Development and validation of a gas chromatographic-mass spectrometric method for quantitative determination of perphenazine in rabbit plasma after sublingual administration.

Perphenazine is a phenothiazine-type antipsychotic that is a potential candidate for sublingual administration due to its extensive first-pass metabolism. In this study, a gas chromatographic-mass spectrometric method was developed for quantification of perphenazine in rabbit plasma after sublingual administration. The plasma samples were purified by mixed-mode solid phase extraction with good recovery (>83%). The method was linear (r(2)>0.99) over a range of 2-64 ng/ml, with a lower limit of quantification of 2 ng/ml. The accuracy was 100+/-4%, and the within-day and between-day precisions were <6.8% R.S.D. and <14% R.S.D., respectively. Perphenazine was stable in stock solutions and plasma. The method was successfully applied for analysing perphenazine in plasma after sublingual administration to rabbits.

HPLC quantification of perphenazine in sheep plasma: application to a pharmacokinetic study.

A high performance liquid chromatographic (HPLC) method for the determination of perphenazine (PPZ) in sheep plasma was developed and validated. The separation was achieved using a 5 microm C18 column (125 mm x 4 mm) with a mobile phase composed of acetonitrile and an aqueous solution of H(3)PO(4) and TBA (inverse gradient). The flow rate was 1.5 mL/min and the UV detection was performed at 258 nm. The method was validated with respect to linearity, intra and inter-day precision and accuracy, limit of quantification, limit of detection and storage stability. This method was used to perform a pilot pharmacokinetic study of PPZ after subcutaneous administration to one ewe.

Quantitation of Haloperidol, Fluphenazine, Perphenazine, and Thiothixene in Serum or Plasma Using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS).

Haloperidol, fluphenazine, perphenazine, and thiothixene are "typical" antipsychotic drugs that are used in the treatment of schizophrenia and other psychiatric disorders. The monitoring of the use of these drugs has applications in therapeutic drug monitoring and overdose situations. LC-MS/MS is used to analyze plasma/serum extracts with deuterated analog of imipramine as the internal standard to ensure accurate quantitation and control for any potential matrix effects. Positive ion electrospray is used to introduce the analytes into the mass spectrometer. Selected reaction monitoring of two product ions for each analyte allows for the calculation of ion ratios which ensures correct identification of each analyte, while a matrix-matched calibration curve is used for quantitation.

Facile synthesis of magnetic molecularly imprinted polymer: Perphenazine template and its application in urine and plasma analysis.

Synthesis of magnetic iron oxide nanoparticles and its surface modification with methacrylic acid (MAA) was performed simultaneously by adding Fe(2+)/Fe(3+) to an alkaline MAA solution under nitrogen atmosphere. MAA coated magnetite (Fe3O4@MAA) has abundant reactive double bonds on the surface that can initiate polymerization. Magnetic molecularly imprinted polymers (MMIPs) were synthesized through distillation-precipitation polymerization of MAA as monomer, perphenazine (PPZ) as template, and ethylene glycol di-methacrylate (EGDMA) as cross linker on Fe3O4@MAA, with concise control of experimental conditions in about 90min. The produced super paramagnetic MMIPs can be separated from the solution in the presence of external magnetic field in less than 1min. Characterizations of the synthesized particles were performed by electron microscopes, thermo-gravimetric analysis (TGA), vibrating sample magnetometer (VSM), Fourier transform infrared (FT-IR) spectroscopy, and BET. The data showed that Fe3O4@MAA was well encapsulated in the polymer shell. The MMIPs showed high porosity. Moreover, MMIPs were used for rapid pre-concentration and separation of PPZ in human plasma and urine without any dilution and pretreatments using high performance liquid chromatography equipped with a photo diode array detector (HPLC-PDA). The calibration curve in urine and plasma has shown the same slope as the external calibration curve. Linear range of 20-5000ngmL(-1), and a detection limit of 5.3ngmL(-1) was obtained. The results showed 97.92% recovery along with the relative standard deviation of 6.07% (n=6) for 1µgmL(-1) PPZ. Pre-concentration factor was 13. The MMIPs adsorbed PPZ in 1min and then desorbed it by MeOH:HOAc in 2min.

Low serum neuroleptic levels predict relapse in schizophrenic patients.

