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.

Identification of P-glycoprotein substrates and inhibitors among psychoactive compounds--implications for pharmacokinetics of selected substrates.

The pharmacokinetics of antipsychotic drugs has become an integral part in understanding their pharmacodynamic activity and clinical effects. In addition to metabolism aspects, carrier-mediated transport, particularly secretion by ABC transporters, has been discussed as potentially relevant for this group of therapeutics. In this study, the psychoactive compounds perphenazine, flupentixol, domperidone, desmethyl clozapine, haloperidol, fluphenazine, fluvoxamine, olanzapine, levomepromazine, perazine, desmethyl perazine, clozapine, quetiapine and amisulpride were characterized in terms of P-glycoprotein (P-gp) affinity and transport. Experimental methods involved a radioligand displacement assay with [3H]talinolol as radioligand and transport--as well as transport inhibition--studies of the P-gp substrate [3H]talinolol across Caco-2 cell monolayers. In addition, the physicochemical descriptors log P and deltalog P were determined to test potential correlations between transporter affinity and lipophilicity parameters. All of the tested antipsychotics showed affinity to P-gp albeit their IC50 values (concentration of competitor that displaced 50% of the bound radioligand) differed by a factor exceeding 1000, when compared using the transport inhibition assay. From the group of P-gp substrates, amisulpride and fluphenazine were selected for in-vivo drug-drug interaction studies in rats to demonstrate the in-vivo relevance of the in-vitro findings. Compounds were administered by intraperitoneal injection either alone or in combination with 50 mg kg(-1) ciclosporin. The concentration versus time profiles for both drugs were followed in serum as well as in brain tissues. Significant differences between the treatments with the antipsychotic alone versus the combination of antipsychotic with ciclosporin were found for amisulpride. The distribution of amisulpride to the brain was increased and systemic serum levels were likewise increased indicating decreased systemic clearance for the combination regimen. For fluphenazine, systemic levels with and without co-administration of ciclosporin were comparable while higher brain-to-serum concentration ratios were found after co-administration of ciclosporin. The findings are explained on the basis of the limited contribution of P-gp-mediated transport to the elimination of fluphenazine and to a direct effect with respect to its distribution into the brain.

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.

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.

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).

The roles of depot injection sites and proximal lymph nodes in the presystemic absorption of fluphenazine decanoate and fluphenazine: ex vivo experiments in rats.

PURPOSE: The release and presystemic absorption of fluphenazine and its decanoate ester from intramuscular depots were investigated. METHODS: Rats were sacrificed in groups of three at various times after injection of drug or prodrug in sesame oil. Muscle tissues at the injection sites and various lymph nodes were excised. Blood (plasma) was harvested by cardiac puncture. RESULTS: Following administration of fluphenazine decanoate, the amount of prodrug at the sites of injection declined exponentially (half-life 3.4 days). Highest concentrations of drug and prodrug were found in iliac and hypogastric lymph nodes nearest to injection sites in which both analytes were detectable 28 days post dose. The half-life for the decline of fluphenazine from lymph nodes (4.6 days) was similar to that from plasma (4.3 days). Following administration of fluphenazine base, only 2.8% of the dose remained at the sites of injection after 2 days. Concentrations of drug in iliac and hypogastric lymph nodes were comparable to those in distal lymph nodes. Fluphenazine concentrations in the lymphatic tissues decreased at about the same rate as plasma concentrations. CONCLUSIONS: The rate limiting step appeared to be slow partitioning of the decanoate from oily deposits at the injection site and proximal lymph nodes with subsequent hydrolysis of the ester group.

Generic substitution--comparing the clinical efficacy of a generic substitute for fluphenazine decanoate with the original product.

