Antidepressant response and fluvoxamine plasma concentrations: a pilot study

The objective of this pilot study was to examine the relation between fluvoxamine (FVX) plasma concentrations, therapeutic response and side effects during a four-week treatment period. Twentytwo patients who met the DSMIV criteria for major depression received 100 mg FVX during the first 2 days of treatment and then 150 or 200 mg/day. No clear relationship between plasma concentrations and side effects was detectable. A relationship between plasma concentrations and clinical efficacy was detectable after 21 days but not after 28 days of treatment. These preliminary results indicate that therapeutic drug monitoring might be useful for patients treated with FVX.     

Effect of fluvoxamine on plasma risperidone concentrations in patients with schizophrenia

The effect of fluvoxamine on plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) was investigated in 11 schizophrenic patients with prevailingly negative or depressive symptoms. Additional fluvoxamine, at the dose of 100 mg/day, was administered for 4 weeks to patients stabilized on risperidone (3-6 mg/day). Mean plasma concentrations of risperidone, 9-OH-risperidone and the active moiety (sum of the concentrations of risperidone and 9-OH-risperidone) were not significantly modified following co-administration with fluvoxamine. After 4 weeks, fluvoxamine dosage was increased to 200 mg/day in five patients and then maintained until the end of week 8. At final evaluation, mean plasma levels of risperidone active moiety were not modified in the six patients who were still receiving the initial fluvoxamine dose, while concentrations increased slightly but significantly (by a mean 26% over pretreatment; P < 0.05) in the subgroup of five subjects treated with a final dose of 200 mg/day. Fluvoxamine co-administration with risperidone was well tolerated and no patient developed extrapyramidal side effects. These findings indicate that fluvoxamine at dosages up to 100 mg/day is not associated with clinically significant changes in plasma risperidone concentrations. However, higher doses of fluvoxamine may elevate plasma risperidone levels, presumably as a result of a dose-dependent inhibitory effect of fluvoxamine on CYP2D6-and/or CYP3A4-mediated 9-hydroxylation of risperidone.     

The CYP2C8 inhibitor gemfibrozil does not increase the plasma concentrations of zopiclone

Objective Zopiclone is a short acting hypnotic, which is metabolised by cytochrome P450 (CYP) 3A4 and 2C8 in vitro. We studied the possible effect of gemfibrozil, an inhibitor of CYP2C8, on the pharmacokinetics and pharmacodynamics of zopiclone.Methods In a randomised 2-phase crossover study, 10 healthy volunteers took 600 mg gemfibrozil or placebo orally twice daily for 3 days. On day 3, each ingested a 7.5 mg dose of zopiclone. Plasma concentrations and urinary excretion of zopiclone and its two primary metabolites, plasma gemfibrozil, and psychomotor performance were measured. The effects of CYP2C8, CYP2C9 and CYP3A4 inhibitors on the depletion of zopiclone (500 nM) were studied in vitro in human liver microsomes.Results The pharmacokinetic variables of the parent zopiclone were not significantly affected by gemfibrozil. However, gemfibrozil raised the mean peak plasma concentration (C_max) of N-oxide-zopiclone (1.6-fold; P<0.001) and that of N-desmethyl-zopiclone (1.2-fold; P<0.001). The mean area under the plasma concentration-time curve () values of N-oxide-zopiclone and N-desmethyl-zopiclone were raised 2-fold (P<0.001) and 1.2-fold (P<0.01), respectively. The renal clearance of N-oxide-zopiclone was reduced by 48% by gemfibrozil (P<0.001). The pharmacodynamic effects of zopiclone, measured using psychometric tests, were not affected by gemfibrozil. In vitro, ketoconazole (1 μM) and itraconazole (8 μM) decreased the elimination rate of zopiclone enantiomers by about 65–95%, while montelukast (16 μM), gemfibrozil (200 μM) and sulfaphenazole (10 μM) had no appreciable effect.Conclusions Gemfibrozil does not increase the plasma concentrations of the parent zopiclone. Accordingly, CYP2C8 does not significantly metabolise zopiclone in vivo. However, as gemfibrozil raises the concentrations of two potentially active metabolites of zopiclone, slightly enhanced effects of zopiclone by gemfibrozil can not be excluded.     

