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1.
Toxicol Lett ; 367: 76-87, 2022 Aug 15.
Article in English | MEDLINE | ID: mdl-35914675

ABSTRACT

Antipsychotic drugs represent a class of lysosomotropic drugs widely used in clinical practice. However, the hepatotoxicity of these drugs has been reported in recent years. Therefore, understanding the changes in cellular homeostasis mediated by these drugs is of great significance for revealing the true mechanisms underlying hepatotoxicity. Perphenazine is a classical antipsychotic drug that can reportedly induce extrapyramidal and sympatholytic side effects. The present research focuses on the toxicity effect of perphenazine on normal human hepatocytes. To assess the hepatotoxicity of continuous administration of perphenazine and investigate potential mechanisms related to apoptosis, human normal L02 hepatocytes were exposed to 10-40 µM perphenazine in vitro. The results showed that perphenazine inhibited cell viability in a concentration and time-dependent manner. Furthermore, 30 µM perphenazine induced intense lysosome vacuolation, impaired lysosomal membrane, and induced lysosomal membrane permeabilization (LMP), ultimately triggering lysosomal cell death in L02 cells. Knockdown cathepsin D(CTSD) also ameliorated perphenazine-induced liver injury via the inhibition of LMP. In vivo, ICR mice received intragastric administration of 10-180 mg/kg B.W. perphenazine every other day for 21 days. 180 mg/kg perphenazine significantly increased histological injury and aminotransferases compared with control. Taken together, our findings suggest that perphenazine can trigger hepatotoxicity through lysosome disruption both in vitro and in vivo.


Subject(s)
Chemical and Drug Induced Liver Injury , Perphenazine , Animals , Apoptosis , Chemical and Drug Induced Liver Injury/pathology , Humans , Lysosomes , Mice , Mice, Inbred ICR , Perphenazine/metabolism , Perphenazine/toxicity
2.
Curr Opin Investig Drugs ; 11(1): 92-100, 2010 Jan.
Article in English | MEDLINE | ID: mdl-20047163

ABSTRACT

In schizophrenia, a psychiatric disorder that affects approximately 1% of the global population and is associated with substantial disability, a significant proportion of patients (usually estimated to be at least 30%) fail to respond to treatment, and many patients have difficulty continuing treatment because of side effects. At the time of publication, all available medications for schizophrenia targeted dopamine and other monoamine neurotransmitters. However, a substantial amount of research suggests that patients with schizophrenia have underlying deficits within the GABA neurotransmitter system. BL-1020, being developed by BioLineRx Ltd under license from Tel Aviv University Ltd and Bar-Ilan Research & Development Co Ltd, is a novel compound consisting of the well-established antipsychotic drug perphenazine and GABA. Preclinical studies of BL-1020 indicated that the compound penetrated the brain and was efficacious in rodents, with a significant reduction in side effects compared with the administration of perphenazine. BL-1020 was well tolerated in all clinical trials conducted, and clinically meaningful improvements were demonstrated in phase II trials in patients with schizophrenia. Further data from phase II and subsequent phase III trials will be required to derive conclusions for BL-1020 regarding overall efficacy.


Subject(s)
Antipsychotic Agents/pharmacology , Antipsychotic Agents/therapeutic use , Dopamine/metabolism , Perphenazine/analogs & derivatives , Receptors, GABA-A/drug effects , Receptors, GABA-A/metabolism , Schizophrenia/drug therapy , gamma-Aminobutyric Acid/analogs & derivatives , Animals , Antipsychotic Agents/adverse effects , Antipsychotic Agents/pharmacokinetics , Antipsychotic Agents/toxicity , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Contraindications , Drug Evaluation, Preclinical , Humans , Patents as Topic , Perphenazine/adverse effects , Perphenazine/pharmacokinetics , Perphenazine/pharmacology , Perphenazine/therapeutic use , Perphenazine/toxicity , Quantitative Structure-Activity Relationship , gamma-Aminobutyric Acid/adverse effects , gamma-Aminobutyric Acid/pharmacokinetics , gamma-Aminobutyric Acid/pharmacology , gamma-Aminobutyric Acid/therapeutic use , gamma-Aminobutyric Acid/toxicity
3.
Pharmacol Biochem Behav ; 94(2): 219-26, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19666045

