Antipsychotic Drug Fluphenazine against Human Cancer Cells.

Drug repurposing is a strategy that can speed up and find novel clinical uses for already-approved drugs for several diseases, such as cancer. This process is accelerated compared to the development of new drugs because these compounds have already been tested in clinical trials and data related to their pharmacokinetics is already described, reducing the costs and time associated with the development of new anticancer therapeutics. Several studies suggest that the repurposing of fluphenazine for cancer therapy may be a promising approach, as this drug proved to reduce the viability of diverse cancer cell lines. In this review, intensive research of the literature was performed related to the anticancer potential of fluphenazine in different human cancer cells. We have found several research articles on the cytotoxic effect of fluphenazine in lung, breast, colon, liver, brain, leukemia, oral, ovarian, and skin cancer and have summarized the main findings in this review. Taken together, these findings suggest that fluphenazine may regulate the cell cycle, reduce cell proliferation, and cause apoptosis in several types of cancer cells, besides being an established calmodulin inhibitor. It was also found that this drug is able to target cancer-related proteins, such as ABCB1 and P-glycoprotein as well as to regulate the Akt and Wnt signaling pathways. Some studies also refer this drug causes DNA alterations and interferes with cell invasion and migration ability as well as with ROS generation. Collectively, these results imply that fluphenazine may be a favorable compound for further research in oncologic therapy.

Risks versus benefits of different types of long-acting injectable antipsychotics.

Since their introduction into clinical practice in the early 1960s, long-acting depot antipsychotics have been widely used as maintenance therapy for patients with schizophrenia. The improved pharmacokinetics of injectable long-acting antipsychotic therapies have provided more reliable drug delivery and reduced differences in peak and trough plasma levels of the drug. Studies that have compared short-acting oral antipsychotics with long-acting injectable antipsychotics, although imperfect, support injectable antipsychotics as having real benefit over oral antipsychotics on patient outcome owing largely to improved adherence. If patients forget or refuse to take their prescribed oral medications, weeks or months may go by before they experience an exacerbation; the effects of nonadherence become apparent too late to preempt the problem. On the other hand, if a patient fails to show up for an injection, the problem of nonadherence can be immediately addressed. When injectable medication is combined with an active psychosocial treatment program that will respond assertively to nonadherence, relapse rates may be reduced. By preventing or delaying relapse, consistent treatment can improve the patient's quality of life and lead to an overall reduction in the cost of care.

19F nuclear magnetic resonance spectroscopy of neuroleptics: the first in vivo pharmacokinetics of trifluoperazine in the rat brain and the first in vivo spectrum of fluphenazine in the human brain.

In vivo 19F nuclear magnetic resonance (19F-NMR) spectroscopy measurements of trifluorinated neuroleptics (fluphenazine--FL and trifluoperazine--TFP) were made in rat brain as well as in human brain. Animal studies were performed at 4.7 Tesla. Using rats that have been treated with FL over a period of 3 weeks, a NMR signal could be detected within 8-15 min. Following a single intravenous injection of TFP, brain levels could be monitored with a time resolution of 30 min. The first 19F-NMR examination of a patient was made at 3.0 Tesla 1 day after injection of FL decanoate (37.5 mg) in the course of which a signal could be detected within 30 min. It is expected that 19F-NMR will become an important tool in psychopharmacological research.

Neuroleptic augmentation with alprazolam: clinical effects and pharmacokinetic correlates.

Alprazolam added to stable doses of neuroleptics in nine schizophrenic patients was associated with a 20%-30% mean reduction in positive and negative symptoms, although clinical response was variable and in some patients particularly brisk. The authors examined the possibilities of a pharmacokinetic effect of alprazolam on neuroleptic plasma levels and of a clinical effect of alprazolam. The modest increase in mean neuroleptic plasma levels did not correlate with clinical change, but those patients with the highest alprazolam plasma levels tended to show more robust clinical responses.

Distribution of fluphenazine and its metabolites in brain regions and other tissues of the rat.

