Administration Of Phenothiazines Research Articles

Phenothiazine normalizes the NADH/NAD+ ratio, maintains mitochondrial integrity and protects the nigrostriatal dopamine system in a chronic rotenone model of Parkinson's disease

Impaired mitochondrial function has been associated with the etiopathogenesis of Parkinson's disease (PD). Sustained inhibition of complex I produces mitochondrial dysfunction, which is related to oxidative injury and nigrostriatal dopamine (DA) neurodegeneration. This study aimed to identify disease-modifying treatments for PD. Unsubstituted phenothiazine (PTZ) is a small and uncharged aromatic imine that readily crosses the blood-brain barrier. PTZ lacks significant DA receptor-binding activity and, in the nanomolar range, exhibits protective effects via its potent free radical scavenging and anti-inflammatory activities. Given that DAergic neurons are highly vulnerable to oxidative damage and inflammation, we hypothesized that administration of PTZ might confer neuroprotection in different experimental models of PD. Our findings showed that PTZ rescues rotenone (ROT) toxicity in primary ventral midbrain neuronal cultures by preserving neuronal integrity and reducing protein thiol oxidation. Long-term treatment with PTZ improved animal weight, survival rate, and behavioral deficits in ROT-lesioned rats. PTZ protected DA content and fiber density in the striatum and DA neurons in the SN against the deleterious effects of ROT. Mitochondrial dysfunction, axonal impairment, oxidative insult, and inflammatory response were attenuated with PTZ therapy. Furthermore, we have provided a new insight into the molecular mechanism underlying the neuroprotective effects of PTZ.

Chlorpromazine-induced lupus with circulating anticoagulant. A case report

The drug-induced lupus erythematosus (DILE) is an autoimmune disorder caused by chronic use of certain drugs, including chlorpromazine. Chlorpromazine-induced lupus associated to circulating anticoagulant antibodies (CAC) would be even less frequent. Our observation is an illustration of this association.We report the case of Mrs. H., 33-year-old, without medical or surgical history, who has been followed in psychiatry since the age of 20 for bipolar disorder type 1. This patient was initially stabilized by an association of fluphenazine, sodium valproate and levomepromazine. The introduction of chlorpromazine in June 2015 induced a leuconeutropenia, which was corrected after stopping this drug. During subsequent decompensations, rechallenge with chlorpromazine and administration of other phenothiazines (levomepromazine, fluphenazine) or atypical anti-psychotics (olanzapine, risperidone, aripiprazole) induced a leuconeutropenia reversible after drug withdrawal. Within the etiological investigation of this leuconeutropenia, physical examination was normal; inflammatory tests (erythrocyte sedimentation rate, serum protein electrophoresis) and serology for hepatitis B and C and HIV were negative; antinuclear antibodies (ANA) titre was positive (1: 160) with a negative antibodies screen; rheumatoid factor and complement levels were normal. Activated partial thromboplastin time (APTT) was prolonged (47/29 s) and not corrected by addition of normal plasma. Lupus anticoagulant antibodies were positive. ANA became negative six months after cessation of implicated drugs. Thus, the diagnosis of “chlorpromazine-induced lupus with CAC” was retained. The pathophysiological mechanism of this association remains a subject of discussion. This induced autoimmunity, involving several anti-psychotics, is a real therapeutic challenge in our patient's case.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Use of a selective serotonin reuptake inhibitor for treatment of episodes of hypertonia and kyphosis in a young adult Scottish Terrier

A 2.5-year-old 12.4-kg (27.3-lb) castrated male Scottish Terrier was evaluated because of episodes of hypertonia and kyphosis for which a presumptive diagnosis of so-called Scottie cramp had been made when the dog was a puppy. Findings of general physical, orthopedic, and neurologic examinations were within reference limits. Pelvic limb hypertonicity and kyphosis without signs of pain were induced with minimal exercise; ambulation returned to normal after a period of rest. Fluoxetine, a selective serotonin reuptake inhibitor, was administered orally at a dosage of 1.2 mg/kg (0.55 mg/lb) once daily for 1 month. After this period of treatment, clinical signs of the disease were greatly reduced; the dosage of fluoxetine was changed to 0.8 mg/kg (0.36 mg/lb) twice daily, and response to treatment continued. Administration of benzodiazepines, vitamin E, or phenothiazines has been recommended for treatment of episodes of hypertonicity, but often does not result in control of clinical signs. It has been suggested that the pathogenesis of this disease is related to deficiencies in concentration or function of serotonin in the CNS; thus, a logical choice for treatment is administration of a serotonin reuptake inhibitor. In the dog of this report, fluoxetine resulted in good control of clinical signs. The use of an effective medication (other than a controlled substance) that is administered once or twice daily, has minimal adverse effects on the patient's mental status, and is inexpensive may lead to better owner compliance and an improved quality of life for affected dogs.