ABSTRACT

The present study explored the involvement of cyclooxygenase (COX) in the pathophysiology of Parkinson's disease (PD). Further, the protective effect of COX-inhibitors against perphenazine-induced catatonia and 1-methyl-4-phenyl-1, 2, 3, 6-tertahydropyridine (MPTP)-induced striatal lesions in rats was evaluated. Administration of perphenazine (5 mg/kg., i.p.) produced severe catatonia (rigid behavior) in rats; the maximum score reached at 4 h (estimated as 100% AUC) and declined within 24 h. An intrastriatal injection of MPTP produced hypolocomotor activity in rats. Both perphenazine and MPTP produced oxidative stress as demonstrated by increased levels of lipid peroxides, nitrite and decreased antioxidant defense system in the whole brain and striatal region, in particular. Pretreatment with various COX-inhibitors viz. rofecoxib, celecoxib, nimesulide or naproxen offered protection against perphenazine-induced catatonia, the effect was more pronounced with rofecoxib. Rofecoxib and celecoxib (both selective COX-2 inhibitors) also reversed the perphenazine-induced oxidative stress. Further, prior treatment with rofecoxib (8 mg/kg, p.o.) reversed both the behavioral and biochemical changes induced by MPTP. These results suggest that COX-inhibitors particularly, rofecoxib offers protection against drug-induced catatonia and MPTP-induced striatal lesions possibly by modulating dopaminergic neurotransmission and/or oxidative stress.


Subject(s)
Catatonia/prevention & control , Corpus Striatum/pathology , Cyclooxygenase Inhibitors/therapeutic use , MPTP Poisoning/prevention & control , Neuroprotective Agents/therapeutic use , Animals , Catatonia/chemically induced , Catatonia/enzymology , Corpus Striatum/drug effects , Corpus Striatum/enzymology , Cyclooxygenase Inhibitors/pharmacology , MPTP Poisoning/enzymology , Male , Motor Activity/drug effects , Motor Activity/physiology , Neuroprotective Agents/pharmacology , Oxidative Stress/drug effects , Oxidative Stress/physiology , Perphenazine/toxicity , Rats , Rats, Wistar
4.
Naunyn Schmiedebergs Arch Pharmacol ; 380(2): 125-33, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19430764

ABSTRACT

Antipsychotic drug perphenazine belongs to the phenothiazine group commonly reported to induce ECG changes and tachyarrhythmias. Data about its effect on ionic membrane currents in cardiomyocytes are missing. We analyzed the effect of perphenazine (0.1-100 microM) on fast sodium current I (Na) and transient outward potassium current I (to) in enzymatically isolated rat right ventricular myocytes by the whole-cell patch-clamp technique at room temperature. Perphenazine reversibly blocked I (Na) (reducing its amplitude; IC(50) = 1.24 +/- 0.10 microM) and I (to) (accelerating its apparent inactivation with a slight decrease of its amplitude; IC(50) = 38.2 +/- 3.5 microM, evaluated from changes of the time integral). The fast time constant of I (to) inactivation was significantly decreased in a concentration-dependent manner (IC(50) = 30.0 +/- 6.6 microM). Both blocks were use and frequency dependent at 3.3 Hz. We conclude that perphenazine causes concentration-, use-, and frequency-dependent block of I (Na) and I (to) . Computer simulations suggest that perphenazine interacts preferentially with I (Na) channels in inactivated states and with I (to) channels in both open and open-inactivated states.