Rats were given 5, 10, or 20 mg/kg oral doses of fluphenazine (FLU) dihydrochloride daily for 15 days. FLU and its sulfoxide (FL-SO), 7-hydroxy (7-OH-FLU) and N4'-oxide (FLU-NO) metabolites were assayed in plasma, liver, kidney, fat, whole brain, and brain regions by specific and sensitive radioimmunoassays (RIA). All metabolites were detected in tissues at higher levels than in plasma, and the levels increased with dose. FLU was 10- to 27-fold higher in brain regions than in plasma. Brain vs plasma levels of FLU correlated more closely than levels of its metabolites. Liver contained the highest levels of all analytes at all doses. FLU-SO was the major metabolite in brain regions (24% to 96% of FLU) and accumulated in fat 43 to 75 times more than FLU. Levels of 7-OH-FLU and FLU-NO were very low in brain (1% to 20% of FLU). FLU-SO and FLU-NO had only 1% to 3% the affinity for D1 and D2 receptors, but 7-OH-FLU had 20% the D2 and 5% the D1 affinity of FLU. The low affinity for dopamine receptors and low brain-levels of metabolites of FLU indicate that they are not likely to contribute importantly to pharmacologic responses of FLU. Also, the estimated relative "activity factor" for these compounds in the brain indicated that the contribution to neuropharmacologic activity by metabolites is less than 1% of FLU. Consequently, clinical monitoring of plasma FLU alone may be sufficient.

Human metabolism of phenothiazines to sulfoxides determined by a new high performance liquid chromatography--electrochemical detection method.

The metabolism of phenothiazine drugs may contribute to both their therapeutic and toxic actions by production of active metabolites in vivo. Idiosyncratic reactions or treatment failure may be a consequence of differing patterns of metabolism in different patients. In this report, a modification of our method for the detection of metabolites of phenothiazines is described, which also permits the simultaneous determination of sulfoxide metabolites in human plasma. Application of this method to human plasma identifies marked individual differences in patterns of phenothiazine metabolism.

Changing from oral to depot fluphenazine.

Many of the problems that occur when patients are changed from oral to depot fluphenazine are caused by the high dosages resulting from the formulas used for dose conversion. The authors propose a new method based on recent information on the pharmacokinetics of fluphenazine decanoate, low-dose treatment strategies in schizophrenia, and their own clinical experience.

Pharmacokinetic and pharmacodynamic studies on high doses of fluphenazine.

Six chronic schizophrenics--earlier refractory to recommended doses of neuroleptic drugs but eventually responding to 250 mg fluphenazine heptanoate weekly--participated in a pharmacokinetic study. Five out of the six patients showed rather constant steady state plasma fluphenazine values on a 250 mg depot weekly. After depot drug withdrawal, the single oral dose pharmacokinetics on 400 mg fluphenazine showed the same variations in Cmax, tmax, t 1/2 and AUC as are observed when recommended doses of fluphenazine are used. We thus could not demonstrate any dose-dependent pharmacokinetics on high oral fluphenazine doses. In half the patients, a biphasic decay in the plasma concentration curve indicated at least two compartments. The patients were then studied for up to 2 years on 200-500 mg fluphenazine as a single daily dose. The fluphenazine plasma levels were rather constant in the individual patients during this period. The plasma prolactin values were related to the fluphenazine values even in the high value area, thus showing a persistent pharmacodynamic variation capacity. The clinical part of the study did not show any relevant findings.

Variation in the single dose pharmacokinetics of fluphenazine in psychiatric patients.

The single dose pharmacokinetics of fluphenazine (2 x 5 mg tablets, Prolixin) were studied in 21 drug free male psychiatric patients (12 black, 9 white). Plasma samples were harvested over a period of 48 h while the patients were on a strictly controlled diet. The results showed wide interpatient variations in all pharmacokinetic parameters including Cmax, AUC, apparent oral clearance, and elimination half-life. It was determined for each of these parameters that the geometric mean gave a better estimate of central tendency than the corresponding arithmetic mean and the distribution was skewed and leptokurtotic. There was no significant difference between blacks and whites in any pharmacokinetic parameter examined. Considerable variations and marked undulations in the elimination portion of the plasma concentration versus time profiles were evident, possibly indicating biliary recycling of the drug. These undulations made it difficult to determine elimination rate constants for several of the patients. Hydrolysis or plasma samples from one patient demonstrated that the conjugate(s) of fluphenazine was present in three to four times the concentration of the unchanged drug.

