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PubMed1976

[Biological fate of 3H-labeled penfluridol. (3) Correlation between concentration of 3H-penfluridol in the brain and its anti-methamphetamine activity].

The Penfluridol (PFL) is a potent and long-acting neuroleptic belonging to the diphenylbutyl piperidine series. The purpose of the present study is to investigate a correlation between the brain concentration of unchanged 3H-PFL and its neuroleptic activity in the methamphetamine-antagonism test. The experimental animal comprised adult male Wistar rats weighing about 200 g. All the rats were administered 3H-PFL orally and killed at appropriate times after administration. After killing blood samples were collected and the brain and liver were excised. The blood was extracted with 4 volumes of ethanol. The brain and the liver were homogenized in 9 volumes of ethanol. The amount of 3H-PFL in the ethanol extract was determined by thin-layer chromatography. The result showed that the drug level in the brain was relatively constant when the dose was the median effective dose (ED50) for the test at those time intervals after administration.

Animals↗

PubMed2006

Penfluridol for schizophrenia.

BACKGROUND: Penfluridol, available since 1970, is an unusual long acting oral antipsychotic agent for the treatment of schizophrenia. It may be considered a depot medication as it is administered once a week. OBJECTIVES: To review the effects of penfluridol for treatment of those with schizophrenia and schizophrenia-like illnesses in comparison to placebo, other antipsychotic medication or no intervention. SEARCH STRATEGY: We undertook electronic searches of the Cochrane Schizophrenia Group's Register (2005), the Cochrane Central Register of Controlled Trials (2003-5) and LILACS (1982-2005). We hand searched references of all identified studies and sought citations of these studies in the Science Citation Index. We contacted the authors of trials and the manufacturer of penfluridol. SELECTION CRITERIA: We reliably selected all randomised clinical trials comparing penfluridol to placebo or typical or atypical antipsychotic drugs for schizophrenia or serious mental illness. DATA COLLECTION AND ANALYSIS: We independently extracted and analysed data on an intention-to-treat basis. We calculated the relative risk (RR) and 95% confidence intervals (CI) of homogeneous dichotomous data using a random effects model, and where possible calculated the number needed to treat. We calculated weighted mean differences (WMD) for continuous data. MAIN RESULTS: We included twenty-five studies with a total of 1024 participants. Most of these studies were undertaken in the 1970s when penfluridol was launched. Ten studies, with 365 patients, compared penfluridol to placebo. In the meta-analysis of medium-term lasting studies, penfluridol was superior to placebo in the main efficacy measures: 'improvement in global state' (n=159, 4 RCTs, RR 0.69 CI 0.6 to 0.8, NNT 3 CI 2 to 10) and 'needing additional antipsychotic' (n=138, 5 RCTs, RR 0.43 CI 0.2 to 0.8, NNT 3 CI 1.8 to 20).A total of 449 patients from eleven studies were randomised to penfluridol or oral typical antipsychotics. There were no particular differences between penfluridol versus chlorpromazine, fluphenazine, trifluoperazine, thioridazine, or thiothixene for the main outcome measures in medium-term trials: 'improvement on global state' (N=2 studies), 'leaving the study early' (N=6), 'needing additional antipsychotic' (N=3), needing antiparkinsonian medication (N=2), and side-effects. Six studies, with 274 patients, compared penfluridol to depot typical antipsychotics. In general, for the efficacy and safety measures, no differences were established, but penfluridol was superior in keeping the patients in treatment; 'leaving the study early' (n=218, 5RCTs, RR 0.55 CI 0.3 to 0.97, NNT 6 CI 3.4 to 50). AUTHORS' CONCLUSIONS: Although there are shortcomings and gaps in the data, there appears to be enough overall consistency for different outcomes. The efficacy and adverse effects profile of penfluridol are similar to other typical antipsychotics; both oral and depot. Furthermore, penfluridol is shown to be an adequate treatment option for people with schizophrenia, especially those who do not respond to oral medication on a daily basis and do not adapt well to depot drugs. One of the results favouring penfluridol was a lower drop out rate in medium term when compared to depot medications. It is also an option for chronic sufferers of schizophrenia with residual psychotic symptoms who nevertheless need continuous use of antipsychotic medication. An additional benefit of penfluridol is that it is a low-cost intervention.

