Fluphenazine Research Articles

Colonic Perforation due to Oral Mannitol

To the Editor.— Oral mannitol has been used as a colonic cleaning agent to prepare patients for surgery and for roentgenographic and endoscopic procedures and as a hyperosmotic agent to treat constipation. 1 The following case report describes the previously unreported hazard of pneumatic explosion of the colon following the use of oral mannitol as a cathartic agent. Report of a Case.— A 52-year-old man was admitted for evaluation of chronic low-back pain and modification of analgesic usage. Constipation requiring over-the-counter laxatives was incidentally noted. Medications, which on admission included up to 150 Percodan and Tylox tablets per month, were changed to methadone hydrochloride; dexamethasone hydrochloride; amitriptyline hydrochloride; fluphenazine hydrochloride; intravenous plasma protein fraction, human (Plasmanate); clonidine hydrochloride; oxybutynin chloride; Naldecon; Urised; and tolmetin sodium. He was initially treated for constipation with Fleet enemas, oral mineral oil, milk of magnesia, and bisacodyl tablets, with minimal results. An abdominal roentgenogram, performed

Suppression of neuroleptic-induced persistent abnormal movements in Cebus apella monkeys by enantiomers of 3-PPP.

Effects of the enantiomers of the dopamine (DA) autoreceptor agonist 3-PPP (0.5-8.0 mg/kg body weight, i.m.) were studied in three Cebus apella monkeys with persistent abnormal movements induced by prior long-term treatment with fluphenazine enanthate. In 2 of the animals, (-)-3-PPP abolished the abnormal movements while producing only negligible acute motor effects (trembling and stereotypy). (+)-3-PPP, administered to one of these monkeys, also produced a dose-dependent suppression of the persistent abnormal movements, along with the appearance of acute motor signs including tongue protrusions, hyperkinesia, and stereotypy; at the highest dose, there was a biphasic effect. In the first phase, there were pronounced acute motor signs but no persistent abnormal movements. In the second phase, there were neither acute nor persistent abnormal movements. One monkey was unaffected by (-)-3-PPP or low doses of (+)-3-PPP; a higher dose (4 mg/kg) produced hyperkinesia and increased persistent abnormal movements in one experimental setting. The suppression of neuroleptic-induced persistent abnormal movements by 3-PPP enantiomers may be related to their ability to act as autoreceptor agonists, while the acute motor signs produced by higher doses of (+)-3-PPP may be due to activation of postsynaptic DA receptors. The present findings suggest that (-)-3-PPP and drugs with a similar pharmacological profile might be effective as symptomatic treatments for tardive dyskinesia, with little chance of inducing acute extrapyramidal side-effects.

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 × 1010 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>48 h post dose. Single plasma level profiles, after an initial injection of 12.5 mg of FPZ decanoate, could be measured>36 d, and, in some cases, up to 100 d post dose.

Low dose fluphenazine decanoate and skills training in schizophrenic outpatients : Stephen R. Marder, M.D. and Robert P. Liberman, M.D. West Los Angeles Veterans Administration Medical Center, Brentwood Division, and the UCLA Department of Psychiatry, Los Angeles, CA, USA

The solubility of fluphenazine decanoate (FD) in binary mixtures of polyethylene glycol 200 (PEG 200) + water at the temperature range from 298.0 K to 318.0 K is reported. The previously trained version of the Jouyban–Acree model for PEG 200 + water, a recently proposed general cosolvency model employing partial solubility parameters, and a combination of the model with van’t Hoff equation were used to predict the solubility of FD in PEG 200 + water at different temperatures. The results show that the Jouyban–Acree model can be used for solubility prediction of FD in PEG 200 + water mixtures at different temperatures. The solubility data as a function of temperature were used to determine the thermodynamic properties of the dissolution process including Gibbs energy, enthalpy and entropy of the solution. An adapted version of the model is used to represent the thermodynamic properties of the solutions in the solvent mixtures and the obtained results were satisfactory. Densities of solute free PEG 200 + water and FD-saturated solutions are also reported.

