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PubMed1997

The effects of perphenazine on the concentration of nortriptyline and its hydroxymetabolites in older patients.

Twenty-five older patients who presented with psychotic depression were treated with a combination of nortriptyline and perphenazine. Plasma levels of nortriptyline, E-, and Z-10-OH nortriptyline (E- and Z-10-OH-NT) were measured before and after addition of perphenazine. The mean (+/-SD) initial nortriptyline dose was 59 +/- 24 mg/day, whereas the mean final nortriptyline and perphenazine doses were 56 +/- 24 and 19 +/- 13 mg/day, respectively. The mean plasma level to dose quotient for perphenazine (0.45 +/- 0.34 nM/mg/day) was comparable to the mean quotient reported previously in older psychotic patients treated with perphenazine alone. After addition of perphenazine, the median quotient of nortriptyline plasma level to nortriptyline dose (L/D) increased significantly (from 6.1 to 8.6). This change was inversely correlated with baseline nortriptyline L/D. The median ratio of E-10-OH-NT to nortriptyline plasma level decreased significantly (from 1.6 to 1.3), whereas the median ratio of Z-10-OH-NT to nortriptyline plasma level did not change significantly. These results are consistent with the known inhibition by perphenazine of the cytochrome P450 2D6 (sparteine/debrisoquine hydroxylase), the major enzyme involved in the oxidative metabolism of nortriptyline, mostly through the formation of E-10-OH-NT. This complex alteration in the metabolism of nortriptyline induced by perphenazine emphasizes the relevance of measuring plasma levels not only of nortriptyline but also of its hydroxymetabolites in older patients who are more likely to be sensitive to their differing cardiovascular, anticholinergic, and cognitive effects.

Aged↗
PubMed1977

Effect of simultaneous treatment with low doses of perphenazine on plasma and urine concentrations of nortriptyline and 10-hydroxynortriptyline.

Plasma levels of nortriptyline and perphenazine were measured in six patients on continuous nortriptyline treatment before, during and after oral administration of perphenazine 4 mg t.i.d. In four patients the plasma levels of the conjugated and unconjugated principal metabolite 10-hydroxynortriptyline were also measured. Urinary excretion of conjugated and unconjugated 10-hydroxynortriptyline and plasma levels of perphenazine were determined in all six patients. During treatment with perphenazine two patients showed a slight increase in the plasma level of nortriptyline. The changes in metabolite excretion rate were inconclusive. Thus, there did not appear to be any important pharmacokinetic interaction between the two drugs at the doses used, which were normal therapeutic doses. The previously reported inhibitory effect of perphenazine on the metabolism of nortriptyline probably depended therefore, either on administration of a higher dose of perphenazine, or on treatment in the reverse sequence--a single dose of nortriptyline was given to patients already receiving perphenazine.

Adult↗
PubMed1997

Prophylaxis for vomiting by children after tonsillectomy: dexamethasone versus perphenazine.

UNLABELLED: The effects of dexamethasone and perphenazine on vomiting after tonsillectomy in children were compared in 226 healthy children aged 2-12 yr. The study was randomized, stratified, blocked, and double-blind. Anesthesia was induced intravenously (I.V.) with propofol or by inhalation with halothane and N2O. Dexamethasone 150 microg/kg or perphenazine 70 microg/kg was administered I.V. after the induction of anesthesia in a double-blind fashion. Perioperative management of emesis, pain, fluids, and patient discharge was all standardized. The groups had similar demographic characteristics. Perphenazine significantly reduced the incidence of in-hospital vomiting compared with dexamethasone (13% vs 36%, P < 0.001). The incidence of out-of-hospital vomiting was almost identical. Overall, the incidence was significantly different for perphenazine vs dexamethasone (33% vs 46%, P = 0.04) using logistic regression analysis. Of note, sex and induction technique were significant predictors of postoperative vomiting (P < 0.05) using logistic regression analysis, with male patients and those patients undergoing I.V. induction vomiting less. In conclusion, perphenazine more effectively decreases vomiting by children after tonsillectomy in an ambulatory hospital setting compared with dexamethasone. IMPLICATIONS: Postoperative vomiting can have many debilitating effects, and children undergoing tonsillectomy are at particular risk. We compared the effects of dexamethasone and perphenazine on vomiting after tonsillectomy in 266 children. We found perphenazine more effective than dexamethasone before discharge from hospital but that the two drugs have similar effects after discharge.

Anesthesia↗
PubMed1981

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

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

Adolescent↗
PubMed1991

A comparison of morphine-perphenazine and midazolam on preoperative sedation and arterial oxygen saturation.

