidal symptoms or tardive dyskinesia.     

Health status and health care costs for publicly funded patients with schizophrenia started on clozapine

OBJECTIVE: The study examined the effect of clozapine treatment on the health care costs and health status of people with schizophrenia who are supported by public funds. METHODS: Thirty-three patients with schizophrenia hospitalized in a state facility were interviewed within one week of starting clozapine and six months later. Health status was assessed with four clinical rating scales measuring severity of psychopathology, negative symptoms, depression, and quality of life. Cost and health care utilization data were collected for the six months before and after initiation of clozapine. RESULTS: Only 52 percent of the subjects stayed on clozapine for six months. Subjects who continued on clozapine were more likely to be discharged within six months than those who did not continue. Six months after clozapine was started, health care costs showed a sayings of $11,464 per person, even after adjustment for pretreatment costs, and health status was improved. CONCLUSIONS: For subjects who continued on clozapine for six months, clozapine treatment was associated with reduced days of psychiatric hospital care, reduced overall costs despite increased outpatient treatment and residential costs, and improved health status.     

Effects of clozapine metabolites and chronic clozapine treatment on rat brain GABAA receptors

Computer science can assist the physician or the surgeon in defining an optimal strategy for an intervention, and then in performing it. This implies introducing new sensors, then processing all the data gathered about the patient, and finally operating systems for guidance of the very act of intervention.     

Rapid and simple chromatographic method for the determination of diazepam and its major metabolites in human plasma and urine

A simple, rapid, sensitive and selective HPLC method has been developed for the analysis of diazepam (DZP) and its major metabolites, N-desmethyldiazepam (DMDZP), temazepam (TZP) and oxazepam (OZP), in plasma and urine, using clonazepam (CZP) as the internal standard and chloroform as the extracting solvent, with a 10 ng/ml limit of quantitation for the four assayed drugs, and an average (+/-S.D.) recovery of 87.7+/-6.46%, 92.9+/-5.31%, 91.4+/-4.01% and 91.7+/-2.68% for DZP, DMDZP, TZP and OZP, respectively (from plasma), and 89.6+/-2.26%, 90+/-4.24%, 87.45+/-0.64% and 94.50+/-0.71% for DZP, DMDZP, TZP and OZP, respectively (from urine). The method has also proved to be selective and reproducible.     

Effect of clozapine on motor function in schizophrenic patients

It is well established that clozapine is less likely than typical antipsychotic drugs to cause clinically discernible extrapyramidal side-effects. There is a paucity of data, however, on clozapine's motor effects. In this report we compare normal controls to groups of chronic schizophrenic patients treated with either typical antipsychotic drugs or with clozapine. Motor function was measured with a target-matching task, a test relying on submaximal sustained force control. Results indicated that patients on clozapine performed with significantly lower accuracy (greater variability) of force control. Even though the clozapine patients were treatment resistant to typical antipsychotic drugs, and many had a history of tardive dyskinesia, we postulate that the observed deficit is likely due to clozapine treatment rather than to earlier treatments or other factors. The observed force control deficit may be the result of an increase in myoclonus and a generally lower level of overall motor activity.     

Response of patients with treatment-refractory schizophrenia to clozapine within three serum level ranges

OBJECTIVE: This study sought to determine the relationships between serum clozapine levels and therapeutic response. METHOD: Fifty-six inpatients who met the DSM-III-R criteria for chronic schizophrenia and who had not responded to extended treatment with classical antipsychotics were randomly assigned to 12 weeks of double-blind treatment with clozapine at one of three serum level ranges: low (50-150 ng/ml), medium (200-300 ng/ml), or high (350-450 ng/ml). Baseline clinical assessments were completed before the patients' regular antipsychotic and anticholinergic drugs were discontinued. During clozapine treatment, serum levels were ascertained weekly to allow adjustment of clozapine doses so as to maintain each patient near the midpoint of his or her assigned serum level range. Clinical assessments were completed after 6 and 12 weeks of treatment. RESULTS: The analyses of the results of treatment supported the superior efficacy of the 200-300 ng/ml and 350-450 ng/ml serum clozapine level ranges over the 50-150 ng/ml range, with no advantage for 350-450 ng/ml over 200-300 ng/ml. Sleepiness increased with increasing serum levels. CONCLUSIONS: Serum clozapine levels per unit of daily dose were at the lower end of the range noted in previous reports, possibly reflecting the current study's dosing schedules of twice or three times a day, the 11- to 13-hour postdose sampling time, and the moderate doses given. Serum clozapine levels, if interpreted in relation to daily clozapine dosing schedules, postdose sampling time, and total daily dose, may help to guide dosing to provide adequate opportunities for therapeutic response and to limit certain side effects of clozapine treatment.     