Relapse occurs in a substantial proportion of schizophrenic patients treated with neuroleptics. The determinants of relapse have been elusive. In our study, low serum neuroleptic levels identified patients who had a relapse during a six-month period. Neuroleptic levels were measured by radioreceptor assay in 61 schizophrenic men and their clinical status was assessed in the subsequent six months. Ten patients had relapses, four showing a worsening of chronic psychotic symptoms and six showing eruption of psychotic symptoms after a period of remission. These ten patients had significantly lower normalized neuroleptic levels than those whose conditions remained stable. The lowest neuroleptic levels occurred in patients who had relapses after a period of remission. Serum neuroleptic levels in drug-responsive patients appear to be a critical determinant of remission. If these observations are replicated, a rational basis may be provided for prescribing and monitoring neuroleptic treatment and perhaps for preventing relapse.

Steady-state serum concentrations of the neuroleptic perphenazine in relation to CYP2D6 genetic polymorphism.

Steady-state serum concentration to dose ratios of the neuroleptic agent perphenazine were related to CYP2D6 metabolizer status for 96 psychiatric inpatients: 88 extensive metabolizers and eight poor metabolizers. The median concentration per dose of the poor metabolizer group (0.195 nmol/L per milligram) was about twice the median (0.098 nmol/L per milligram) of the 56 extensive metabolizers without interacting medicine (p < 0.01). The rest of the extensive metabolizers (n = 32), who were comedicated with drugs that compete with perphenazine for metabolism by CYP2D6, had an intermediate median value of 0.140 nmol/L per milligram. The range of concentration/dose values for the total extensive metabolizer group extended from 0.025 to 0.688 nmol/L per milligram, that is, an almost thirtyfold variation. The concentration/dose range of the eight poor metabolizer subjects was 0.096 to 0.750 nmol/L per milligram. Serum levels not corrected for dose overlapped to a large degree among the groups, with a total range from 0.5 to 12 nmol/L. This study points toward a limited information value of CYP2D6 genotyping in the context of therapeutic drug monitoring of perphenazine.

Plasma level monitoring of antipsychotic drugs.

Psychotic patients treated with identical doses of antipsychotic drugs have been shown to have great interindividual differences in their steady state plasma concentration. Therefore, monitoring treatment by dosage adjustment alone is of little value. If antipsychotic blood levels can be related to clinical response then their routine measurement may well result in well defined guidelines to individualised optimal dosage. Despite the considerable effort expended in this field and the many interesting testable hypotheses generated, little substantive evidence for an acceptable plasma level monitoring guide has been reported to date. Work on metabolite level profiles, intra- and extracellular drug concentration differences, more detailed clinical rating scales, and improved experimental design, all show great promise for the future. Investigation of the pharmacokinetics and the elucidation of the often complex metabolic pathways of individual antipsychotic drugs are generating the data base required for the rational pharmacotherapy of these most severely ill patients. Until more data are available, routine monitoring of antipsychotic drug plasma levels remains of research interest.

Binding of phenothiazine neuroleptics to plasma proteins.

The binding of chlorpromazine, trifluoperazine, perphenazine, desipramine, propranolol and salicylic acid to human plasma and isolated plasma proteins was studied using equilibrium dialysis. Unlike salicylic acid, an acidic compound only bound to human serum albumin, the basic drugs were bound to all plasma protein fractions studied (albumin, alpha 1-acid glycoprotein, lipoproteins, gamma-globulins) with alpha 1-acid glycoprotein an important binding protein for each of them. The interaction of chloropromazine, perphenazine and trifluoperazine with alpha 1-acid glycoprotein was studied using Scatchard analysis. The primary class of binding sites revealed a low capacity (n = 0.5-1) and a high affinity (K = 10(5)-10(6) M-1) for the phenothiazines. The interaction of chlorpromazine, perphenazine and trifluoperazine with albumin was of the high capacity-low affinity type. In binding studies using plasma obtained from healthy volunteers, alpha 1-acid glycoprotein was found to be a very important binding protein for the basic drug studied with the exception of desipramine. This shows that results derived from binding studies using isolated protein fractions should be interpreted with caution.

The relationship between blood perphenazine levels, early resolution of psychotic symptoms, and side effects.

Serum perphenazine concentrations and early resolution of psychosis were examined to determine if blood level monitoring could be used to maximize drug efficacy while limiting extrapyramidal side effects (EPS). Sixty-six acutely psychotic inpatients were given perphenazine 0.5 mg/kg/day for 10 days, and their response was rated blind to blood level. Although 36 of 66 patients showed resolution of psychosis, neither perphenazine nor N-dealkylated perphenazine levels were related to global response or to Brief Psychiatric Rating Scale (BPRS) totals. Improvement in two individual BPRS items (hallucinations and conceptual disorganization) was related to serum perphenazine levels and suggestive of a lower therapeutic threshold of 0.8 ng/mL. Perphenazine level was not correlated with EPS; but benztropine, given only if required for serious EPS, was more likely to be used when perphenazine levels were elevated. The data suggest that higher perphenazine levels were no more effective than moderate levels but that higher levels may be associated with increased EPS; the data also suggest that individual symptoms rather than global response were associated with a lower therapeutic perphenazine threshold.