The effectiveness of midazolam and a mixture of morphine-perphenazine premedication to produce sedation and their effects on preoperative oxygen saturation (SaO2) were examined. Eighty-five patients whose SaO2 measured with a pulse oximeter was greater than 90% and who were not receiving narcotic sedatives or oxygen were randomized to three groups. Each patient had his SaO2 recorded before premedication with placebo (saline), midazolam 0.08 mg.kg-1 or morphine 0.15 mg.kg-1 with perphenazine 2.5-5.0 mg im. From 30-90 min later, prior to anaesthesia SaO2 was repeated, and a sedation score was obtained by a blinded observer using a seven point scale. Median sedation scores were greater for midazolam (4) than for morphine-perphenazine (2) and placebo (1) (P less than 0.0001). As well, there was a decrease in the SaO2 in the morphine-perphenazine group (1.7 +/- 2.7%, P less than 0.001) but not in the midazolam and placebo groups (0.1 +/- 2.3%, -0.8 +/- 2.1%). In conclusion midazolam produced greater sedation than morphine-perphenazine and placebo without effect on SaO2 whereas morphine-perphenazine showed a decrease in SaO2 preoperatively.

Adult↗
PubMed1997

Perphenazine decreases vomiting by children after tonsillectomy.

PURPOSE: To test the hypothesis that perphenazine decreases the incidence of vomiting by children after tonsillectomy. METHODS: Healthy children (n = 260) aged 2-12 yr undergoing elective tonsillectomy on a day care surgical basis were studied in this randomised. stratified, blocked, double-blind investigation. General Anaesthesia was induced intravenously with propofol or by inhalation with halothane and N2O. Perphenazine 70 micrograms.kg-1 up to 5 mg or placebo i.v. was administered before surgery. Management of perioperative fluids, emesis and pain were all standardised. RESULTS: The groups were similar with respect to demographic data. There was less vomiting after perphenazine during the first 24 hr after surgery 42% (95% CI = 34%-50%) vs 57% (95% CI = 48%-66%, placebo), P < 0.01. On the day of surgery, both in and out-of hospital emesis were decreased by perphenazine. The perphenazine treated patients required fewer rescue antiemetics than the control group, P < 0.05. Each episode of in-hospital vomiting delayed discharge by 20 +/- 7 min (mean +/- SD), P = 0.007. CONCLUSION: The prophylactic administration of perphenazine decreases vomiting by children after tonsillectomy.

Antiemetics↗
PubMed1990

Inhibition of ox brain glutamate dehydrogenase by perphenazine.

Factors affecting the inhibition of ox brain glutamate dehydrogenase (GDH) by the antipsychotic drug perphenazine have been studied. Inhibition was found to be of mixed type with respect to 2-oxoglutarate and competitive towards NADH. However, the data indicate that perphenazine binds to a site distinct from the catalytic site to which NADH binds. Perphenazine also enhanced the high-substrate inhibition by these two substrates. Inhibition by perphenazine was not affected by the allosteric effector GTP but it was enhanced by increasing pH, in the range of 6.3 to 7.6, and diminished by increasing ionic strength. Low concentrations of perphenazine relieved the inhibition of GDH by phosphatidylserine and cardiolipin. However, at higher concentrations phosphatidylserine did not interfere with the inhibition by perphenazine whereas cardiolipin relieved it. The possible significance of these interactions in terms of the behaviour of this antipsychotic drug in vivo are discussed.

Animals↗
PubMed1976

The effects of perphenazine on self-administration behavior.

In Experiment 1.6 rhesus monkeys prepared with intravenous catheters responded on a fixed-ratio 10 schedule for either an injection of 0.2 mg/kg of cocaine or 0.5 mg/kg of pentobarbital during a daily 3 hr session. The substitution of saline or various doses of perphenazine resulted in very low rates of responding. These results indicate that perphenazine is not a positive reinforcer. Pretreating animals maintained on 0.1 mg/kg or 0.2 mg/kg of cocaine with perphenazine resulted in increases in rate of self-administration at some doses and a decrease in rate at higher doses. The dose of perphenazine which resulted in the maximal increase in cocaine self-administration was directly related to the dose of cocaine maintaining responding. Pretreating animals maintained on 0.5 mg/kg of pentobarbital with perphenazine had no effect at doses which increased cocaine self-administration but decreased rate of pentobarbital self-administration at higher doses. These results indicate that perphenazine is capable of antagonizing some of the effects of cocaine.

Animals↗
PubMed2005

Stability and characterization of perphenazine aerosols generated using the capillary aerosol generator.

