Disease relevance of perphenazine

• Perphenazine, 1 mg i.m. daily, a dose known to cause hyperprolactinemia, also impaired the efficacy of A-43818 [1].
• MTW9-P, an ovariectomy-responsive tumor developed in rats maintained on daily perphenazine injections, had 4-fold-higher prolactin binding than had MTW9MtT, an ovariectomy-nonresponsive tumor developed in rats bearing the mammosomatotropic pituitary tumor, MtTW10 [2].
• We describe a patient who we suspect had perphenazine-induced lupus erythematosus with CAC [3].
• A 51 year old woman sustained ventricular fibrillation while receiving perphenazine and protriptyline [4].
• In the lactating rats, there was striking mucosal hyperplasia of both jejunum and ileum but, despite the hyperprolactinaemia, there were no such changes in villus height, crypt depth, or in mucosal wet weight, protein, or DNA/unit length intestine in the perphenazine-injected or pituitary-transplanted animals [5].

Psychiatry related information on perphenazine

• This report presents results of a double-blind, randomized, placebo-controlled clinical trial designed to evaluate the combination of perphenazine and amitriptyline hydrochloride with that of perphenazine alone in the treatment of 35 ambulatory chronic schizophrenic patients in whom depressive symptoms developed [6].
• This double-blind, placebo-controlled study compared the acute efficacy of the selective serotonin reuptake inhibitor citalopram and the neuroleptic perphenazine with placebo for the treatment of psychosis and behavioral disturbances in nondepressed patients with dementia [7].
• This was associated with a significant increase in central nervous system side effects of perphenazine, including oversedation, extrapyramidal symptoms, and impairment of psychomotor performance and memory (p < 0.05) [8].
• The ethers which result from this change have increased lipophilicity compared to their ability to inhibit perphenazine-induced catatonia in rats [9].
• Improvement in two individual BPRS items (hallucinations and conceptual disorganization) was related to serum perphenazine levels and suggestive of a lower therapeutic threshold of 0.8 ng/mL [10].

High impact information on perphenazine

• A significant decrease was seen, however, in basal and perphenazine-stimulated levels of prolactin after pregnancy in both the younger and older first-pregnancy groups but not in the controls [11].
• Importantly, exposure to perphenazine, a compound that induces mammary gland differentiation but does not confer protection, does not induce p53 expression, indicating that p53 is not a differentiation marker [12].
• Proliferation and differentiation of the mammary gland does not explain this phenomenon, as shown by the relative ineffectiveness of perphenazine, a potent mitogenic and differentiating agent [13].
• Rats bearing these tumors were randomly assigned to no treatment, 7-day castration, and 7-day castration followed by 1-, 3-, 7-, and 10-day treatment with estradiol benzoate (5 micrograms) and perphenazine (1 mg) to stimulate prolactin release [14].
• Cytosol estradiol binding was determined in MTW9-MtT, 47.6 +/- 3.6 (N = 9), Kd 9.9 +/- 2.0 X 10(-11) M; MTW9-P, 195.5 +/- 9.1 (n = 16), Kd 27.6 +/- 4.7 X 10(-11) M; MTW9-P after perphenazine was withdrawn, 86.0 +/- 6.0 (n = 6), Kd 9.9 +/- 1.5 X 10(-11) M [15].

Chemical compound and disease context of perphenazine

• To test these hypotheses, we examined PRL responsiveness to TRH and the dopamine antagonist, perphenazine (PZ), in patients with pituitary macroadenomas who had hypopituitarism and others with intact pituitary function (controls) [16].
• CONCLUSION: Fluoxetine when used in combination with perphenazine for the treatment of patients with psychotic depression has a response rate similar to the reported rates of response for tricyclic antidepressants (TCAs) plus antipsychotics, amoxapine, and electroconvulsive therapy [17].
• SKF 38893 (5 mg/kg) reduced the cataleptogenic effect of SCH 23390 but failed to reverse haloperidol- or perphenazine-induced catalepsy [18].
• SKF 38393 (10 mg/kg), however, protected the animals against perphenazine- induced catalepsy [18].
• 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) [19].