Oral contraceptives increase the plasma concentrations of chlorpromazine

A 21-year-old female inpatient who was enrolled in a population pharmacokinetic study of chlorpromazine was given an oral chlorpromazine dose of 100 mg three times daily, and plasma concentrations of chlorpromazine were measured weekly. This dose was well tolerated during the first week of therapy. In the second week the patient took a combined oral contraceptive; this was followed by severe dyskinesias and tremor. Plasma chlorpromazine levels were found to be about sixfold higher than those in the first week, although the dose of chlorpromazine had not changed. This observation suggests that the oral contraceptive increased the plasma concentration of chlorpromazine.     

Acute risperidone treatment did not increase daily cigarette consumption or plasma levels of cotinine and caffeine: a pilot study

Excessive cigarette smoking and caffeine intake are often seen in schizophrenic patients being treated with antipsychotic drugs, particularly typical antipsychotic drugs. Using nicotine and caffeine sometimes influences psychotic symptoms in these patients. Clozapine is the only antipsychotic drug reported to reduce the amount of cigarette smoking, however, still remains controversial of its efficacy. In the present study, we examined the effect of acute risperidone treatment on the amount of cigarette smoking and plasma levels of cotinine and caffeine in schizophrenic patients. Treatment with risperidone for 4 weeks did not increase daily cigarette consumption or plasma levels of cotinine and caffeine. The results suggest that acute risperidone treatment does not promote the intake of nicotine and caffeine at least by 4 weeks in schizophrenic patients.     

Codeine added to paracetamol induced adverse effects but did not increase analgesia.

1 In a double-blind crossover study identical oral surgical procedures were performed on two separate occasions in 24 outpatients. 2 At one operation they were given tablets containing paracetamol + codeine phosphate (400 mg + 30 mg), and at the other plain paracetamol (400 mg). The day of operation 2 tablets were taken 3, 6 and 9 h after surgery, the following two days 1 tablet four times daily. 3 Several measurements/assessments were recorded for a paired comparison of the postoperative courses. 4 No increase In the analgesic effect could be demonstrated by addition of codeine to paracetamol. 5 On the day of operation 18 patients reported adverse effects like nausea, dizziness and drowsiness with paracetamol + codeine, while only 3 patients experienced side effects with paracetamol alone (P less than 0.001). 6 Measurements revealed almost identical swelling after the two operations. 7 Compared with results obtained in previous studies, the present findings indicate that paracetamol may exert anti-inflammatory activity and reduce postoperative swelling, even when given 3 h after surgery. 8 On the day of operation and the following two days 20 patients preferred the treatment with plain paracetamol, while only 4 favoured paracetamol + codeine (P less than 0.001).     

Relationship between clinical effects of fluvoxamine and the steady-state plasma concentrations of fluvoxamine and its major metabolite fluvoxamino acid in Japanese depressed patients

Objectives

The relationship between clinical effects of fluvoxamine (FLV) and the steady-state plasma concentrations (Css) of FLV and its major metabolite fluvoxamino acid (FLA) was studied.

Methods

The subjects were 49 Japanese patients with major depressive disorder receiving FLV 200 mg/day for 6 weeks. Depressive symptoms and side effects were evaluated by the Montgomery Åsberg Depression Rating Scale (MADRS), and the UKU Side Effect Rating Scale, respectively. The Css of FLV and FLA were measured by HPLC, and the CYP2D6 genotyping was performed by PCR methods.