Low-dose neuroleptic therapy for children with childhood-onset pervasive developmental disorder

An open study of the therapeutic effects of low-dose neuroleptic treatment was performed on 12 consecutively hospitalized children, aged 7-11, who satisfied DSM-III criteria for childhood-onset pervasive developmental disorder. While receiving an average dose of 0.04 mg/kg per day of haloperidol or fluphenazine hydrochloride, the patients exhibited significant reductions in hyperactivity and aggressive symptoms and significant improvement in peer relations. This dose of neuroleptic was associated with minimal side effects. The authors conclude that low doses of potent neuroleptics may be effective treatment for some patients suffering from childhood-onset pervasive developmental disorder.

Characteristics of oral movements in rats during and after chronic haloperidol and fluphenazine administration.

Rats were chronically administered either haloperidol (HAL) or fluphenazine (FLU) via depot injections for 8 months, given these same drugs in their drinking water for the next 2 months, and then withdrawn from the drugs. Throughout the experiment the animals were tested repeatedly in an enclosed tube using a computerized device which measured computer-scored movelets (CSMs) and, in the latter half of the experiment, were also scored by a human observer in the tube, as well as in an open cage, for observed oral movements (OMs). In the tube, the animals in both neuroleptic-treated groups showed initial decreases in the number of CSMs and made sluggish CSMs; these effects were generally larger in the FLU animals. After 6 months of chronic neuroleptics, the HAL-treated animals showed increased oral movements, both as reported by the human observer and in CSMs of all amplitudes, and this effect increased upon drug withdrawal. FLU-treated animals showed a more persistent depression of both OMs and CSMs of large amplitudes. However, the behavior most characteristic of both neuroleptic-treated groups was the gradual development of increases in CSMs of the smallest amplitudes measurable. A different pattern was observed in the open cage test, where both neuroleptic groups showed significant increases in vacuous OMs during drug administration which rapidly became attenuated upon drug withdrawal. These results indicate a complex syndrome of oral activity in the drugged animals which changed over time. The measure of oral activity which most clearly showed the time-course for late-onset changes in oral activity was CSMs of the smallest amplitudes.

Persistence of Fluphenazine in Plasma after Decanoate Withdrawal

We discontinued fluphenazine decanoate using a double-blind, crossover random order design, in 12 recent onset clinically stable schizophrenics who had been given fluphenazine decanoate 12.5 mg intramuscularly every 2 weeks for at least 1 year prior to drug withdrawal. Each condition (drug or placebo) lasted 12 weeks. Using a radioimmunoassay verified by comparison to a gas chromatographic-mass spectrometric method, plasma fluphenazine levels were measured every 2 weeks during drug continuation and drug withdrawal conditions. No patient relapsed over the 24-week period of the study. Mean fluphenazine levels between drug continuation and withdrawal conditions showed a progressively larger difference over time, although significant differences were not seen until week 8. By week 12 after drug withdrawal, 33% of subjects still showed notable plasma fluphenazine levels. On the basis of our preliminary findings, we suggest that 2-week intervals between injections may be too short and that wider intervals may achieve similar clinical results.

Diminished D2 dopamine receptor function and the emergence of repetitive jaw movements.

Oral movements in rats, repetitive jaw movements (RJM), can be induced in a dose dependent manner by a specific D1 agonist, SKF 38393, and decreased by D2 receptor stimulation with a specific D2 agonist, LY 141865. Irreversible D1 receptor inactivation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline severely reduced oral responses induced by SKF 38393, whereas such blockade of D2 receptors greatly augmented the D1 mediated behavior. Further, we found that chronic prolonged D2 receptor blockade following administration of fluphenazine decanoate facilitated repetitive jaw movements.

Fluphenazine decanoate dose and severity of depression in patients with post-psychotic depression

The authors examined the fluphenazine decanoate dose and the fluphenazine plasma levels in comparison with measures of severity of depression in schizophrenic and schizoaffective patients. All patients were selected for study on the basis of having stable, syndromally defined, antiparkinsonian non-responsive syndromes of post-psychotic depression. No meaningful relationships were found. The implications of this observation with regard to the notion that depressive symptomatology in such patients is neuroleptic-induced is discussed.

The sulfoxidation of fluphenazine in schizophrenic patients maintained on fluphenazine decanoate.