Plasma concentrations of perphenazine and its sulphoxide metabolite during continuous oral treatment.

Plasma concentrations of perphenazine (PPZ) (Trilafon) and perphenazinesulphoxide (PPZSO) were estimated during a 2-week period in 16 patients receiving peroral PPZ treatment for various psychotic disorders. The results demonstrated that the average concentration of three plasma samples was a reasonably good expression of the steady-state plasma level despite a great fluctuation in the concentration from sample to sample. Increased doses in three of the patients resulted in disproportionate increases in the plasma levels. Neurological side effects were recorded and their relation to plasma concentrations are discussed.

Plasma levels of perphenazine (Trilafon) related to development of extrapyramidal side effects.

Thirteen acute psychotic patients received continuous oral treatment with perphenazine for a period of 8 weeks. Blood samples for quantification of perphenazine, perphenazine sulphoxide and prolactin were drawn twice weekly. Simultaneously, the therapeutic outcome and the degree of extrapyramidal side effects were recorded. The following conclusions were made: 1. In accordance with results achieved in one of our earlier investigations, a high risk of provoking extrapyramidal side effects was associated with plasma levels of perphenazine exceeding about 3 nmol/l. 2. An excellent therapeutic outcome was associated with plasma concentrations of perphenazine above 1.5 nmol/l. 3. Plasma concentrations of perphenazine and prolactin were poorly correlated to each other (R = 0.49). 4. A significant correlation (R = 0.85) was shown between the scores for the Brief Psychiatric Rating Scale and the Comprehensive Psychopathological Rating Scale.

Perphenazine decanoate and cis(z)-flupentixol decanoate in maintenance treatment of schizophrenic outpatients. Serum levels at the minimum effective dose.

Two groups of schizophrenic outpatients were treated with perphenazine decanoate (N = 20) and cis(z)-flupentixol decanoate (N = 24) respectively. Every 3 months the dose was gradually reduced until symptoms appeared that were suggestive of a prodromal phase of a psychotic episode. A slightly higher dose was then promptly reinstituted (the minimum effective dose). At each dose level, two blood samples were drawn for determination of serum concentration. The mean minimum effective dose of perphenazine decanoate was 99.3 mg/2 weeks (range 21.6-270.5), while the mean minimum effective dose of cis(z)-flupentixol decanoate was 60 mg/2 weeks (range 20-250). The corresponding mean serum level of perphenazine decanoate was 7.3 nmol/l (range 2.0-18.1) and of cis(z)-flupentixol decanoate 7.8 nmol/l (range 1.2-37.0). There was a significant correlation between the administered doses and the corresponding serum levels for both drugs (r = 0.87, P less than 0.01). A weak positive correlation was found between serum levels at the minimum effective dose and symptom intensity (BPRS total score) (r = 0.53, P less than 0.02) for perphenazine, but not cis(z)-flupentixol. No correlation was found between serum levels and side effects or length of neuroleptic treatment. It is concluded that the serum drug concentrations corresponding to the lowest effective dose are so variable that routine serum level monitoring may be of limited value in the long-term maintenance treatment of schizophrenia.

Therapeutic advantages of monitoring plasma concentrations of perphenazine in clinical practice.

Two hundred and twenty-eight acute paranoid psychotic in-patients received continuous treatment with perphenazine for a period of at least 5 weeks, before blood samples were taken to determine perphenazine plasma levels and conclusions regarding therapeutic efficacy and motor side effects. Patients with plasma concentrations within the range of 2-6 nmol/l showed an excellent antipsychotic response, concomitantly with a low incidence of extrapyramidal side effects. However, patients with plasma levels below or above this range either demonstrated a poor therapeutic response or a high degree of side effects respectively. The results indicate that with increasing age significantly lower doses of perphenazine are required to ensure an optimal clinical response. No difference, however, was seen between sexes with regard to dose response.

A cross-validation study on the relationship between central D2 receptor occupancy and serum perphenazine concentration.