Results

The Css of FLV and FLV+FLA showed significant negative correlations with the final MADRS score. The Css of FLV, FLA and FLV+FLA were significantly higher in the responders (final MADRS score ≤10) than in non-responders. The proportion of responders was significantly higher in the patients with the Css of FLV, FLA and FLV+FLA above 150, 55 and 180 ng/ml, respectively. In the multiple regression, the Css of FLV+FLA showed a significant negative correlation with the final MADRS score. In the logistic regression, the Css of FLA had a significant effect on the differentiation of responders from non-responders. The incidence of side effects was low, and the development of nausea, the most frequent one, was not dependent on any Css. The number of mutated CYP2D6 alleles causing absent or decreased enzyme activity was not related to the therapeutic response or development of nausea.

Conclusions

The present study suggests that there is a therapeutic threshold for the Css of FLV and probably also for the Css of FLA, and the Css of FLV+FLA above 180 ng/ml best predicts a good therapeutic response.     

Grapefruit juice can increase the plasma concentrations of oral methylprednisolone

Objective: To investigate whether the pharmacokinetics of orally administered methylprednisolone and plasma cortisol concentrations are affected by administration of grapefruit juice. Methods: In a randomised, two-phase, cross-over study, ten healthy subjects received either 200 ml double-strength grapefruit juice or water three times a day for 2 days. On day 3, 16 mg methylprednisolone was given orally with 200 ml grapefruit juice or water. Additionally, 200 ml grapefruit juice or water was ingested 0.5 h and 1.5 h after methylprednisolone administration. Plasma concentrations of methylprednisolone and cortisol were determined using liquid chromatography/mass spectrometry (LC/MS/MS) over a 47-h period. Results: Grapefruit juice increased the total area under the plasma methylprednisolone concentration–time curve (AUC_0–∞) by 75% (P < 0.001) and the elimination half-life (t _1/2) of methylprednisolone by 35% (P < 0.001). The peak plasma concentration of methylprednisolone (C_max) was increased by 27% (P < 0.01). Grapefruit juice delayed the time to the C_max from 2.0 h to 3.0 h (P < 0.05). There was no significant difference in the plasma cortisol concentrations, measured after methylprednisolone administration, between the water and grapefruit juice phases. However, grapefruit juice slightly decreased the morning plasma cortisol concentrations before methylprednisolone administration (P < 0.05). Conclusions: Grapefruit juice given in high amounts moderately increases the AUC_0–∞ and t _1/2 of oral methylprednisolone. The increase in t _1/2 suggests that grapefruit juice can affect the systemic methylprednisolone metabolism. The clinical significance of the grapefruit juice–methylprednisolone interaction is small, but in some sensitive subjects high doses of grapefruit juice might enhance the effects of oral methylprednisolone. Received: 17 February 2000 / Accepted in revised form: 9 May 2000     

Solid-phase microextraction for the assay of levomepromazine in human plasma

Solid-phase microextraction (SPME) was investigated as sample preparation for the assay of the neuroleptic drug levomepromazine in human plasma. A mixture of human plasma, water, chloramitriptyline as internal standard, and aqueous NaOH was extracted with a 100-microm polydimethylsiloxane (PDMS) fiber (Supelco). The desorption of the fiber was performed in the injection port of a gas chromatograph at 260 degrees C [HP 5890; BPX-5 (SGE): 30 m x 0.53 mm ID, 1-microm film capillary; nitrogen-phosphorus selective detection]. As repeatedly found for SPME analysis of drugs in plasma, the recovery was low (i.e., 7% for levomepromazine). However, the analyte and internal standard were well separated and the calibration was linear from 5 to 180 ng/mL. The within-day precision was 2%, 4%, and 19% at concentrations of 160 ng/mL, 80 ng/mL, and 5 ng/mL, respectively. The between-day precision was 3%, 7%, and 19%, respectively. The limit of determination was 5 ng/mL. The comparison with an established liquid-liquid extraction gas-liquid chromatography method revealed good agreement for spiked samples and patient samples. No interfering peaks of drugs coadministered with levomepromazine or of endogenous substances were found. It is concluded that the method can be used in the therapeutic drug monitoring and clinical toxicology of levomepromazine.     