Comparative study of the pharmacokinetics of zuclopenthixol decanoate and fluphenazine decanoate.

Seventeen outpatients were treated with depot neuroleptics, zuclopenthixol decanoate in Viscoleo or fluphenazine decanoate in sesame oil, with dosage intervals of 3 weeks. During the 4th, 6th, and 8th dosage interval blood samples were drawn in oxalated tubes. Plasma concentrations of the active neuroleptic drugs, zuclopenthixol and fluphenazine, were determined by high performance liquid chromatography. The concentrations indicated some interindividual as well as intraindividual variations. For zuclopenthixol the maximum concentration was most often seen at day 7 after injection, whereas the kinetics of the fluphenazine concentrations was more variable. There was an indication of more fluctuation in the 4th dosage interval than in the 8th dosage interval, possibly due to the fact that steady state has not yet been achieved at the 4th dosage interval.

Pharmacokinetics of haloperidol and fluphenazine decanoates in chronic schizophrenia.

In a double-blind comparison of haloperidol decanoate and fluphenazine decanoate given 4-weekly for 60 weeks as maintenance therapy in 38 chronic schizophrenic in-patients, plasma haloperidol, fluphenazine and prolactin levels were measured at regular intervals by radioimmunoassay. After the first injection, the mean plasma haloperidol level was highest at week 1 and fell gradually towards week 4. Mean pre-dose haloperidol levels changed little after week 8. Results suggested an absorption half-life of 4 weeks, although, in three cases steady state was only achieved after 11 monthly injections. Steady state levels of both haloperidol and fluphenazine correlated highly with dose. In two sub-groups observed at steady state, both drugs produced a biphasic pattern of plasma drug concentration between injections, a rapid rise on day 1 followed by stable elevated levels and a gradual return to pre-injection concentration by the end of week 4. In the fluphenazine sub-group there was a second peak on day 7 and a steeper decline, so that the mean area-under-curve in week 4 was 64% of that in week 1. Drug injections at steady state induced an increase in prolactin secretion in all of the fluphenazine sub-group and in half of those receiving haloperidol. Plasma prolactin changes resembled those for drug concentrations, but differences in times of peaks on day 1 resulted in weak correlations. Fluphenazine appeared more potent than haloperidol in provoking prolactin secretion.

Fluphenazine levels during maintenance treatment of recent-onset schizophrenia: relation to side effects, psychosocial function and depression.

RATIONALE: The utility of fluphenazine levels during maintenance treatment of schizophrenia is still unclear. OBJECTIVES: This study investigated the relationship between fluphenazine levels and a variety of clinical measures during maintenance treatment of schizophrenia. METHODS: Fluphenazine levels, side effects, depression and psychosocial outcome were measured at five time points over approximately 1 year in 59 recent onset schizophrenic patients treated with a maintenance dose of injectable fluphenazine decanoate. Negative symptoms were evaluated at the 1-year endpoint. RESULTS: Fluphenazine levels showed marked intraindividual variability even when measurements were restricted to the second 6 months of treatment, by which time steady state levels should have been achieved. No consistent relationship was found between fluphenazine levels and any of the outcome measures. CONCLUSIONS: The results of this study suggest that fluphenazine plasma levels do not routinely add relevant clinical information beyond that of dose in evaluating potential side effects or negative consequences during maintenance treatment with the decanoate form of the medication.

Fluphenazine decanoate. Its steady-state pharmacologic profile and relationship to tardive dyskinesia.

A sensitive radioimmunoassay was developed to determine the steady-state, fixed-dose pharmacokinetic profile of fluphenazine decanoate in nine outpatients. To see if neuroleptic blood levels measured by this assay correlated with a clinical event, we performed a cross-sectional study of fluphenazine blood levels in 11 patients with and 17 patients without tardive dyskinesia. The results do not support the hypothesis that fluphenazine decanoate serum levels correlate with TD occurrence.

The determination of the steady-state pharmacokinetic profile of fluphenazine decanoate by gas chromatography/mass spectrometry detection.