Perphenazine (a potent antiemetic) was aerosolized using capillary aerosol generator to generate respirable condensation aerosols from drug in propylene glycol (PG) solutions, by pumping the liquids through a heated capillary tube. The study characterized the stability of perphenazine during and following aerosol generation. The stability-indicating HPLC method (C-8 column with a mobile phase of 52% 0.01 M pH 3.0 acetate buffer+48% acetonitrile) also enabled the study of perphenazine stability in solution under acidic, basic, oxidizing and photolysing conditions. An LC-MS (ESI+) method was used to characterize the degradation products. Perphenazine was found to be stable in acidic and basic conditions, while perphenazine sulfoxide was the major product formed in dilute peroxide solutions. Two photo-degradation products were formed in PG that were tentatively identified by LC-MS; one of these was synthesized and confirmed to be 2-[4-(3-phenothiazin-10-yl-propyl)-piperazino]-ethanol. Both photolysis products showed that aromatic dechlorination had occurred and one appeared to also result from interaction with the solvent. Within an aerosolization energy window of 84-95 J, fine particle aerosols were generated from perphenazine PG formulations with no significant degradation. Small amounts of degradation products were produced in all samples during aerosolization at elevated (non-optimal) energies. These were largely consistent with those seen to result from oxidation and photolysis in solution, showing that oxidation and dehalogenation appeared to be the main degradation pathways followed when the CAG system was overheated.

Aerosols↗
PubMed2002

Quantification of perphenazine in eurasian otter (Lutra lutra lutra) urine samples by gas chromatography-mass spectrometry.

Perphenazine enanthate has been used in wild animals as a tranquilizer during the period of adaptation to new environments to reduce stress, mortalities and injuries. A gas chromatographic procedure for the quantitative measurement of perphenazine in otter urine has been developed and validated. The method involved an enzymatic hydrolysis with beta-glucuronidase-arylsulfatase from Helix pomatia, followed by a solid-phase extraction with Bond Elut Certify cartridges. The resulting organic phase was evaporated, and the dry extract was derivatised with MSTFA to form the O-TMS derivative. The derivatised extracts were analysed by gas chromatography-mass spectrometry using SIM acquisition mode, measuring three diagnostic ions (m/z 246, 372 and 475). Another phenothiazine derivative, fluphenazine, was used as the internal standard (I.S.). Extraction recoveries for perphenazine and I.S. were 87.6 +/- 8.2% (n=4) and 106.7 +/- 13.4% (n=4), respectively. The calibration curves were linear in the range from 4 to 100 ng/ml (r2=0.99). The limits of detection and quantification were estimated as 1.2 and 3.5 ng/ml, respectively. Precision and accuracy obtained in intra-assay studies were in the ranges of 1.3-8.7 and 1.7-19.5%, respectively, using control samples containing 6, 16 and 60 ng/ml of perphenazine. In inter-assay experiments, precision ranged from 4.3 to 14.9% and accuracy from 3.1 to 11.8%. Examples of the application of the perphenazine quantification method in otter urines after administration of perphenazine enanthate are presented.

Animals↗
PubMed2000

Identification of the human cytochrome P450 isoforms mediating in vitro N-dealkylation of perphenazine.

AIMS: To identify the human cytochrome P450 (CYP) isoforms mediating the N-dealkylation of the antipsychotic drug perphenazine in vitro and estimate the relative contributions of the CYP isoforms involved. METHODS: cDNA-expressed CYP isoforms were used to identify the isoforms that are able to mediate the N-dealkylation of perphenazine, which is considered a major metabolic pathway for the drug. Using human liver microsomal preparations (HLM), inhibition studies were carried out to establish the relative contributions of the CYP isoforms involved in the N-dealkylation reaction. RESULTS: CYP isoforms 1A2, 3A4, 2C8, 2C9, 2C18, 2C19 and 2D6 were able to mediate the N-dealkylation of perphenazine. Reaction velocities and their relative abundance in HLM suggested that CYP1A2, 3A4, 2C19 and 2D6 were the most important contributors to N-dealkylation. Apparent Km values of CYP1A2 and CYP2D6 were in the range 1-2 microM, and Km values of CYP2C19 and CYP3A4 were 14 microM and 7.9 microM, respectively. Ketoconazole inhibition of N-dealkylation mediated by a mixed HLM indicated that CYP3A4 accounted for about 40% of perphenazine N-dealkylation at therapeutically relevant concentrations. The contribution of the CYP isoforms 1A2, 2C19 and 2D6 amounted to 20-25% each as measured by the percentage inhibition obtained by addition of furafylline, fluvoxamine or quinidine, respectively. HLM-mediated N-dealkylation of perphenazine accounted for 57% of the total amount of substrate consumed during incubation. CONCLUSIONS: The present in vitro study suggests that CYP isoforms 1A2, 3A4, 2C19 and 2CD6 are primarily involved in the N-dealkylation of perphenazine. The relatively modest role of CYP2D6 is at variance with in vivo studies, which indicate a greater contribution of this isoform. Alternative metabolic pathways, corresponding to 43% of the HLM-mediated metabolism of the drug, may depend more strongly on CYP2D6.