Subject(s)
Antipsychotic Agents/toxicity , Perphenazine/toxicity , Potassium Channels/drug effects , Sodium Channels/drug effects , Animals , Antipsychotic Agents/administration & dosage , Computer Simulation , Dose-Response Relationship, Drug , Heart Ventricles/cytology , Heart Ventricles/drug effects , Inhibitory Concentration 50 , Male , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Patch-Clamp Techniques , Perphenazine/administration & dosage , Potassium Channels/metabolism , Rats , Rats, Wistar , Sodium Channels/metabolism
5.
Chem Res Toxicol ; 19(1): 156-63, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16411669

ABSTRACT

This paper reports the results of an in vitro evaluation of the phototoxic potential of stable photoproducts formed by UVA photolysis of three phenothiazines, perphenazine, fluphenazine, and thioridazine, in a water environment. Perphenazine gave a single product due to dechlorination. From thioridazine, the two major products formed; the endocyclic sulfoxide and the endocyclic N-oxide in which the 2-SCH3 substituent was replaced by a hydroxy group were tested. From fluphenazine, two products have been examined as follows: an exocyclic N-piperazine oxide and a carboxylic acid arising from hydrolysis of the 2-CF3 group. The phototoxicity of the isolated photoproducts has been studied in order to determine their possible involvement in the photosensitizing effects exhibited by the parent drugs, using hemolysis and 3T3 fibroblasts viability as in vitro assays. As fluphenazine, perphenazine, and thioridazine did, some photoproducts proved phototoxic. In particular, the perphenazine dechlorinated photoproduct and the thioridazine N-oxide were found to exert phototoxic properties similar to the parent compounds. Therefore, our data suggest that some phenothiazine photoproducts may play a role in the mechanism of photosensitivity of these drugs. Because some of these photoproducts correspond to metabolic products of phenothiazines found in humans, it cannot be ruled out that metabolites of phenothiazines can be phototoxic in vivo.


Subject(s)
Antipsychotic Agents/toxicity , Phenothiazines/toxicity , Animals , Antipsychotic Agents/chemistry , BALB 3T3 Cells , Cell Proliferation , Cell Survival , Erythrocytes/drug effects , Fluphenazine/chemistry , Fluphenazine/toxicity , Hemolysis , In Vitro Techniques , Mice , Perphenazine/chemistry , Perphenazine/toxicity , Phenothiazines/chemistry , Photolysis , Solutions , Thioridazine/chemistry , Thioridazine/toxicity , Ultraviolet Rays
6.
Int J Biochem Cell Biol ; 37(4): 901-8, 2005 Apr.
Article in English | MEDLINE | ID: mdl-15694848

ABSTRACT

In order to gain insights into the mechanism of phototoxicity of the neuroleptic drugs fluphenazine, perphenazine and thioridazine in cultured cells, studies were performed with murine 3T3 fibroblasts, aimed at identifying some cellular targets responsible for photoinduced cell death and possible cytotoxic reactive species involved in the photosensitization process. 3T3 fibroblasts incubated with 5 microM drugs and irradiated with UVA light (up to 8 J/cm2) underwent cell death, the extent of which depended on light dose. Of the three drugs, fluphenazine exhibited the highest phototoxicity and 100% cell death was achieved with a light dose of 5 J/cm2. Superoxide dismutase and alpha-tocopherol exerted a dose-dependent protective effect against drug phototoxicity, whereas N-acetylcysteine failed to do so. These findings indicate that superoxide anion and other free radical intermediates, generated in lipophilic cellular environments, play a role in photoinduced toxicity. Phototreatment of drug-loaded cells induces release of the cytosolic enzyme lactate dehydrogenase and causes loss of activity of mitochondrial NADH dehydrogenase, indicating that plasma membrane and mitochondria are among the targets of the phototoxicity of these drugs.


Subject(s)
Antipsychotic Agents/toxicity , Cell Membrane/drug effects , Fluphenazine/toxicity , Mitochondria/drug effects , Perphenazine/toxicity , Thioridazine/toxicity , Ultraviolet Rays , 3T3 Cells , Animals , Cell Membrane/radiation effects , Mice , Mitochondria/radiation effects
7.
Pharmacology ; 68(2): 81-8, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12711835