RATIONALE: There is a need for laboratory measures to guide clinical treatment with antipsychotic drugs. For serum concentration of the classical antipsychotic drug perphenzine an optimal therapeutic interval has been identified between 2 and 6 nmol/l. Positron emission tomography (PET) studies have suggested an optimal interval in central dopamine D2 receptor occupancy of between 65 and 80%. OBJECTIVES: The aim of the present cross-validation study in clinically stable schizophrenic patients was to examine the relationship between the optimal interval in central D2 receptor occupancy and the therapeutic window for serum perphenazine concentration. METHODS: Six patients who had responded to maintenance treatment with perphenazine decanoate were examined with PET and [11C]raclopride during steady-state conditions. Blood sampling was carried out for minimum serum perphenazine concentration and during the PET examination. RESULTS. The serum perphenazine concentration was between 1.8 and 9 nmol/l and the D2 receptor occupancy varied between 66 and 82%. The relationship between central receptor occupancy and serum drug concentration was curvilinear. Mild extrapyramidal symptoms were present in the patient with the highest D2 receptor occupancy. CONCLUSIONS. The previously suggested therapeutic window in serum perphenazine concentration is in good agreement with the optimal interval suggested for central D2 receptor occupancy. Serum concentrations at low dose levels may therefore serve as a useful tool in clinical monitoring of antipsychotic drug treatment.

Neuroleptic plasma levels.

There is enormous variation in plasma levels of most neuroleptics in patients on the same dose. Much of the past research on the relation between plasma levels of antipsychotic drugs and clinical change, however, has been difficult to interpret. It does appear that decreased bioavailability, at least in public institutions, is rarely the cause of treatment failure. Aberrantly low plasma levels are more likely due to surreptitious noncompliance or drug interactions with enzyme inducers such as carbamazepine. Therapeutic plasma level ranges, in which good antipsychotic effect occurs without undue side effects, have been tentatively identified for perphenazine, haloperidol, fluphenazine, and chlorpromazine. The extent to which aberrantly high plasma levels are associated with inferior antipsychotic response is unclear. Antipsychotic plasma levels may be most useful when the distinction between side effects and worsening psychosis is unclear. The utility of high neuroleptic plasma levels in the treatment-resistant patient is unclear.

The relationship between perphenazine plasma levels and clinical response in acute schizophrenia.

1. Twelve patients with schizophrenia according to RDC participated in a double-blind study, comparing two dose levels of perphenazine, 16 or 32 mg, during four weeks. 2. The patients were assessed with a subscale to CPRS and global scores, measuring improvement of regular intervals during four weeks. 3. Blood samples for assay of plasma perphenazine were collected once a week. 4. These results are in many respects in accordance with earlier published data with perphenazine, that is a good clinical response is achieved with a plasma concentration of perphenazine between 1-5 nmol/L. 5. No incidence of severe adverse symptoms were observed.

Logarithmic transformation in bioequivalence: application with two formulations of perphenazine.

The rationale for using the logarithmic transformation on concentration-dependent pharmacokinetic parameters a priori is presented. This rationale is based on theoretical pharmacokinetic and statistical grounds, but is also applicable to the practice of physicians in dealing with variations of drug treatment within and between patients. The implications of the transformation on data analysis, specifically analysis of variance, and estimation and inference from the analysis as it pertains to bioequivalence decisions are explored. Implementation of the transformation is shown, with an example of two perphenazine formulations in a single-dose crossover study. It is concluded that the transformation has to be accepted on theoretical grounds because sample sizes are too small in bioequivalence studies and too susceptible to extreme values to state with any certainty the actual distribution of pharmacokinetic parameters or their differences within a subject.

Perphenazine distribution in a postmortem case.

The case of a 34-year-old, mentally challenged, Caucasian female found dead in a group home is presented. Empty containers of perphenazine and valproic acid were found next to her bed. The perphenazine had been prescribed to another patient. No anatomic cause of death was determined at autopsy. Comprehensive testing of the heart blood for ethanol and drugs identified perphenazine at a concentration of 4.4 mg/L and valproic acid at a concentration of 950 mg/L. The distribution of perphenazine in other specimens was consistent with previously reported phenothiazine cases. The medical examiner ruled that the cause of death in this case was multiple drug intoxication and the manner of death was suicide.

[Relations between the levels of neuroleptics and the doses, the therapeutic effects and the side effects]. / Relation des taux des neuroleptiques avec les doses, les actions thérapeutiques et les effets secondaires.

The mass fragmentography and the gas-liquid chromatography are available actually for quantitation of very low levels of neuroleptics. The Radio-immunological assay is full of promise. Their plasma levels are not correlated with their dosage in a man to another, but, for some of them, there is lineary relation for one person. A correlation between their levels and their clinical efficacy is not certainly demonstrated for thioridazine and non transformed chlorpromazine; it could be possible for his sulphoxide metabolite and for butaperazine. The sides-effects are relatively correlated with their levels in the begining of the therepautic. The antiparkinsonian drugs, the antidepressants and the lithium could influenced them.