Antipsychotic Agents↗

PubMed1983

A preliminary study of sex-related differences in prolactin responses to dopamine blockade and insulin hypoglycemia and in penfluridol plasma levels in schizophrenic patients.

Twelve healthy chronic schizophrenic patients were treated with the long-acting oral dopamine (DA) receptor blocker penfluridol (100 mg orally) for 6 weeks. Plasma prolactin (PRL) levels were measured during insulin-tolerance tests (ITT) performed at the end of the drug-free period (7-10 days) and during weeks 1 and 6 of penfluridol treatment. Simultaneous PRL and penfluridol plasma levels were determined just prior to, and at 8, 72 and 120 h after penfluridol administration during weeks 1, 5, and 6. During penfluridol treatment women (N = 4) had a greater increase in their maximal PRL increments after ITT as compared to the men (N = 8). Analyses of (peak) plasma penfluridol and PRL concentrations 8 h after penfluridol administration revealed a trend towards lower plasma penfluridol levels during weeks 5 and 6 and significantly higher PRL levels in women compared to men during weeks 1 (P less than 0.01), 5 (P less than 0.02), and 6 (P less than 0.02). The consistent sex-related differences in the PRL responses to DA blockade, and to insulin-induced hypoglycemia and in the penfluridol plasma levels in our study support the view that sex-related changes need to be considered not only in the hormonal responses to various pharmacological agents, but also in the assessment of the plasma levels of these drugs.

Adult↗

PubMed1975

The effect of long-term penfluridol treatment on the sensitivity of the dopamine receptors in the nucleus accumbens and in the corpus striatum.

The effect of local application of dopamine to the nucleus accumbens or corpus striatum on locomotor activity was studied in rats 4 days after withdrawal from a 6 weeks term of penfluridol medication. The bilateral application of dopamine into the nucleus accumbens of penfluridol-treated rats produced a very marked increase in coordinated locomotor activity which was 3-5 times higher than that of rats not treated with penfluridol. This effect of dopamine in both penfluridol-treated and control rats was antagonized by intraperitoneally administered haloperidol. The bilateral application of dopamine into the corpus striatum of penfluridol-treated animals produced a marked stereotyped behavioural syndrome in all rats studied, whereas no signs of stereotyped behaviour were observed in any of the rats not treated with penfluridol. The results indicate that long-term treatment of rats with the dopamine receptor blocking agent penfluridol produces an increase in the sensitivity of the dopamine receptors in the nucleus accumbens and corpus striatum and that the nucleus accumbens may play a role in locomotor activity.

Animals↗

PubMedDate not supplied

Penfluridol blockade of apomorphine: dependence of duration on species and endpoint.

Penfluridol, at relatively low doses, blocks apomorphine-elicited emesis in dogs and apomorphine-elicited floor pecking in pigeons for over a month. In mice tested for apomorphine-elicited hypothermia, and in rats tested for apomorphine-elicited chewing behavior, however, the anti-apomorphine activity of penfluridol does not persist for longer than 2-3 days even when high doses of penfluridol are given. In rabbits tested for apomorphine-induced hyperthermia and gnawing, on the other hand, penfluridol blocks apomorphine for about a week. Thus, of the 5 species tested, only in rabbits does the duration of penfluridol's anti-apomorphine action approximate the 1-week duration reported from human therapeutic trials. In mice given high-dose penfluridol apomorphine consistently elevates body temperatures, rather than exerts its usual hypothermic response. Conversely, in rabbits given penfluridol apomorphine tends slightly to decrease body temperatures, rather than exert its usual hyperthermic response.

Animals↗

PubMedDate not supplied

Study of penfluridol and chlorpromazine in the treatment of chronic schizophrenia.