ABSTRACT

L-Dopa plus carbidopa treatment remains the first-line therapy in Parkinson's disease. The use of catechol-O-methyltransferase (COMT) and/or monoamine oxidase (MAO) inhibitors as an adjunct to L-dopa therapy has yielded varying degrees of success. Quercetin, a flavonoid present in many plants, is reported to inhibit COMT and MAO activities, the key enzymes involved in the metabolism of dopamine. In the present study we have studied the effect of quercetin on the L-dopa plus carbidopa combination against perphenazine and reserpine-induced catalepsy in rats. Neuroleptic-induced catalepsy is a widely accepted animal model for testing the drugs used in parkinsonism. Catalepsy in rats was induced by administration of perphenazine (5 mg/kg i.p.) or reserpine (2.5 mg/kg i.p.) + alpha-methyl-P-tyrosine (200 mg/kg i.p.). Catalepsy in animals was assessed by using the bar test. The quercetin dose (25-100 mg/kg, p.o.) dependently reversed perphenazine- as well as reserpine-induced catalepsy. When quercetin was combined with a subthreshold dose of L-dopa plus carbidopa, the anticatatonic effect was potentiated. Pretreatment with a central COMT inhibitor, 3,5-dinitrocatechol (OR-486) (10 mg/kg p.o.), or a MAO-B inhibitor, selegiline (5 mg/kg i.p.), also potentiated the actions of threshold dose of quercetin against perphenazine- or reserpine-induced catalepsy. On the other hand adenosine (100 mg/kg i.p.), which is known to decrease the release of catecholamines through an action on presynaptic A(1) receptors, partly reversed the protective effect of quercetin against perphenazine-induced catalepsy. Quercetin through its COMT and MAO enzyme-inhibiting properties might potentiate the anticatatonic effect of L-dopa plus carbidopa treatment. The results of the present study strongly suggest that quercetin could serve as an effective adjunct to L-dopa therapy in Parkinson's disease.


Subject(s)
Antiparkinson Agents/therapeutic use , Catalepsy/drug therapy , Catechol O-Methyltransferase Inhibitors , Levodopa/therapeutic use , Quercetin/therapeutic use , Animals , Catalepsy/chemically induced , Male , Monoamine Oxidase Inhibitors/therapeutic use , Perphenazine/toxicity , Rats , Rats, Wistar , Reserpine/toxicity
8.
Indian J Exp Biol ; 40(8): 882-8, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12597016

ABSTRACT

Parkinson's disease is one of the most common neurodegenerative disorders affecting large majority of population who are older than age of 65. Apart from dopamine, acetylcholine and glutamate, adenosinc has also been identified in the basal ganglia. Adenosine modulates the release of a variety of neurotransmitters including dopamine. In order to establish adenosine-dopamine interactions in drug-induced catatonia we studied the effect of adenosine in drug-induced catatonia in mice. In the present study adenosine dose dependently produced catatonia when assessed on rota-rod and bar tests in mice. Adenosine also potentiated the catatonic effect of perphenazine. L-dopa plus carbidopa or OR-486 (a potent centrally acting COMT inhibitor) completely reversed adenosine-induced catatonia. Since reversal by scopolamine of adenosine-induced catatonia was not to the same extent as with l-dopa and OR-486 it appears that catecholamines particularly dopamine rather than cholinergic modulation is more important in adenosine induced catatonia. The motor dysfunction (catatonia) could be easily assessed using rota-rod test apparatus in mice.


Subject(s)
Adenosine/toxicity , Brain/drug effects , Catatonia/chemically induced , Animals , Antiparkinson Agents/pharmacology , Carbidopa/pharmacology , Catatonia/pathology , Catatonia/prevention & control , Catechol O-Methyltransferase Inhibitors , Catechols/pharmacology , Disease Models, Animal , Drug Synergism , Drug Therapy, Combination , Female , Injections, Intraperitoneal , Levodopa/pharmacology , Male , Mice , Motor Activity/drug effects , Perphenazine/toxicity
9.
Cell Mol Neurobiol ; 21(6): 705-16, 2001 Dec.
Article in English | MEDLINE | ID: mdl-12043843