This study uses the highly sensitive method of gas chromatography/mass spectrometry to compare the basic steady-state pharmacokinetic parameters of two fluphenazine decanoate formulations. Sixteen stable outpatients participated in a two-way crossover design study of the bioavailability of a new formulation of FPZ Dec, i.e., 10 mg/ml, to the standard 25 mg/ml formulation. When compared to a 1 ml injection of the standard formulation (25 mg/ml) over a two-week, steady-state period, we found bioequivalence as evidenced by similar mean areas under the curve (hrs x ng/ml). We did find that the injection volume of the same dose (2.5 ml of a 10 mg/ml formulation) results in a statistically significantly higher maximum serum level of parent fluphenazine. A tendency toward faster time to peak level was observed with the 10 mg/ml formulation but the difference was not statistically significant. Both of these differences are considered too small to be clinically significant. In a subgroup of 10 patients, pre-injection serum fluphenazine levels correlated significantly (Pearson r = 0.78, p < 0.05) with serum prolactin levels.

Fluphenazine plasma level monitoring for patients receiving fluphenazine decanoate.

BACKGROUND: Finding a dose of an antipsychotic for maintenance therapy that is both safe and effective can be difficult because clinicians are unable to titrate dose against clinical response in patients who are already stable. Therapeutic monitoring of antipsychotic plasma levels has the potential for helping clinicians in dosage selection. With this in mind, we evaluated the usefulness of monitoring fluphenazine plasma levels for patients with schizophrenia who were receiving maintenance treatment with fluphenazine decanoate. METHOD: Thirty-one patients with schizophrenia were randomly assigned to low, medium, or high (0.1-0.3, 0.3-0.6, 0.6-1.0 ng/ml) plasma levels of fluphenazine. The dose of fluphenazine decanoate was adjusted in order to maintain patients in their assigned range. Side effects, psychopathology, and psychotic exacerbations were measured during the year following randomization. RESULTS: All of the psychotic exacerbations occurred during the first eight weeks following randomization, before patients had adequate time to reach their plasma level assignments. We did not find a relationship between plasma levels of fluphenazine and clinical outcomes or side effects. CONCLUSION: Our results do not provide support for the usefulness of monitoring fluphenazine plasma levels for patients receiving fluphenazine decanoate.

A multidimensional (pharmacokinetic and clinical-biological) approach to neuroleptic response in schizophrenia. With particular reference to drug resistance.

Despite the undisputable effectiveness of the available neuroleptic medications (NDs), short and long term outcome of schizophrenic disorders is often unsatisfactory and drug resistance phenomena are not uncommon. The causes of variability in the response seem to be primarily due to the heterogeneity of schizophrenic syndromes in terms of clinical history, symptoms, and biological patterns. The high non-compliance rate is an important source of therapeutic failure particularly during long-term treatment. The lacking or poor response to NDs can be linked to peculiar drug disposition patterns, which lead generally to inadequate plasma concentrations (too low or too high). To deal with pharmacokinetic aspects two main topics are discussed in this paper: (A) the interindividual differences in bioavailability and metabolism and (B) the plasma level-clinical response relationship. The knowledge of these aspects can significantly contribute to reducing some pseudo-drug resistance phenomena. Moreover, the need to combine these data with the new acquisitions on the pathophysiology of these disorders is emphasized, to deal properly with the complexity of drug response mechanisms during therapy with NDs. New heuristic paradigms for schizophrenic disorders, stemming from the evidences of their heterogeneity, in terms of clinical course, outcome and biological findings, should be considered in relation to response. Accordingly, the concept of 'therapeutic window' (as conceived in the '70s) for NDs (as for antidepressants) needs to be reexamined in relation to recent clinical, neurochemical and neuromorphological data. Finally, the indications for NDs monitoring (particularly for drugs like haloperidol and fluphenazine) are reported, suggesting that a multidimensional operational strategy could be particularly suitable to deal with drug resistance problems.

A highly sensitive and specific radioimmunoassay for quantitation of plasma fluphenazine.