Alkylation↗
PubMed1979

[A comparative study of the longacting neuroleptics perphenazin-enanthate and fluspirilene (author's transl)].

The clinical profile and side-effects of perphenazin-enanthate and fluspirilene were compared in 45 female chronic schizophrenic patients. 100 mg perphenazin-enanthate fortnightly or 8 mg fluspirilene weekly were administered. During the four months' period the psychopathological and somatic symptoms were evaluated by means of the AMP-system and the self-evaluation scale PD-S (v. Zerssen). A covariance analysis was carried out covering 12 AMP syndromes and 6 PD-S factors. The antipsychotic effect of both drugs was similar concerning the paranoid, the hallucinatory-desintegrative and the catatonic syndromes. A significant difference with regard to perphenazin-enanthate was found in the AMP-syndromes of hostility, hypochondria, and autonomic symptoms. Neither drug induced any depression. In the self-rating scale, the factors anxiousness and depressivity were also significantly lower in the perphenazin-enanthate regime. The patients under perphenazin-enanthate required a smaller amount of antiparkinsonian drugs. The more pronounced sedative effect of perphenazin-enanthate can be recommended in hostile and restless schizophrenic patients, whereas fluspirilene should be given to inactive autistic patients.

Chronic Disease↗
PubMed1995

The efficacy of prophylactic ondansetron, droperidol, perphenazine, and metoclopramide in the prevention of nausea and vomiting after major gynecologic surgery.

The prophylactic antiemetic efficacy of intravenous (i.v.) ondansetron, droperidol, perphenazine, and metoclopramide was evaluated in a prospective, double-blind study of 360 ASA physical status I-III patients undergoing total abdominal hysterectomy (TAH). Subjects were randomized to receive i.v., one of ondansetron 4 mg, droperidol 1.25 mg, perphenazine 5 mg, metoclopramide 10 mg, or placebo prior to induction of anesthesia. Hypotension immediately after administration of metoclopramide was observed in two patients and four patients given ondansetron developed profound systolic hypotension at induction of anesthesia. Twenty-two percent of patients receiving droperidol became sedated. Postoperatively, patients developing severe nausea, retching, or vomiting, defined as severe emetic sequelae (SES), were deemed to have failed antiemetic prophylaxis and received antiemetic rescue. A significantly larger number of patients who received i.v. ondansetron (63%), droperidol (76%), and perphenazine (70%) were free of SES when compared to placebo (43%); P < 0.05. Metoclopramide was ineffective. Although ondansetron, droperidol, and perphenazine were effective in providing antiemetic prophylaxis, only i.v. perphenazine was free of side effects. Hence, we conclude that perphenazine is the best choice for antiemetic prophylaxis after TAH.

Akathisia, Drug-Induced↗
PubMed1999

Preoperative oral antiemetics for reducing postoperative vomiting after tonsillectomy in children: granisetron versus perphenazine.

UNLABELLED: In a prospective, randomized, double-blinded trial, we evaluated the efficacy of two antiemetics given orally, granisetron and perphenazine, for preventing postoperative vomiting after tonsillectomy with or without adenoidectomy in children. One hundred pediatric patients, ASA physical status I, aged 4-10 yr, received either granisetron 40 microg/kg or perphenazine 70 microg/kg (n = 50 each) orally 1 h before surgery. We used a standard general anesthetic technique. The rate of complete response, defined as no emesis and no need for rescue antiemetic medication, during 0-3 h after anesthesia was 86% with granisetron and 60% with perphenazine; the corresponding rate 3-24 h after anesthesia was 86% and 62%, respectively (P < 0.05). No serious adverse events were observed in any of the groups. In conclusion, preoperative oral granisetron is more effective than perphenazine for preventing postoperative vomiting in children undergoing tonsillectomy with or without adenoidectomy. IMPLICATIONS: We compared the efficacy of granisetron and perphenazine given orally for preventing postoperative vomiting after tonsillectomy with or without adenoidectomy in children. Preoperative oral granisetron was more effective than perphenazine.

Adenoidectomy↗
PubMed2006

Cost-effectiveness of second-generation antipsychotics and perphenazine in a randomized trial of treatment for chronic schizophrenia.