UNLABELLED: Long-acting neuroleptics have become the mainstay of the long-term treatment of schizophrenia, improving compliance and thus preventing relapse. Since schizophrenia is a common condition and treatment is usually long-term, this has important financial implications. OBJECTIVE: Generic substitution is an important cost-saving measure and generic psychopharmacological agents are also currently available in South Africa. There have been concerns about the quality of these products, but these often arise from anecdotal reports. This study was undertaken to compare the clinical efficacy of a generic substitute of fluphenazine decanoate with the original product. DESIGN AND SETTING: The study was a double-blind randomised trial involving two parallel groups--generic substitution v. original product. Chronic schizophrenics, aged between 18 and 65 years, who had been on a constant dose of fluphenazine decanoate for at least 3 months preceding the trial, all treated as outpatients in the community, were studied. The Positive and Negative Syndrome Scale (PANSS) (positive scale) was used as measuring scale and patients were evaluated at inclusion and then every 2 weeks for the next 12 weeks. RESULTS: Both groups had a median change of zero in PANSS scores over the 12-week period. No clinically significant differences between the change in PANSS score were found in respect of the two products. CONCLUSIONS: Generic substitution could play an important role in containing the costs of health care in South Africa. Concerns about the quality and efficacy of these drugs should be investigated. In this study, no significant differences in the efficacy of the two products were found.

Studies on the mechanism of absorption of depot neuroleptics: fluphenazine decanoate in sesame oil.

PURPOSE: The purpose of the present study was to investigate the pharmacokinetic characteristics of fluphenazine (FLU) and its decanoate (FLU-D) after intravenous and intramuscular administration to dogs. METHODS: A group of four beagle dogs was used in all intravenous and intramuscular experiments, with washout periods of no less than three months between doses. RESULTS: After intravenous FLU-D, the pharmacokinetics of the prodrug (mean +/- SD) were as follows: Clearance (CL) 42.9 +/- 6.3 L/h; terminal half-life (t1/2) 3.5 +/- 0.8 h; volume of distribution (Vd) 216 +/- 61 L. The fractional availability of FLU was 1.0 +/- 0.2. After intravenous FLU, the volume of distribution of FLU (51 +/- 17.8 L) was some 4 fold less than that of the prodrug. Simulations (Stella II) suggested that the rate limiting step was slow formation of FLU from the prodrug in the tissue compartment. After intramuscular FLU-D in sesame oil, the apparent t1/2 of FLU was 9.7 +/- 2.0 days whereas after intramuscular FLU base in sesame oil, the apparent t1/2 was only 7.7 +/- 3.4 h showing that the absorption of FLU itself from the intramuscular site and proximal lymph nodes is relatively rapid. CONCLUSIONS: The rate limiting step after intramuscular FLU-D appeared to be the slow partitioning of the prodrug out of the sesame oil at the injection site and in proximal lymph nodes.

Serum neuroleptic levels during reduced dose fluphenazine decanoate maintenance therapy.

Forty-one remitted and chronically psychotic schizophrenic out-patients completed a two-year clinical trial during which they were assigned, on the basis of their clinically determined maintenance dosages, to one of two reduced, fixed-dose fluphenazine decanoate (FD) regimens: 35 mg/4 wks (19 patients) or 10 mg/4 wks (22 patients). Eighty-one percent of chronically psychotic patients, who represented 74% of the high dose group, relapsed, in comparison with only 38% of remitted patients (p < .001), who represented 86% of the low dose group. During this study serum neuroleptic levels were assessed, using the radioreceptor assay, before the administration of each FD injection and whenever a patient relapsed. Overall, 334 serum neuroleptic activity measurements were performed. Serum neuroleptic levels were detectable in all patients and were higher, although not significantly, in the 35 mg/4 wks group. The dichotomous clinical outcome of chronically psychotic and remitted patients occurred within the framework of essentially similar serum neuroleptic levels. These findings suggest that: 1) serum neuroleptic levels can be monitored during low dose FD treatment, 2) the poor maintenance therapy outcome of chronically psychotic patients cannot be accounted for by inadequate neuroleptic bioavailability, 3) a majority of remitted FD maintained patients retain their clinical response at serum neuroleptic levels lower than those initially attained at steady state.