This study presents data on the use of penfluridol, a once-a-week orally administered, antipsychotic agent, in the treatment of chronic schizophrenic patients. Fifty-nine patients participated in the initial dose titration segment during which doses of penfluridol were adjusted weekly until the patients' condition became stabilized. The starting dose did not exceed 60 mg per week, and the maximum weekly dose did not exceed 140 mg. Forty-one of these patients continued on to participate in a double-blind comparison of penfluridol with chlorpromazine. Maximum doses did not exceed 140 mg per dose per week for penfluridol and 7350 mg per week for chlorpromazine in the double-blind segment. Patients were abruptly switched from their previous neuroleptic medication to penfluridol without loss of control. Side effects, mainly extrapyramidal in nature, were readily alleviated with benztropine mesylate. Penfluridol, administered orally once a week, appeared to be well tolerated; it was comparable to daily chlorpromazine in treating and maintaining schizophrenic patients.

Adult↗

PubMed1975

The effect of penfluridol and some psychotropic drugs on monoamine metabolism in central nervous system.

Five neuroleptics: penfluridol, haloperidol, chlorpromazine, pimozide and oxypertine, and two benzodiazepine minor tranquilizers; chlordiazepoxide and diazepam, were studied in mice and rats. When the drugs were injected i.p. in mice, all neuroleptics increased the brain homovanillic acid (HVA) concentration but two benzodiazepines did not change it. Of the drugs tested, only pimozide increased the brain level of 5-hydroxyindoleacetic acid. Penfluridol accelerated the turnover rate of brain dopamine (DA), wheras haloperidol accelerated both DA and noradrenaline turnover rates. In rats, oral administration of penfluridol caused an increase in the striatal HVA and 3,4-dihydroxyphenylacetic acid which persisted longer than that following haloperidol. The concentration of brain 3-methoxy-4-hydroxyphenylethylene glycol, however, was not affected by penfluridol even when the drug was administered at a high dose. Based on these and earlier findings, it is concluded that the effect of penfluridol on DA metabolism resembles that of typical neuroleptic compounds and penfluridol acts only on DA neurons as a long-acting DA receptor blocker.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1987

Penfluridol, chlorprothixene and haloperidol block fast axonal transport in an order of potency consistent with a mechanism related to inhibition of calmodulin.

The effects of the inhibitors of calmodulin penfluridol, chlorprothixene and haloperidol on fast axonal transport, the content of adenosine triphosphate and creatine phosphate and the density of axonal microtubules, were measured in spinal nerves of the bullfrog in vitro. These drugs inhibited the fast orthograde transport of [3H]leucine-labelled proteins: 35 microM penfluridol, 70 microM cis-chlorprothixene, and 200 microM haloperidol were needed to produce and approximately 50% inhibition of transport, and the order of potency was, therefore, penfluridol greater than cis-chlorprothixene greater than haloperidol; the trans isomer of chlorprothixene was as effective as the cis isomer-of chlorprothixene in inhibiting fast axonal transport. None of these drugs significantly reduced the density of microtubules in unmyelinated axons of nerves, incubated as for a transport experiment. Exposure to the concentration of these drugs which inhibited transport did not reduce significantly the content of adenosine triphosphate of the nerves, except for a 22% reduction by trans-chlorprothixene, and they had no significant effect on the content of creatine phosphate except for a 27% reduction by penfluridol and a 20% reduction by trans-chlorprothixene. The inhibition of axonal transport by these drugs can therefore not be explained either by an interference with oxidative metabolism or by disruption of microtubules. The order of potency of penfluridol, chlorprothixene and haloperidol as inhibitors of fast axonal transport parallels their known order of potency as antagonists of calmodulin; inhibition of axonal transport may therefore be related to inhibition of the function of calmodulin by these drugs.

Adenosine Triphosphate↗

PubMed1983

Inhibition of growth and of thymidine incorporation into DNA in Tetrahymena by chlorpromazine, pimozide and penfluridol.