Highly sensitive radioimmunoassays were applied to study the sulfoxidation of fluphenazine in 30 schizophrenic patients maintained on either 5 mg or 25 mg fluphenazine decanoate by intramuscular injection every 14 days over a period of 6 months. The presence of the sulfoxide metabolite was detected in all but one of the patients, such that 97% of the 340 plasma samples analysed contained the metabolite. Interpatient variations in plasma levels of fluphenazine, fluphenazine sulfoxide, and in drug to metabolite plasma level ratios were several fold higher than the corresponding intrapatient variations at both dosages. There were statistically significant tendencies for mean plasma fluphenazine levels to rise and mean plasma sulfoxide levels to fall over the 6-month period of study among patients on the high dose, consistent with our previously reported observation that it takes 3-6 months to establish a steady state of fluphenazine with this dosage regimen. By contrast, there were no statistically significant changes in mean plasma levels of either fluphenazine or its sulfoxide in patients on the low dose. Nevertheless, there was a significant rise in fluphenazine to fluphenazine sulfoxide mean plasma level ratios in both dosage groups. It is difficult to assess the significance of the changes in the drug to metabolite ratios with time, since there are no kinetic data on the phase II metabolism (conjugation) of fluphenazine or fluphenazine sulfoxide. This study shows that sulfoxidation is an important major pathway in the metabolism of intramuscularly-administered fluphenazine, and implies that metabolic sites other than gut wall are also involved in the process.

Fluphenazine see Trifluoperazine

Fluphenazine see Trifluoperazine

Plasma prolactin and fluphenazine concentrations in patients receiving fluphenazine decanoate: stability over injection intervals.

Plasma prolactin and fluphenazine concentrations were measured in a group of 17 patients (9 males, 8 females) with schizophrenia who were receiving chronic treatment with fluphenazine decanoate. Neither measure was significantly correlated with clinical effect, as measured by the Brief Psychiatric Rating Scale, at any of the 5 pre-injection times examined. None of the measures showed statistically significant (P greater than 0.05; MANOVA) variations with time. Neither measure showed a significant correlation with the dose (expressed as mg/kg) of fluphenazine. The implications of the study for monitoring chronic treatment of schizophrenia are discussed.

SINGLE CASE STUDY

A patient is described with operationally diagnosed chronic schizophrenia who simultaneously experienced repeated "attacks" during which times he had intense apprehension and autonomic hyperactivity entirely similar to that usually described under the rubric of "panic attacks" in nonschizophrenic patients. Delusional and hallucinatory symptoms were also transiently exacerbated during these episodes. Alprazolam, as an adjunct to fluphenazine decanoate, was effective in ameliorating these symptoms. Diagnostic and treatment implications are discussed.

Depot neuroleptic medication and serum levels by radioreceptor assay: prolactin concentration, electrocardiogram abnormalities and six-month outcome.

Twenty-six chronic schizophrenic patients on well-established depot neuroleptic regimes with stable doses (16 on fluphenazine decanoate, 10 on flupenthixol decanoate) had serum neuroleptic levels measured by radioreceptor assay (RRA) and were followed for six months. The serum prolactin (PRL) concentration and resting electrocardiogram (ECG) were also taken at the beginning of the study period. Correlations had previously been noted between RRA measured neuroleptic levels and outcome in both acute and chronic patients on oral medication. However, in this study of depot medication no significant correlations were found between serum neuroleptic concentration, serum prolactin concentration and the clinical state or outcome. The prevalence (33%) and type of ECG abnormality observed was similar to that previously reported.

Depot Neuroleptic Medication and Serum Levels by Radioreceptor Assay

Twenty-six chronic schizophrenic patients on well-established depot neuroleptic regimes with stable doses (16 on fluphenazine decanoate, 10 on flupenthixol decanoate) had serum neuroleptic levels measured by radioreceptor assay (RRA) and were followed for six months. The serum prolactin (PRL) concentration and resting electrocardiogram (ECG) were also taken at the beginning of the study period. Correlations had previously been noted between RRA measured neuroleptic levels and outcome in both acute and chronic patients on oral medication. However, in this study of depot medication no significant correlations were found between serum neuroleptic concentration, serum prolactin concentration and the clinical state or outcome. The prevalence (33%) and type of ECG abnormality observed was similar to that previously reported.

Fluphenazine Decreases Anxiety Not Related to Withdrawal

Fluphenazine Decreases Anxiety Not Related to Withdrawal

Alterations in peripheral and central dopamine receptor sensitivity after subchronic treatment with fluphenazine and sulpiride.