Absolute bioavailability of oral immediate and slow release fluphenazine in healthy volunteers.

OBJECTIVE: The present study was conducted with the aim of investigating the absolute bioavailability of fluphenazine in healthy volunteers after administration of immediate and slow release oral formulations. METHODS: The oral dose was 12 mg fluphenazine hydrochloride. The intravenous bolus dose was 2.5 mg. Fourteen healthy volunteers of both sexes were enrolled in this randomised, crossover trial. Twelve volunteers completed the trial according to protocol. RESULTS: The concentration maxima after administration of the slow release formulation were approximately half those measured after the immediate release formulation and were recorded later by a factor of 2 (immediate release: Cmax = 2.3 ng.ml-1, tmax = 2.8 h; slow release: Cmax = 1.2 ng.ml-1, tmax = 4.6 h). The concentrations measured 10 min after intravenous bolus administration of 2.5 mg fluphenazine hydrochloride were approximately 100 times higher (261 ng.ml-1). The geometric means for the absolute bioavailability of fluphenazine were 2.7% for the immediate release formulation and 3.4% for the slow release formulation. The absolute bioavailability of fluphenazine is thus much lower than previously generally accepted.

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.

Monitoring plasma levels of fluphenazine during chronic therapy with fluphenazine decanoate.

This study was conducted to examine the interpatient variability in steady-state plasma concentrations of fluphenazine by repeat depot intramuscular administration, and to determine the relationship between these concentrations and clinical state. Steady-state pre-dose concentrations of fluphenazine in plasma were measured using a sensitive and specific gas chromatography/mass spectrometry (GC/MS) assay in 24 patients with schizophrenia who were receiving continuous treatment with depot intramuscular fluphenazine decanoate. Clinical response was measured using the Andreasen Scale for positive and negative symptoms. Steady-state plasma concentrations of fluphenazine ranged from undetectable (< 0.1 ng/ml) to 27.9 ng/ml, with a median of 0.5 ng/ml. No significant associations were found between plasma concentration and dosage, or age and sex of the patient. Steady-state plasma concentrations in patients taking anticholinergic agents were significantly higher than in patients not receiving such drugs (P < 0.05 by Mann-Whitney U-test). Poorer control, expressed as the sum of the negative symptom scores or the sum of the positive and negative symptom scores, was related to higher log transformed plasma concentration of fluphenazine and higher fluphenazine decanoate dosage. The log transformed plasma concentrations of fluphenazine and the fluphenazine decanoate dosages were weakly related. Patients receiving another antipsychotic drug in addition to fluphenazine decanoate tended to have poorer clinical control and higher dosages of fluphenazine decanoate. These results indicate the useful role that plasma level monitoring can fulfil in identifying patients who are therapy-resistant despite high plasma levels.

Impact of clinical pharmacokinetics on neuroleptic therapy in patients with schizophrenia.