The antipsychotic drugs chlorpromazine, pimozide, and penfluridol caused a 50% inhibition of growth of Tetrahymena at concentrations of 4.5, 5.5, and 1.5 microM, respectively. The degree of growth inhibition was dependent on the concentration of cells; higher drug concentrations were needed to produce inhibition of denser cell cultures. Binding studies with penfluridol showed that 50% growth inhibition resulted when approximately 50 mumoles of drug were bound per 10(6) cells. A 20-min preincubation of cells with chlorpromazine (14.7 microM) inhibited DNA synthesis by 46%, and with penfluridol (4 microM) DNA synthesis was inhibited by 27%. The incorporation of labeled thymidine into the thymidine triphosphate pool was inhibited by chlorpromazine but not by penfluridol, indicating that the drugs produce their growth inhibitory effects by different mechanisms. TDP kinase activity was demonstrated in a particle-free fraction of the cells. Its enzymatic activity was not affected by added chlorpromazine, penfluridol, or calmodulin, suggesting that inhibition of DNA synthesis by these drugs may be a consequence of growth inhibition.

Animals↗

PubMed1979

Penfluridol: a neuroleptic drug designed for long duration of action.

1. Penfluridol is a unique, long-acting, oral neuroleptic belonging to the diphenylbutylpiperidines. The synthesis of penfluridol represented the result of a well-planned scientific search for a highly lipophilic compound structurally related to haloperidol and pimozide. 2. Because of its unusual lipophilicity, penfluridol distributes extensively in fatty tissues following oral administration. This depot effect produces a very slow release of drug from the tissues, and results in a very long duration of activity. 3. Penfluridol is extensively metabolized by oxidative N-dealkylation to afford, as isolated metabolites, the beta-glucuronide conjugate of the diphenylbutyric acid derivative A1 and the unconjugated basic piperidine moiety B1. It is assumed, at this time, that the pharmacological activity is attributable to the parent compound. 4. When administered clinically at oral doses of 20 to 100 mg/week, penfluridol has been found to be an effective antipsychotic agent. This frequency of dosing is consistent with the pharmacokinetic behavior of the drug in man, and does not appear to result in any inappropriate accumulation of the drug in patients. Wide variations in steady-state levels and plasma elimination half-life have been observed in patient populations.

Animals↗

PubMed2005

Safety of haloperidol and penfluridol in pregnancy: a multicenter, prospective, controlled study.

OBJECTIVE: To assess the safety of the butyrophenone neuroleptics haloperidol and penfluridol in pregnancy. METHOD: The rate of major anomalies was compared between a cohort of pregnant women counseled for gestational exposure to haloperidol or penfluridol and a control group counseled for nonteratogen exposure. This multicenter, prospective, controlled study was conducted within the European Network of Teratology Information Services (ENTIS) and included women who contacted 1 of 4 teratology information services for counseling between January 1989 and December 2001. RESULTS: We followed up on the outcomes of 215 pregnancies exposed to haloperidol (N = 188) or penfluridol (N = 27)-78.2% (of 206) were in the first trimester-and compared to outcomes of 631 ENTIS controls. The rate of congenital anomalies did not differ between the haloperidol/penfluridol-exposed group and the control group (6/179 = 3.4% vs. 22/581 = 3.8%, p = .787). No difference was found by limiting the analysis to those exposed to butyrophenones during the first trimester. There were 2 cases of limb defects in the butyrophenone-exposed group (1 after haloperidol and 1 after penfluridol exposure) and none in the controls. A higher rate of elective terminations of pregnancy (8.8% vs. 3.8%, p = .004), a higher rate of preterm birth (13.9% vs. 6.9%, p = .006), a lower median birth weight (3155 g vs. 3370 g, p < .001), and a lower median birth weight of full-term infants (3250 g vs. 3415 g, p = .004) were found in the butyrophenone-exposed group compared to the controls. CONCLUSION: This study suggests that haloperidol and penfluridol do not represent a major teratogenic risk. Since a possible association between butyrophenone exposure and limb defects cannot be ruled out with this sample size, a level II ultrasound with emphasis on the limbs should be considered in pregnancies with first trimester exposure.

Abnormalities, Drug-Induced↗

PubMed1975

[Effects of penfluridol, a psychotropic agent, on operant behavior of rats].