BACKGROUND: Second-generation antipsychotics have largely replaced first-generation antipsychotics for the treatment of schizophrenia, but a large-scale cost/effectiveness analysis has not been attempted. METHOD: Patients with schizophrenia (N=1,493) were assigned to treatment with a first-generation antipsychotic (perphenazine) or one of four second-generation drugs (olanzapine, quetia-pine, risperidone, or ziprasidone) and followed for up to 18 months. Patients with tardive dyskinesia were prohibited from assignment to perphenazine. Patients could be reassigned at any time to another second-generation drug, including clozapine, but not to perphenazine. The cost analysis included medications plus health services use. Quality-adjusted life year (QALY) ratings were assessed on the basis of Positive and Negative Syndrome Scale (PANSS) subscale scores and side effects. An intention-to-treat analysis included all available observations, classified by initial drug assignment, and costs of reassignment of most patients to another second-generation drug. The analysis was repeated considering only treatment on initially assigned medications. RESULTS: Although QALY ratings, PANSS scores, and other quality of life measures indicated modest improvement over 18 months, there were no significant differences between perphenazine and any second-generation medication. Average total monthly health care costs were 300 dollars-600 dollars (20%-30%) lower for perphenazine than for second-generation antipsychotics because of lower drug cost. Differences in costs remained when maximally discounted drug prices were used for all patients and when only observations during treatment with the first medication were included. CONCLUSIONS: Treatment with perphenazine was less costly than treatment with second-generation antipsychotics with no significant differences in measures of effectiveness. However, the trial was limited by a high dropout rate, and longer-term neurological and metabolic side effects require further study.

Adolescent↗
PubMed1975

Amitriptyline-perphenazine interaction in ambulatory schizophrenic patients. A controled study of drug interaction.

In a double-blind placebo, controlled clinical study, lasting 12 weeks, 48 male and 48 female ambulatory schizophrenic patients were randomly assigned to one of four treatments: placebo; amitriptyline hydrochloride, 125 mg/day; perphenazine, 20 mg/day; or amitriptyline-perphenazine, 20 mg/day. Treatment groups contained an equal number of male and female patients. Perphenazine alone or in combination was substantially more effective in reducing psychopathological disorder than was the placebo, but there was no evidence to indicate the superiority of the amitriptyline-perphenazine combination over perphenazine alone. Amitriptyline alone was not substantially better than placebo and could not be considered an efficacious medication for the maintenance treatment of these patients. Less response to treatment was made by patients with longer-term records of prior hospitalization.

Adult↗
PubMed1982

Effect of perphenazine on growth and zinc-65 uptake of the rat prostatic adenocarcinoma, R 3327.

Prolactin affects the growth and function of both normal and carcinatomous prostate tissue. Therefore, the effect of modifying prolactin secretion on the growth of the adenocarcinoma of the rat prostate (R3327) was studied, utilizing chronic administration of the dopamine antagonist perphenazine. At 4 and 8 weeks after tumor inoculation, perphenazine (0.5 and 1.0 mg per dose) was injected for 12-16 weeks. Tumors weighed at autopsy showed that the 0.5 mg dose resulted in significantly smaller and the 1.0 mg dose, in significantly larger tumors than the controls. Perphenazine at both doses increased serum prolactin, but the increase was greater when 0.5 mg was administered. There was a higher uptake of 65Zn when the tumor growth was inhibited as in the animal receiving 0.5 mg of perphenazine. Several possible explanations are offered for the results, including the fact that prolactin might follow a bell-shaped curve in its effect on the tumor and that perphenazine might have other mechanisms of action besides dopamine antagonism.

Adenocarcinoma↗
PubMed1982

Dose-response relationships of perphenazine in the treatment of acute psychoses.

A group of 26 acute psychotic patients received continuous oral treatment with perphenazine for a period of 5 weeks. Once-weekly blood samples were drawn for measurements of perphenazine levels and, simultaneously, the therapeutic outcome was registered. Another 26 acute psychotic patients received continuous oral treatment with perphenazine for a period of up to 4 weeks. A single blood sample was drawn and the perphenazine concentration was related to the appearance of extrapyramidal side effects. The following conclusions were made: (1) a high risk of provoking extrapyramidal side effects was associated with plasma levels of perphenazine above 3 nmol/l; (2) plasma levels below 2 nmol/l were associated with a poor therapeutic outcome; (3) a 'therapeutic window' between 2 and 3 nmol/l gives maximal therapeutic effect with a low risk of provoking extrapyramidal side effects.

Acute Disease↗