Antisera of high sensitivity and selectivity were obtained from rabbits immunized with conjugates of hemisuccinylated fluphenazine and porcine thyroglobulin. The antiserum selected (titer 1:6000) for the development of the RIA was obtained after a priming dose and a single iv booster injection three months later. This antiserum had negligible crossreactivity with known available metabolites of fluphenazine (FPZ) and an affinity constant of 2 X 10(10) L/mol. Tritiated FPZ was further purified by HPLC and used as a ligand. The method detects as little as 20 pg/mL of plasma (4 pg/RIA tube) after 1 mL of plasma is extracted. The extraction was performed at a basic pH with heptane: isoamyl alcohol (99:1); the solvent was then back extracted using an acetic phosphate buffer. Recoveries were uniformly high (88.6 +/- 2.1%), and this aqueous buffer extract was used directly in the RIA procedure. The assay has intra- and interassay coefficients of variation of 5.8 and 8.2%, respectively, in a plasma concentration of 95 pg/mL. Results using this procedure have been cross validated against an HPLC procedure (r = 0.952, slope = 1.032, intercept = 0.009, n = 18). In a single-dose FPZ study (10 mg, po), plasma FPZ levels in 25 normal volunteers could be monitored greater than 48 h post dose. Single plasma level profiles, after an initial injection of 12.5 mg of FPZ decanoate, could be measured greater than 36 d, and, in some cases, up to 100 d post dose.

19F magnetic resonance imaging and spectroscopy of a fluorinated neuroleptic ligand: in vivo and in vitro studies.

The bulk biodistribution of a trifluorinated neuroleptic (fluphenazine) was studied using 19F magnetic resonance imaging (MRI). Fifteen male Sprague-Dawley rats were injected with fluphenazine (120 mg/kg) and scanned in a G.E. CSI 2.0 tesla MRI system. The rats were killed following scanning and the brains were removed. The excised brains were then scanned using 1H and 19F MR techniques. The fluorinated neuroleptic was imaged at the injection site, spectroscopically detected in vivo in the head, and spectroscopically localized in the whole brain. These data suggest that in vivo 19F MRI of fluorinated agents is possible and could have clinical and research applications to the neurosciences.

Comparative bioavailability of two tablet formulations of fluphenazine dihydrochloride in drug-free psychiatric patients.

The comparative bioavailability of a new tablet formulation of fluphenazine dihydrochloride (5 mg) and a reference product (fluphenazine dihydrochloride, Prolixin, 5 mg) was assessed in drug-free psychiatric patients. Twenty-six patients were initially entered in the study, of whom 22 completed the protocol. Each patient received the test (T) and the reference formulation (R) in a balanced two-way crossover design. Plasma concentrations of fluphenazine were monitored over a period of 48 h after drug administration using a sensitive HPLC method. One patient did not show any measurable plasma concentration for one formulation at any sampling time and, therefore, bioavailability was assessed in the remaining 21 patients. All pharmacokinetic parameters showed wide intersubject variation. The maximum plasma concentration (Cmax), time to Cmax, and area under the curve up to the last measurable concentration (AUClast0), infinity (AUCinfinity0), or truncated areas (such as AUC16(0), AUC24(0) were compared by analyses of variance and found not to be significantly different in each case across the formulations. Except for AUC24(0), AUC32(0), and AUC48(0), ANOVA of all other parameters showed a high power (greater than 80%) to detect a 20% difference in the mean value of each bioequivalence parameter between T and R. The two formulations were found to be bioequivalent in that confidence intervals of the mean values of AUCinfinity0, AUClast0, truncated AUCs, or Cmax for T:R ratios were, in each case, well within the acceptable range of 100 +/- 20%.

Pharmacokinetics of fluphenazine, a highly lipophilic drug, estimated from a pulse dose of a stable isotopomer in dogs at steady state.

The potential utility of a pulse dose of a deuterium-labeled isotopomer (FLU-D(4)) in elucidating the pharmacokinetics of fluphenazine (FLU) at steady state was investigated in dogs. The single-dose oral pharmacokinetics of FLU in dogs were established. After resting the dogs for 3 weeks, the animals were dosed to steady state with oral FLU administered at 12-h intervals. Following 15 doses, one dose of FLU was replaced by a pulse dose of FLU-D(4), after which dosing with FLU was resumed. FLU and FLU-D(4) plasma concentrations were determined by tandem mass spectrometry. Comparable estimates of apparent oral clearance were calculated from (i) a single dose of FLU, (ii) a pulse dose of FLU-D(4), and (iii) over a dosing interval at steady state. Average steady-state plasma concentrations were reliably predictable from a pulse dose of FLU-D(4).