Cimetidine does not increase alpha 1-acid glycoprotein serum concentrations.

Serum concentrations of alpha 1-acid glycoprotein (AAG) were studied in six healthy, male volunteers before and after administration of cimetidine, 300 mg by mouth every 6 h for 2 days. Serum AAG concentrations were measured at three different times during the first day, i.e. before cimetidine administration, and on the fourth and sixth days, after commencing cimetidine administration. Neither cimetidine treatment nor time of day contributed significantly to differences in serum AAG concentration, and no interaction of these factors was observed. It is concluded that altered drug-AAG binding as a result of cimetidine therapy is not likely to be an important mechanism contributing to cimetidine drug interactions.     

反相高效液相色谱法测定人血浆中马来酸氟伏沙明浓度

目的:建立高效液相色谱法测定人血浆中马来酸氟伏沙明浓度。方法:以安定为内标,待测血浆样品经乙醚萃取后,用高效液相色谱法紫外进行检测。色谱柱为 Discovery~(?)RP Amide C_(16)(5μm,150 mm×4.6 mm),柱温35 ℃;流动相为乙腈-0.05 mol·L~(-1)醋酸铵(40:60),流速1.2 mL·min~(-1);检测波长250 nm。结果:血浆中马来酸氟伏沙明浓度线性范围为1.56～99.6 ng·mL~(-1),最低定量浓度1.56 ng·mL~(-1);回收率为95.7%～106.1%。结论:本法分离效果良好,灵敏度高,回收率高,能满足于人体血药浓度测定及药代动力学研究。     

Elevated plasma levels of clozapine after concomitant use of fluvoxamine

Selective serotonin reuptake inhibitors can be added to clozapine therapy in order to treat remaining negative symptoms and obsessive compulsive symptoms. The present case report describes a 44yearold man exhibiting extremely elevated plasma levels of clozapine after the addition of fluvoxamine, up to 4160 mcg/l. The elevated plasma levels of clozapine, which were discovered 6 months after the SSRI was added, is likely to be caused by a drugdrug interaction. Clozapine is a substrate of CYP 1A2 and is predominantly metabolised in the liver. Of the SSRIs, fluvoxamine is one of the most potent inhibitors of the isoenzyme CYP 1A2. This case serves to emphasise the need for continuous attention to drugdrug interactions, especially when they might be easily overlooked due to the lack of clear symptoms.     

Individualised aminoglycoside dosage based on pharmacokinetic analysis is superior to dosage based on physician intuition at achieving target plasma drug concentrations.

1. A prospective randomised trial was conducted to compare aminoglycoside dose prediction based on individually measured pharmacokinetic data, with dosage based on physician intuition. 2. After 2 days of therapy more patients in the pharmacokinetic group had achieved both peak (6-10 mg 1(-1] and trough (1-2 mg 1(-1] target plasma concentrations (P = 0.007), peaks alone (P = 0.01) and troughs alone (P = 0.01). Their mean (s.e. mean) peak concentration was 6.49 +/- 0.39 mg 1(-1) compared with 4.27 +/- 0.52 mg 1(-1) in the control group (P = 0.001), with trough concentrations of 1.44 +/- 0.22 mg 1(-1) and 0.94 +/- 0.21 mg 1(-1) respectively (P = 0.054). 3. After 5 days of therapy, peak and trough concentrations were still significantly higher in the pharmacokinetic group despite empirical dose adjustment (P = 0.01 and P = 0.013 respectively). 4. The mean (s.e. mean) daily dose of aminoglycoside was higher in the computer group (312 +/- 17 mg vs 203 +/- 13 mg, P = 0.001). 5. These findings suggest that dose estimation based on measured pharmacokinetic parameters is superior at achieving target plasma drug concentrations.