Effects of penfluridol, a diphenylbutylpiperidine type psychotropic agent, on operant behavior were investigated and compared with those of chlorpromazine and haloperidol in rats trained on the following 5 schedules. Fixed ratio (FR 30) of food reinforcement and differential water reinforcement of low rate (DRL 20 sec) schedules were used for positively reinforced behaviors. Continuous (Sidman-type) and discriminated avoidance schedules were used for negatively reinforced behaviors. Conditioned suppression of response (CER) under FR 30 developed by stimulus presentation with electric shock was also applied. When 1 mg/kg of penfluridol was given orally, no change was observed in respondings of all the performances. At higher doses (2 approximately 8 mg/kg, p.o.), the respondings were inhibited in proportion to the dosage except in DRL performance, in which only correct response rate decreased at 8 mg/kg. These inhibitory effects were observed more apparently in the negatively reinforced behaviors than in the positively reinforced ones. Furthermore, a clear dose-effect relationship was obtained in the former. CER was not all attenuated by 2 approximately 8 mg/kg of penfluridol, thus a diazepam-like effect was not confirmed. These behavioral effects suggested that penfluridol has neuroleptic properties similar to those observed with chlorpromazine or haloperidol. However, in general, the inhibitory effects reached the maximum level approximately at 16 hr and lasted for 2 approximately 3 days after oral administration of the drug. Intensity of the effect of penfluridol was estimated to be about 1/8 approximately 1/10 that of haloperidol, according to the results obtained in the avoidance performances.

Animals↗

PubMedDate not supplied

The comparative metabolism and disposition of penfluridol-3H in the rat, rabbit, dog, and man.

Penfluridol, 1-[4,4-bis(4-fluorophenyl)butyl]-4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol, was well absorbed by the rat, rabbit, dog, and man after single oral doses of drug in solution. Penfluridol and its metabolites were widely distributed in tissues of male rats and cleared slowly. The terminal plasma t 1/2 for penfluridol was greater than 40 hr for the rabbit, 227 hr for the dog, and 199 hr for man. Fecal excretion of total radioactivity predominated in the rat, rabbit, and dog whereas in man excretion was evenly divided between urine and feces. The major biotransformation pathways of penfluridol in the rat, rabbit, dog, and man were oxidative N-dealkylation followed by beta-oxidation, conjugation of penfluridol, and conjugation of the acidic metabolites.

Animals↗

PubMed1976

[Activity of a new neuroleptic, penfluridol (R-16341) in long-term treatments].

The difficulties of regular drug intake in long term treatments for psychotic patients gave rise to the need of using medicines at the longest possible intervals, facilitating thus adequate control and regularity. Penfluridol is a neuroleptic meeting that requirement: it is necessary only one dose per week. This paper reviews the results of Penfluridol in 26 patients (20 inpatients and 6 outpatients), ages between 17 and 54 with a mean of 36.8, sex feminine, and the following diagnoses: schizophrenia, paranoid: 14, simple: 8, hebephrenic: 3, catatonic: 1. The patients, divided in two groups of 13 each, had one oral dose a week, of between 10 and 100 mg, during 90 days. The first group took only Penfluridol, suppressing any other medicaments. The other group added Penfluridol to the prescriptions already in use. The results, as described in tables I and II, were evaluated according to 36 items. The general evaluation was positive with no negative biases. The side effects were scarce and temporary: insomnia in 7 cases during the first week, and extra-pyramidal symptoms in another 7 cases, that were controlled with antiparkinsonians. The conclusion is that Penfluridol is a valuable contribution to longterm treatments in psychoses.

Administration, Oral↗

PubMedDate not supplied

A long-term study of penfluridol in chronic schizophrenia.