Plasma concentrations and pharmacokinetics of idebenone and its metabolites following single and repeated doses in young patients with mitochondrial encephalomyopathy

The stability of enoxaparin sodium in 0.9% sodium chloride injection in polyvinyl chloride (PVC) containers was studied. Triplicate solutions of 120 mg (1.2 mL) of enoxaparin (as the sodium salt) and 98.8 mL of 0.9% sodium chloride injection were prepared in 250-mL PVC containers and stored at room temperature (20-22 degrees C). Samples were taken immediately after preparation and at 0.25, 0.5, 0.75, 1, 4, 12, 16, 24, and 48 hours. Inspections for color change and precipitation were performed with a clarity inspection station and a magnifying glass. Samples of the three admixtures were evaluated in duplicate for pharmacologic activity by an automated coagulation heparin assay. Throughout the 48-hour study period, the enoxaparin admixtures were free of color change, evolution of gas, and precipitates. The pharmacologic activity of enoxaparin in the PVC containers remained > 94% of the initial measured activity for 48 hours. Enoxaparin 1.2 mg/mL (as the sodium salt) in 0.9% sodium chloride injection in PVC containers was stable for up to 48 hours at 20-22 degrees C.     

Determination of nalidixic acid and its two major metabolites in human plasma and urine by reversed-phase high-performance liquid chromatography

This paper describes a precise and sensitive method for analysis of nalidixic acid and its two major metabolites in plasma and urine following the oral administration of a therapeutic dose in humans. After addition of an internal standard (oxolinic acid), 1-ml samples of plasma or urine are extracted at acidic pH with chloroform. The extracts are purified by re-extraction with sodium hydroxide solution and then chloroform. The final extracts are evaporated to dryness, reconstituted in mobile phase and injected into a high-performance liquid chromatograph equipped with RP-8 column and UV detector operating at 254 nm. The limit of sensitivity of the method is lower than 0.5 micrograms/ml of plasma or urine for each compound. The applicability of the method to pharmacokinetic studies of nalidixic acid in humans is demonstrated.     

Plasma concentrations of artemether and its major plasma metabolite, dihydroartemisinin, following a 5-day regimen of oral artemether, in patients with uncomplicated falciparum malaria

OBJECTIVE: To compare maternal and perinatal outcome of pregnancies complicated by pregnancy induced hypertension and HELLP syndrome with the outcome of pregnancies complicated by pre-eclampsia only. DESIGN: It was a retrospective cohort study. Fifty one patients with pregnancy induced hypertension and HELLP syndrome were matched with 51 pre-eclamptic patients according to parity and gestational age on admission in hospital. Management was expectant, treatment only symptomatic and delivery was mainly effectuated because of fetal condition. RESULTS: There was no maternal mortality in either group; maternal morbidity was more frequent in the HELLP group. Immediate intervention within a few hours of admission because of fetal distress more often occurred in the HELLP group. In both groups 41 children (80%) are still alive, with one major handicapped child in each group. Logistic regression analysis identified gestational age on admission and antihypertensive treatment on admission as significant contributors to perinatal mortality or major handicap. Whether the patient belonged to the HELLP group or the pre-eclamptic group had no influence on outcome. CONCLUSION: Expectant management of pregnancy induced hypertension with HELLP syndrome and pre-eclampsia without HELLP syndrome results in similar maternal and perinatal outcome. Perinatal outcome is strongly influenced by gestational age and the severity of hypertension as expressed by the need of antihypertensive treatment, irrespective of the underlying syndrome.     

Measurement of excretion characteristics of theophylline and its major metabolites

Analysis of urinary excretion after administration of 320 mg of theophylline to six normal volunteers appears to indicate the occurrence of capacity limited formation of most of the theophylline metabolites and non-linear renal excretion of theophylline. The renal clearance is elevated at high concentrations where the metabolic clearance is reduced. Even though the individual process of elimination is non-linear, the compensating relationship appears to yield a constant total elimination clearance. The implication of these results in chronic therapy and dose adjustment is discussed.     