The effects of subchronic treatment with the antipsychotic drugs fluphenazine and sulpiride on the sensitivity of peripheral neuronal dopamine receptors and central dopamine autoreceptors were evaluated. The ability of apomorphine, a dopamine agonist, to inhibit electrically induced sympathetic vasoconstriction in pithed rats, and apomorphine-induced inhibition of spontaneous locomotor activity in awake rats were used as indices of peripheral and central dopamine receptor sensitivity, respectively. A single injection of fluphenazine decanoate, a long-acting preparation of fluphenazine, enhanced the central locomotor inhibitory effect of low doses of apomorphine 4 and 6 weeks after drug administration, whereas the antidopaminergic effect on peripheral dopamine receptors was prolonged and persisted at least up to 6 weeks. In another set of experiments rats were treated with fluphenazine hydrochloride and sulpiride for 10 days and subsequently challenged with apomorphine after various withdrawal times. Both antipsychotic drugs augmented the inhibitory effect of apomorphine in the periphery, although the time courses of the potentiation were different. Both treatments also enhanced the locomotor inhibitory effect of apomorphine. These results are in line with our previous finding that long-term treatment with dopamine antagonists can induce neuronal dopamine receptor up-regulation also outside the central nervous system. Peripheral neuronal dopamine receptors thus show similar adaptive responses to long-term blockade as central dopamine autoreceptors, and may serve as a useful experimental model in studies concerned with mechanisms of dopaminergic autoregulation in the central nervous system.

Fluphenazine decanoate in acute and maintenance therapy of schizophrenia

1. 1. The knowledge of the pharmacokinetic profile of fluphenazine decanoate (FPZ-D) suggested it was suitable for treatment of schizophrenic patients not just during the maintenance phase of the disease but also during acute relapses. 2. 2. 27 acute schizophrenic in-patients (diagnosed according to the DSK III) were treated with FPZ-D, 25 mg i.m. with repeated administrations (after 2, 4, 30 days). 3. 3. FPZ-D proved effective in all cases, already after the second day and particularly on Brief Psychiatric Rating Scale items such as delusion, hallucinations, hostility. 4. 4. Extrapyramidal side-effects, appeared in about 40% of the patients. 5. 5. The use of the drug both in the acute phase and maintenance schizophrenia therapy is envisaged, overcoming the problems deriving from the rejection by patients of any therapeutic tool and consequently the therapeutic “milieu”.

Effects of neuroleptic treatments on peripheral opioid secretion.

The effects of short- and long-term neuroleptic therapy on peripheral secretion of beta-endorphin (beta-EP) and beta-lipotropin (beta-LPH) were examined in 25 chronic schizophrenic patients. Haloperidol was given to 8 patients for 10 days (group A: 0.1 mg/kg b.w./day) and to another group of 8 patients for 30 days (group B: 10-18 mg/day). The other 9 patients were given a combination of haloperidol (6-30 mg/day) with either chlorpromazine (25-75 mg/day), clotiapine (40-60 mg/day), or fluphenazine decanoate (25-75 mg/month) for 14-18 months (group C). beta-EP and beta-LPH levels were assayed before and after each treatment. Haloperidol plasma levels were assayed in group B patients at the end of treatment. beta-EP mean basal levels were higher in patients than in controls; however, beta-LPH mean basal levels were higher only for group A patients. After treatment, the mean levels did not differ from those prior to therapy in groups A and B, while beta-LPH levels were significantly higher in group C. Level increases or decreases in single patients did not correlate with drug dose or duration of treatment, with baseline peptide levels or with the clinical effects of the various treatments.

Plasma fluphenazine concentrations in outpatients receiving fluphenazine decanoate (Modecate)

AbstractPlasma fluphenazine concentrations were measured by neuroleptic radioreceptor assay in 17 outpatients receiving chronic treatment with intramuscular fluphenazine decanoate. The range of concentrations was 0.5–2.4 μg/L over the dosage range of 0.30–3.2 mg/d. Age, sex and smoking status had no influence on plasma fluphenazine concentrations, which were not correlated with dose (expressed as mg/kg/d). There was no significant correlation between plasma concentration and clinical status of the patients. No difference in plasma concentration between patients with extrapyramidal signs or tardive dyskinesia and those without signs were observed.