ABSTRACT

Typical neuroleptic therapy often results in extrapyramidal symptoms (EPS) and tardive dyskinesia (TD). Recent reports reveal neurotoxic activity in some neuroleptics. We hypothesized that neurotoxicity might be implicated in EPS. This study aims to evaluate the neurotoxic activity of typical and atypical neuroleptics and to determine the possible role of neurotoxicity in neuroleptic-induced EPS. Perphenazine, haloperidol, clozapine, sulpiride, and risperidone (10-100 microM) were administered, either alone or combined with dopamine, to primary mouse neuronal or intact brain culture and to a human neuroblastoma (NB) cell line (SK-N-SH). Cell viability (measured by neutral red and alamar blue), DNA fragmentation (flow cytometry-NB) were determined. Neuroblastoma: perphenazine, clozapine, and haloperidol (100 microM) decreased viability by 87, 43, and 34% respectively. Sulpiride and risperidone were not toxic. At 10 microM, toxicity decreased markedly. Dopamine (125 microM) potentiated the perphenazine-induced toxicity. Flow cytometry of NB cells treated with perphenazine (2.5-40 microM) showed an increase (perphenazine 20 microM, 40 microM, 48 h) in fragmented DNA (74.7% and 95.0% vs. 8.7% in controls). Lower concentrations increased the G1 phase and decreased S phase in the cell cycle. In primary neurons, perphenazine, haloperidol, and clozapine, but not risperidone and sulpiride, induced a significant neurotoxic effect, which, in intact brain culture, was absent (haloperidol and clozapine) or lowered (perphenazine). Dopamine (0.5 mM) did not modify the effect of the drugs in the primary cultures. Neuroleptics possess differential neurotoxic activity with higher sensitivity of neoplasm tissue (NB compared to primary cultures). The order of toxicity was perphenazine > haloperidol = clozapine:sulpiride and risperidone were not toxic. Neurotoxicity is independent of dopamine and is associated with cell cycle arrest and apoptosis. With the exception of clozapine, neurotoxicity seems relevant to neuroleptic-induced EPS and TD.


Subject(s)
Antipsychotic Agents/toxicity , Brain/drug effects , Dyskinesia, Drug-Induced/metabolism , Neurons/drug effects , Neurotoxins/toxicity , Animals , Basal Ganglia Diseases/chemically induced , Basal Ganglia Diseases/metabolism , Basal Ganglia Diseases/physiopathology , Brain/metabolism , Brain/physiopathology , Cell Cycle/drug effects , Cell Survival/drug effects , Cell Survival/physiology , Clozapine/toxicity , DNA Fragmentation/drug effects , Dopamine/metabolism , Dopamine/toxicity , Dose-Response Relationship, Drug , Dyskinesia, Drug-Induced/genetics , Dyskinesia, Drug-Induced/physiopathology , Female , Haloperidol/toxicity , Humans , Iatrogenic Disease/prevention & control , Mice , Mice, Inbred ICR , Neurons/metabolism , Perphenazine/toxicity , Pregnancy , Risperidone/toxicity , Tumor Cells, Cultured
10.
J Neural Transm (Vienna) ; 103(10): 1153-61, 1996.
Article in English | MEDLINE | ID: mdl-9013402

ABSTRACT

To clarify clinical roles of sigma receptor binding affinity of neuroleptics, neck dystonia induced by microinjection of sigma receptor ligands and neuroleptics into rat red nucleus was investigated. DTG and (+)-3-PPP, putative sigma receptor agonists, induced neck dystonia in dose-dependent and reversible manner. Haloperidol and perphenazine induced dystonia in the same way as sigma receptor agonists, whereas zotepine and (-)-sulpiride did not. The rank order of potency in induction of dystonia and sigma receptor affinity of these compounds showed positive correlation. Although BMY-14802 has a high affinity for sigma receptors, it never produced dystonia by itself. On the other hand, combined injection of BMY-14802 with DTG attenuated DTG-induced dystonia. Therefore, it is suggested that typical neuroleptics such as haloperidol act agonistic and atypical neuroleptics such as BMY-14802 act antagonistic at rubral sigma receptors in the induction of neck dystonia.