Seasonal influence on platelet 5-HT levels in patients with recurrent major depression and schizophrenia

The influence of seasons on platelet serotonin (5-HT) concentration was determined in 88 unipolar depressed and 117 schizophrenic male inpatients, and 90 normal male controls. Platelet 5-HT concentrations showed moderate, but insignificant intragroup seasonal variations in healthy controls and in the groups of depressed (psychotic and nonpsychotic) and schizophrenic (positive and negative) patients. In spring, platelet 5-HT concentrations were higher in schizophrenic patients than in normal controls or in depressed patients, while in other seasons platelet 5-HT concentrations were not significantly different between the groups. Higher platelet 5-HT concentrations were detected in psychotic when compared to nonpsychotic depressed patients in summer, fall, and winter. Increased platelet 5-HT concentrations observed in schizophrenic patients with positive symptoms clearly separated these patients from patients with negative schizophrenia, especially in spring, summer, and fall. Our results indicate the necessity to match patients with regard to the season of the sampling, and to divide depressed and schizophrenic patients into subtypes.     

Simultaneous determination of spironolactone and its metabolites in human plasma

This study describes a specific, precise, sensitive and accurate method for determination of unchanged spironolactone and its major active metabolites in human plasma. After one-step liquid-liquid extraction, analysis of the parent drug and its metabolites was performed in one chromatographic run, using a high performance liquid chromatography (HPLC) method with a programmed switchover of the UV wavelength. Spironolactone and 7 alpha-thiomethyl-spironolactone were detected at 245 nm, while canrenone and internal standard were detected at 280 nm. The column used was an S5 ODS2 (500 mm x 4.6 mm i.d.). The mobile phase was a mixture of acetonitrile-aqueous orthophosphoric acid (pH 3.4). Chromatographic separations were performed at 5 degrees C. The standard curves were linear over the range 10-400 ng ml-1 for spironolactone and 10-600 ng ml-1 for 7 alpha-thiomethyl-spironolactone and canrenone. The precision and accuracy of the method were confirmed by relative standard deviations below 10% for different concentrations, except for the concentration equal to the quantitation limit, where these parameters ranged from 12-15%. The recovery was above 80% for all investigated compounds and for the internal standard. The assay proved to be suitable for pharmacokinetic studies of spironolactone.     

The use of clozapine in the treatment of aggressive schizophrenia

The effect of coadministration of ritonavir and didanosine (ddI) on the pharmacokinetics of these drugs was investigated in a single-center, three-period, crossover study. Eighteen asymptomatic, HIV-positive men were assigned randomly to 6 different sequences of 3 regimens: ddI (200 mg every 12 hours) alone for 4 days, ritonavir (600 mg every 12 hours) alone for 4 days, and 4 days of ddI with ritonavir under dose-staggering conditions. Although not statistically significant, ritonavir concentrations were slightly higher on average (<10%) with concurrent administration of ddI compared with those of ritonavir alone. In contrast, ddI concentrations were lower with concurrent administration compared with those of ddI alone; maximum concentration and area under the concentration-time curve were reduced by about 15% (p < .05). The ddI elimination rate constant was unaffected by ritonavir, suggesting no change in ddI's systemic metabolism. Adverse events were similar between regimens. The relatively minor changes in ritonavir and ddI pharmacokinetics are probably not clinically relevant; therefore, dosage adjustment of either compound appears unnecessary when administered concurrently. However, the combination regimen of ddI and ritonavir continue to be evaluated clinically.     

Cerebrospinal fluid monoamine metabolites in fluoxetine-treated patients with major depression and in healthy volunteers

Cerebrospinal fluid (CSF) levels of the monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), 3-methoxy-4-hydroxyphenylglycol (MHPG), and homovanillic acid (HVA) were measured in three groups: 46 healthy volunteers; 9 medication-free patients with DSM III-R major depressive disorder, recurrent; and these same 9 patients following at least 4 weeks of fluoxetine treatment at 20 mg/day. CSF monoamine metabolite levels in medication-free patients did not differ from healthy volunteers; however, CSF 5-HIAA and MHPG decreased significantly from 95.9 +/- 24.6 (all values +/- SD) to 64.2 +/- 26.1 pmol/ml and from 46.7 +/- 14.2 to 42.6 +/- 11.6 pmol/ml, respectively, following fluoxetine treatment. Fluoxetine also significantly decreased mean Hamilton Depression Rating Scale scores from 23.2 +/- 6.5 to 17.4 +/- 5.0 and significantly increased the CSF HVA/5-HIAA ratio.     