Biological context of perphenazine

• Median serum prolactin levels increased from 50 ng/ml in the controls to 570 ng/ml in the perphenazine treated animals and to 600 ng/ml in the pituitary transplanted rats-levels comparable with those seen in lactation (870 ng/ml) [5].
• This study assessed the extent of changes in CYP2D6 isozyme activity in vivo after pretreatment with paroxetine and its consequences on perphenazine kinetics and central nervous system effects [8].
• The data suggest that the disposition of the antipsychotic drug perphenazine covaries with polymorphic debrisoquin hydroxylation [20].
• RESULTS: The CYP2D6 genotype significantly predicted the oral clearance of perphenazine and zuclopenthixol (p < 0.01 by multiple regression) [21].
• The pharmacokinetics of a single oral dose of 6 mg perphenazine was studied in a group of six slow and six rapid hydroxylators of debrisoquin [20].

Anatomical context of perphenazine

• Hyperprolactinaemia, induced by perphenazine injections (5 mg/kg/day for two or seven weeks) or transplantation of four pituitary glands from donor animals to beneath the renal capsule in the recipient, was confirmed by radioimmunoassay [5].
• Perphenazine in breast milk and serum [22].
• Perphenazine, DAPZ, and 7-hydroxyperphenazine affinities were examined in vitro by competition-binding analysis to isolated human receptors expressed in transfected cell lines [23].
• Previously we demonstrated an approximately 20% loss of nerve cells in the basal ganglia of rats following treatment with perphenazine enanthate 3.4 mg/kg s.c. every 2nd week during 12 months [24].
• This progressive decline in yield was greatly reduced if perphenazine had been implanted in the median eminence (ME) [25].

Associations of perphenazine with other chemical compounds

• After a regression in tumor size induced by oophorectomy and daily administration of Tamoxifen, perphenazine was able to restore original tumor size despite continued treatment with Tamoxifen [26].
• During acute treatment nonresponding patients also received brief adjunctive pharmacotherapy with lithium or perphenazine [27].
• The CYP2D6 genotype predicts the oral clearance of the neuroleptic agents perphenazine and zuclopenthixol [21].
• In patients who are at steady state with paroxetine, a reduction of perphenazine dose may be required to prevent central nervous system side effects [8].
• Data on liver enzyme elevations were collected in a retrospective study of 7,263 treatment courses with haloperidol, clozapine, perphenazine, and perazine [28].

Gene context of perphenazine

• Preoperative dynamic testing of PRL secretion in hypopituitary patients demonstrated an increase in PRL levels after TRH, but not after PZ, administration [16].
• Significant relationships between CYP2D6 genotype and steady-state concentrations have been reported for perphenazine, zuclopenthixol, risperidone and haloperidol when used in monotherapy [29].
• CONCLUSIONS: An association was observed between polymorphisms in HTR2A and HTR2C genes and occurrence of acute EPS in schizophrenic patients treated with perphenazine monotherapy [30].
• Maternal administration of perphenazine decreased the incidence of cannibalism in colonies of interferon-gamma, interleukin (IL-4, IL-10, and IL-12) knockout mice of the DBA/1 and C57BL/6 background strains [31].
• The ratio of prolactin depleted from the pituitary gland to prolactin detected in serum after perphenazine injection, which reflected the metabolic clearance rate of prolactin, was highest in two strains with a high incidence of mammary tumors and relatively lower in low-tumor strains [32].

Analytical, diagnostic and therapeutic context of perphenazine

• MTW9-MtT does not regress after ovariectomy (OVEX) alone, while, MTW9-P regresses rapidly whether or not rats are maintained on perphenazine [15].
• In a double-blind study lasting for 4 weeks, the authors compared the effectiveness of amoxapine, an antidepressant with potential antipsychotic properties, with a combination of amitriptyline plus perphenazine in the treatment of 38 patients who had the diagnosis of major depression with psychotic features (psychotic or delusional depression) [33].
• This study points toward a limited information value of CYP2D6 genotyping in the context of therapeutic drug monitoring of perphenazine [34].
• Because EP-stimulated tumours regressed after treatment with bromocriptine and dormant tumours in non-oestrogenized rats grew out after treatment with perphenazine, prolactin is the major growth-stimulating hormone in this model [35].
• Prophylaxis for vomiting by children after tonsillectomy: dexamethasone versus perphenazine [36].

References