Subject(s)
Antipsychotic Agents/therapeutic use , Dopamine Antagonists/toxicity , Dystonia/drug therapy , Guanidines/toxicity , Nerve Tissue Proteins/antagonists & inhibitors , Piperidines/toxicity , Pyrimidines/therapeutic use , Receptors, sigma/antagonists & inhibitors , Red Nucleus/drug effects , Torticollis/drug therapy , Animals , Antipsychotic Agents/administration & dosage , Antipsychotic Agents/pharmacology , Antipsychotic Agents/toxicity , Dibenzothiepins/toxicity , Dopamine D2 Receptor Antagonists , Dystonia/chemically induced , Haloperidol/toxicity , Male , Microinjections , Nerve Tissue Proteins/physiology , Perphenazine/toxicity , Pyrimidines/administration & dosage , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley , Receptors, Dopamine D2/physiology , Receptors, sigma/agonists , Receptors, sigma/physiology , Red Nucleus/physiology , Sulpiride/toxicity , Torticollis/chemically induced
11.
Acta Pol Pharm ; 51(3): 275-81, 1994.
Article in English | MEDLINE | ID: mdl-7872020

ABSTRACT

The toxicity of "Polfa" perphenazine and its profile of pharmacological properties were estimated. LD50 values calculated in rats were 2000 mg/kg and 325 mg/kg, after p.o. and i.p. administration respectively. Chronic toxicity of the perphenazine was evaluated during the period of 3 month of the drug treatment p.o. or i.p. in the rats and mice. Decrease of the locomotor activity of perphenazine was observed after the highest dose (15 mg/kg) of the drug, only in the first weeks of the experiment. Also the cataleptogenic effect of perphenazine observed in the mice was diminished during 3 month of the experiment. Moreover, perphenazine did not induced significant changes in the blood morphology and histology of the internal organs.


Subject(s)
Perphenazine/toxicity , Animals , Body Weight/drug effects , Lethal Dose 50 , Male , Motor Activity/drug effects , Organ Size/drug effects , Rats , Rats, Wistar
12.
Arch Int Pharmacodyn Ther ; 278(2): 236-48, 1985 Dec.
Article in English | MEDLINE | ID: mdl-3938209

ABSTRACT

Anticatatonic effects of systemic and intracerebroventricularly administered GABAergic agents (GABA, muscimol piracetam, sod. valproate) were studied in rats against perphenazine-induced catatonia. All GABAergic agents, except piracetam, were found to posses anticatatonic actions as they significantly blocked perphenazine-induced catatonia. When these GABAergic agents were administered simultaneously with anticholinergic (scopolamine) or dopaminergic (bromocriptine) substances there was potentiation of the anticatatonic effect. The protective effect of GABAergic agonists and GABA antagonist and its modification by anticholinergic and dopaminergic agents has been explained on the basis of neurotransmitter interaction.


Subject(s)
Catatonia/prevention & control , Dopamine/physiology , Parasympatholytics/pharmacology , gamma-Aminobutyric Acid/physiology , Animals , Bromocriptine/pharmacology , Catatonia/chemically induced , Drug Synergism , GABA Antagonists , Injections, Intraventricular , Male , Muscimol/pharmacology , Perphenazine/toxicity , Piracetam/pharmacology , Rats , Rats, Inbred Strains , Scopolamine/pharmacology , Time Factors , Valproic Acid/pharmacology
14.
Br J Cancer ; 43(6): 832-41, 1981 Jun.
Article in English | MEDLINE | ID: mdl-6788061