The moderate affinity of clozapine at H3 receptors is not shared by its two major metabolites and by structurally related and unrelated atypical neuroleptics

We determined the affinity and/or potency of two metabolites of clozapine (clozapine-N-oxide and N-desmethylclozapine) and of five atypical neuroleptics, chemically related (olanzapine) or unrelated to clozapine (remoxipride, risperidone, thioridazine, zotepine), at H3 receptors. The specific binding of 3H-N alpha-methylhistamine to rat brain cortex homogenates was inhibited by the seven compounds; the pKi values were: N-desmethylclozapine (5.33); clozapine-N-oxide (4.18); olanzapine (5.45); thioridazine (4.91); zotepine (4.75); remoxipride (4.51) and risperidone (4.43). Three compounds were examined in a functional H3 receptor model as well. The electrically evoked tritium overflow from superfused mouse brain cortex slices, which represents quasi-physiological noradrenaline release, was not affected by N-desmethylclozapine (3.2 and 10 microM), clozapine-N-oxide (3.2-100 microM) and olanzapine (3.2-32 microM). On the other hand, the three compounds shifted to the right the concentration-response curve of histamine for its inhibitory effect on the evoked overflow; the apparent pA2 values were 5.84, 4.21 and 5.80, respectively. The present study shows that five atypical neuroleptics of different chemical classes and the two major metabolites of clozapine possess a lower affinity and/or antagonistic potency at H3 receptors than clozapine itself (pKi 6.15, pA2 6.33; Kathmann M, Schlicker E, G?thert M (1994). Psychopharmacology 116: 464-468).     

Effect of flunixin meglumine on plasma prostanoid concentrations in horses with colic in the perioperative period

In the present study the significance of eicosanoids in the development of shock in horses on the basis of ileus has been investigated using the prostanoids thromboxane B2 (TXB2) and prostaglandine E2 (PGE2) as indicators. The prostanoid synthesis inhibitor flunixin meglumine was to be examined regarding its efficacy in the effective blockade of the synthesis of these mediators within the peri-operative timeframe as well as its effects on clinical signs and laboratory parameters. 21 horses suffering from ileus and ready for surgical intervention received an intravenous flunixin dosis of 1.1 mg/kg body weight immediately after the initial examination and prior to the surgical procedure. 20 colic horses receiving surgical treatment without application of the drug served as control group. Reference data concerning the approximate standard plasma levels of the prostanoids were determined in 10 healthy horses. Plasma levels of thromboxane B2 and prostaglandine E2 in all colic horses, treatment group as well as controls, initially proved to be significantly higher than the reference values in healthy horses. The untreated control group showed plasma levels highly exceeding the standards within the course of investigation. The application of flunixin meglumine resulted in an effective inhibition of the prostanoid synthesis. Post-operatively as well as within the whole period of investigation the plasma levels of PGE2 and TXB2 of the treated group were considerably lower than those of the control group. Flunixin meglumine had a favorable effect on several cardiovascular parameters. The experimental data concerning the effects of flunixin meglumine thus could be validated in a clinical setting, especially the effective inhibition of the cyclooxygenase enzyme system. The application of the prostanoid synthesis inhibitor flunixin meglumine can be judged as being effective in limiting shock progress in the peri-operative setting given reliable diagnosis.     

Pharmacokinetics and hypotensive effect of diltiazem in rabbits: comparison of diltiazem with its major metabolites

To assess the contribution of its metabolites to the antihypertensive effects of diltiazem, a previously established rabbit model has been used to compare the pharmacokinetics and haemodynamic effects of the drug with those of its major metabolites deacetyldiltiazem (M1) and deacetyl-N-monodemethyldiltiazem (M2). Diltiazem, M1 and M2 were administered separately to each animal (n = 5 or 6 per study group) as a single 5 mg kg(-1) intravenous dose. Blood samples, systolic and diastolic blood pressure (SBP and DBP) and heart rate were recorded for each rabbit up to 8 h, and urine samples were collected for 48 h post-dose. Plasma concentrations of diltiazem and its major metabolites were determined by HPLC. The results showed that systemic clearance (CL) and volume of distribution at steady state (Vdss) were smaller for diltiazem than for the metabolites. Diltiazem and the metabolites reduced both SBP and DBP, the effects of diltiazem being most potent. Their effects on heart rate were highly variable and not statistically different between treatment groups (P > 0.05). These results indicate that diltiazem is a more potent hypotensive agent than M1 or M2, possibly because of the higher plasma concentrations secondary to the smaller CL and Vdss of diltiazem compared with the metabolites. The effects of the metabolites might, however, be more sustained.