Penfluridol, a member of the novel diphenylbutylpiperidine class of antipsychotic drugs, is the first long-acting oral neuroleptic. The population of the present study consisted of 24 chronic schizophrenic patients (14 males, ten females) whose treatment with penfluridol was initiated in our previous open/double-blind trial lasting 32 weeks 1; mean age was 42.2 years and mean duration of illness, 15.4 years. During one additional year in an uncontrolled clinical study, penfluridol in the form of 20-mg capsuent procedures included BPRS, CGI, NOSIE, vital signs, and laboratory measurements. During this long-term treatment with penfluridol, the scores of a cluster of BPRS items that included emotional withdrawal, conceptual disorganization, motor retardation, uncooperativeness, and blunted affect showed a progressively significant improvement. This indicated that the Bleulerian primary symptoms in chronic schizophrenics can be improved by the long-term administration of this long-acting neuropleptic with concomitant betterment of social adaptation and activity. The percentage of failure was very low (four patients) and was marked by instability of psychopathology with periods of excitation. The incidence of extrapyramidal reactions necessitating the administration of an antiparkinsonian drug during the length of trial was 35 per cent. No serious effects nor significant laboratory test changes were observed.

Adult↗

PubMed1978

Comparative effects of penfluridol on circling behavior and striatal DOPAC and serum prolactin concentrations in the rat.

A single s.c. injection of penfluridol (3 mg/kg) to rats elevated serum concentrations of prolactin for more than 96 h whereas it increased striatal concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and inhibited apomorphine-induced circling behavior for less than 48 h. The dose of penfluridol needed to elevate serum concentrations of prolactin (0.1 mg/kg) was less than that required to elevate striatal concentrations of DOPAC (1 mg/kg) or inhibit apomorphine-induced circling (3 mg/kg). Furthermore, the penfluridol-induced increase of striatal DOPAC was more susceptible to reversal by apomorphine than was the increase of serum prolactin concentrations. These results suggest that the dopamine receptors in the pituitary, which are normally activated by dopamine released from tuberoinfundibular neurons, are more sensitive to the blocking actions of systemically administered penfluridol than are dopamine receptors in the striatum.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1975

Peroral and parenteral administration of long-acting neuroleptics: a double-blind study of penfluridol compared to flupenthixol decanoate in the treatment of schizophrenia.

Fifty-six out of 60 schizophrenic patients completed a double-blind study of two long-acting neuroleptics, penfluridol (peroral) and flupenthixol decanoate (parenteral). Half of the patients were on maintenance therapy of flupenthixol prior to the study, the other half on penfluridol. The actual double-blind study (12 weeks) was commenced after a preliminary period of 4 weeks, the patients in the two main groups being randomly divided into two further groups, one continuing the medication unchanged, the other changing to the alternative drug. It was found possible to make a sudden switch from penfluridol to flupenthixol decanoate and vice versa without any significant change in the condition of the patient. The same dosage (in 70% of the patients from 40 to 80 mg) of penfluridol was used per week as was employed for flupenthixol decanoate per fortnight. Changes in the intensity of the symptoms (total Brief Psychiatric Rating Scale (BPRS) score) were moe pronounced in the preliminary period (during unchanged treatment) than on changed medication in the blind period. Both drugs induced approximately the same degree of akathisia, Parkinsonism and autonomic side effects. The practical consequences of equipotent therapeutical effect of a peroral and parenteral long-acting neuroleptic are briefly discussed.

Administration, Oral↗

PubMed1983

Penfluridol decreases secretagogue-induced TSH, GH, and LH secretion in vitro: a possible role for calcium-calmodulin.

This study was designed to investigate the effects of penfluridol, a potent neuroleptic calmodulin inhibitor, on basal and secretagogue-stimulated secretion of thyroid-stimulating hormone (TSH), growth hormone (GH), and luteinizing hormone (LH). The drug had no effect on basal TSH or LH release, but decreased GH release in a dose-related manner. TSH, LH, and GH secretion stimulated by calcium ionophore A23187 or 50 mM K+ was decreased by penfluridol as was TSH and GH release stimulated by dibutyryl-cAMP (dbcAMP). Penfluridol reversibly abolished the stimulatory effect of thyrotropin-releasing hormone (TRH) on TSH release in perifused dispersed pituitary cells. The compound inhibited hormonal release without affecting hormonal synthesis and cellular morphology (trypan blue exclusion test). Penfluridol appears to inhibit hormonal secretion by interfering with the calcium-calmodulin system in the anterior pituitary; therefore calmodulin may be an important link in the stimulus-secretion coupling of adenohypophyseal hormones.

Animals↗