ABSTRACT

The effects of hormone and drug treatments on plasma prolactin (PRL) levels and mammary tumour growth were investigated in rats bearing continuously growing DMBA-induced mammary tumours that responded to bilateral adreno-ovariectomy (Ax + Ox), Oestrogen (E2) administration increased both plasma PRL and tumour growth, but was unable to sustain tumour growth when the PRL level was reduced by concurrent injection of ergocornine (Eg). Perphenazine (Pz) produced a dose-related increase in plasma PRL, but stimulation of tumour growth in the absence of E2 required a minimal level of plasma PRL induced by Pz (0.15 mg/100 g body wt/day or more). Progesterone (P) (3 mg/day) alone, although without effect on PRL levels, maintained static tumour growth (i.e. it had a slight stimulatory effect) irrespective of the duration of treatment. The increase in plasma PRL levels above the basal values in the Ax + Ox controls following injections of combined P + Pz (0.1 mg/100 g/day) was sufficient to sustain static tumour growth, but not to reactivate growth. Enhancement of both plasma PRL and tumour growth did not occur until P and higher doses of Pz (0.3 mg/100 g/day) were injected jointly; this treatment, however, while unable to stimulate continuous tumour growth, was able to maintain static growth when plasma PRL was reduced by concurrent injections of P + Pz + Eg. From these findings it is postulated that the mechanism of action whereby P maintains static tumour growth is different from that of PRL and independent of circulating PRL levels.


Subject(s)
Mammary Neoplasms, Experimental/pathology , Prolactin/blood , 9,10-Dimethyl-1,2-benzanthracene , Adrenalectomy , Animals , Castration , Dose-Response Relationship, Drug , Ergolines/pharmacology , Estradiol/toxicity , Female , Mammary Neoplasms, Experimental/blood , Mammary Neoplasms, Experimental/chemically induced , Perphenazine/toxicity , Progesterone/toxicity , Rats
15.
Pol J Pharmacol Pharm ; 32(2): 199-204, 1980.
Article in English | MEDLINE | ID: mdl-6109278

ABSTRACT

For studying if piperazine-ring plays a role in teratogenicity pairs of compounds of similar structure and action (perphenazine-chloropromazine, chlorcyclizine--thenalidine, haloanisone--haloperiodol) had been selected, where only one of them contained piperazine-ring. The applied single doses were 3.7 X 10(-4) M/kg. Experiments were carried out on Wistar/H-Riop pregnant rats; equimolar doses of three drug-pairs were given orally on the 13th, 14th, or 15th gestational days, respectively. Perphenazine and chlorcyclizine, as alkyl-piperazine derivatives induced cleft palate and micromelia, while chlorpromazine and thenalidine did not. After the methoxyphenyl-piperazine containing substance--haloanisone--micromelia was higher as compared to that containing no piperazine moiety (haloperidol). These results indicate that the piperazine-ring may play an important role in the teratogenicity of drugs in rats.


Subject(s)
Fetus/drug effects , Piperazines/toxicity , Teratogens/toxicity , Animals , Chlorpromazine/toxicity , Cleft Palate/chemically induced , Female , Haloperidol/toxicity , Perphenazine/toxicity , Rats , Structure-Activity Relationship
16.
Pediatr Pharmacol (New York) ; 1(2): 153-60, 1980.
Article in English | MEDLINE | ID: mdl-7346737

ABSTRACT

Perphenazine (PER), a potent phenothiazine, was administered to rats in a dose of 5 mg/kg, IP, daily for 19 days (experiment I) and 26 days (experiment II). In the first experiment, weights 3 days after treatment ended were PER 308 +/- 16 gm and saline controls 329 +/- 25 gm (P less than 0.01). Lengths were also smaller (221 +/- 2.2 mm vs 230 +/- 1.0 mm, P less than 0.05), and the slope of the growth curves for weight and length differed significantly as well. In a second experiment, the liquid diet pair-feeding technique was employed and demonstrated that the growth retardation due to PER could not be accounted for by a decrease in food intake. Pair-fed saline-treated rats who ate 2% less than PER-treated rats had a weight of 264 +/- 6 gm at the end of treatment compared to 236 +/- 9 gm for PER treated (P less than 0.01). It is concluded that PER treatment produces growth retardation and that this is not due simply to decreased food intake. The inhibition of growth hormone secretion produced by PER may be the mechanism of its growth-retarding effect. Since phenothiazines are administered chronically to children with mental disorders it would be important to determine if they produce a growth-retarding effect in humans.


Subject(s)
Growth Disorders/chemically induced , Perphenazine/toxicity , Animals , Body Weight/drug effects , Eating/drug effects , Male , Rats , Rats, Inbred Strains , Tail , Time Factors
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