This review covers some recent work on: 1. The effects of route of administration on the pharmacokinetics of fluphenazine and some of its metabolites; 2. The clinical pharmacokinetics of fluphenazine in acute patients medicated with oral fluphenazine; 3. The clinical pharmacokinetics of haloperidol in acute patients medicated with oral haloperidol; 4. The clinical pharmacokinetics of fluphenazine in the maintenance of individuals with chronic schizophrenia with fluphenazine decanoate; 5. A systematic dose reduction study in maintenance treatment refractory patients with oral haloperidol. A study in which plasma levels of fluphenazine and fluphenazine sulfoxide were measured in a group of DSM-III-R patients with schizophrenia before and after switching from oral fluphenazine to depot fluphenazine, decanoate revealed much higher levels of fluphenazine sulfoxide with oral medication compared with those found with depot fluphenazine. These data illustrate the effect of "first pass" metabolism after oral fluphenazine. Thus in a group of 33 patients randomly assigned to receive 5 mg, 10 mg or 25 mg oral fluphenazine daily, steady state plasma fluphenazine levels at each dose were significantly lower that those of fluphenazine sulfoxide or 7-hydroxy-fluphenazine, although there were no significant differences between the levels of fluphenazine and fluphenazine N4-oxide. On the other hand, plasma levels of the parent drug were significantly higher than those of any metabolite in a corresponding group of patients at steady state on depot medication. These observations underscore the importance of route dependent differences in the pharmacokinetics of fluphenazine which can lead to problems when switching patients from oral to depot neuroleptics. The concept of "disabling side-effects" is an important development in understanding relationships between plasma levels of neuroleptic drugs and clinical response in patients with schizophrenia. Risk-benefit analysis shows clearly that evaluation of relationships between plasma levels and clinical response must take into account the consequences of side-effects which the patient feels have a negating effect on therapy. Emerging data on putative therapeutic plasma level ranges in maintenance therapy are potentially important and may be particularly useful in the maintenance of patients on low dose therapy. It is noteworthy that in a carefully executed dose reduction study in treatment resistant patients under medication with haloperidol, the mean lowest effective dose (8.7 ng/mL) lay within the optimal therapeutic range (5 ng/mL to 12 ng/mL) found in acutely psychotic patients. The study showed that gradual dose reduction of neuroleptic was possible in chronic treatment resistant patients with schizophrenia who were originally thought by ward staff to require high doses of neuroleptic.(ABSTRACT TRUNCATED AT 400 WORDS)

Metabolism of phenothiazine and butyrophenone antipsychotic drugs. A review of some recent research findings and clinical implications.

Whereas some metabolites of antipsychotic drugs are psychoactive and contribute to clinical improvement, recent studies have provided evidence that certain metabolites contribute to side-effects which can be disabling enough to negate clinical improvement as regards the psychosis. The route of administration of the drug can determine the amount of metabolite produced in the body and affect how the patient feels in response to the treatment.

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.

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.

Rationalizing neuroleptic polypharmacy in chronic schizophrenics: effects of changing to a single depot preparation.

This study investigated the effects of transferring patients on combined depot and oral neuroleptics to a single depot preparation; a secondary objective was to assess the effects of transferring patients from one depot neuroleptic to another. It was found that, whereas transferring from one depot preparation (flupenthixol) to another (fluphenazine) had no clear disadvantage for the patients, changing over from a combined oral and depot (fluphenazine) regimen to equivalent doses of depot alone resulted in an unacceptably high rate of relapse. The reasons for this may relate to either the unique pharmacokinetics of these drugs or subtle qualitative differences between them. It is suggested that caution is necessary whenever attempts are made to rationalize polypharmacy in schizophrenic patients.

Timing of acute clinical response to fluphenazine.

The time course of clinical improvement was studied in 41 schizophrenic and schizoaffective acute in-patients treated for 28 days with 10, 20 or 30 mg/day of oral fluphenazine hydrochloride in a double-blind, randomised study. Significant improvement was seen in the four BPRS factors: thinking disturbance, hostile-suspiciousness, withdrawal-retardation and anxious depression. The first two of these factors were improved by day 5. Significant improvement was seen up to day 22 for three of the four factors, but without significant improvement during the last week (although scores continued to drop). The half of the sample showing greater overall improvement did not improve faster than the sample as a whole. These more improved subjects did not differ significantly from the less improved subjects in the thinking disturbance factor until day 15, suggesting that at least a two-week neuroleptic trial would be necessary to begin to differentiate more and less responsive patients. The longer-term course of improvement cannot be determined from these data. The withdrawal-retardation and anxious depression factors showed their greatest improvement later than the 'positive' symptom factors, suggesting that the former may improve as a result of change in the latter.