Drug-Induced Ocular Disorders

While beneficial therapeutically, almost all medications have untoward effects on various body tissues and functions, including the eye in which organ toxic reactions are readily detectable. Every part of the eye and all ocular functions could be affected adversely. In this review, we describe the most commonly recognized drug-induced ocular disorders, their specific clinical features, the medications that can cause the problem, the differential diagnosis and possible mechanisms of action, as well as guidelines for the management of the adverse reactions. The eyelids are most frequently involved in drug toxicity that commonly manifests as inflammation, hypersensitivity reaction or dermatitis. Drug-induced keratoconjunctival disorders present mainly as conjunctival hyperaemia (red eye), with or without superficial corneal involvement. Frequently, drug preservatives in topical ocular medications induce these adverse effects. Treatment of blepharospasm with Botox may lead to drooping of the eyelids and corneal exposure. Intraoperative floppy iris syndrome is a drug-induced reaction in patients treated with tamsulosin and who undergo cataract surgery. Certain sulfa-based drugs can cause swelling of the ciliary body and lead to the development of angle-closure glaucoma. In addition, adrenergic agents, certain beta(2)-adrenergic agonists and anticholinergic agents may induce pupillary dilation and precipitate angle-closure glaucoma in susceptible patients. Glucocorticoids administered systemically, topically or intravitreally are known to increase intraocular pressure, which can lead to the development of open-angle glaucoma in susceptible patients. This painless form of glaucoma has also been associated with the use of the anticancer agents docetaxel and paclitaxel. The toxic effects of systemic and topically applied drugs may manifest as cloudiness of the lens. Long-term use of glucocorticoids produces a characteristic posterior subcapsular cataract and, although the opacities may remain stationary or progress, they rarely regress upon drug withdrawal. Systemic administration of phenothiazines or busulfan induce cataractous changes in the anterior or posterior cortex, respectively. Many systemic drugs reach the retina through the vascular supply. Aminoquinolines induce a characteristic bull's eye maculopathy. Phenothiazines bind to melanin granules and can cause a severe phototoxic retinopathy. Typical tamoxifen retinopathy manifests as crystalline deposits in the inner retina. Some patients treated with retinoids have decreased night vision and abnormal dark-adaptation. Patients on long-term treatment with linezolid may develop an optic neuropathy (swollen or pale optic disc), symmetric painless decrease of visual acuity and colour vision, and bilateral visual field defects. A probable link exists between amiodarone and a bilateral optic neuropathy that is very similar to nonarteritic ischaemic optic neuropathy (NAION). The most common adverse effects of cGMP-specific phosphodiesterase type 5 inhibitors (erectile dysfunction drugs) are changes in colour perception, blurry vision and increased light sensitivity; recently these drugs have been also implicated in the development of NAION. A bilateral, retrobulbar optic neuropathy that manifests as loss of visual acuity or colour vision and visual field defect is associated with the use of ethambutol. Many different kinds of medications can cause similar ocular adverse reactions. Conversely, a single medication may affect more than one ocular structure and cause multiple, clinically recognizable disorders. Clinicians should be mindful of drug-induced ocular disorders, whether or not listed in product package inserts, and, if in doubt, consult with an ophthalmologist.

Akathisia Is No Less Likely If Prochlorperazine Is Given Slowly

Akathisia, a sensation of restlessness, anxiety, dysphoria, and paresthesias, is a known adverse effect of administration of intravenous phenothiazine

Multiple cytochrome P-450 subfamilies are co-induced with P-glycoprotein by both phenothiazine and 2-acetylaminofluorene in rats

We studied the effects of two P-glycoprotein (P-gp) inducers, 2-acetylaminofluorene (2-AAF) and phenothiazine (PTZ), administered intraperitoneally, on the activities and content of hepatic cytochrome P-450 (CYP) subfamilies in hepatic microsomes of Sprague–Dawley rats. After 4-day administration of 2-AAF or PTZ, the P-gp content was increased. The total CYP content after PTZ treatment was significantly increased compared with that of controls. The CYP1A, CYP2B and CYP3A2 contents were induced, while the CYP2C6, CYP2C11 and CYP2E1 contents remained unaffected. A marked increase in CYP1A1 was found after administration of each compound. Ethoxyresorufin O-deethylase, pentoxyresorufin O-deethylase, and testosterone 6β hydroxylation activities showed a significant increase after both 2-AAF and PTZ treatments. In particular, ethoxyresorufin O-deethylase exhibited more than ten times greater activity than that of the controls after the treatments. These results suggest that P-gp inducers affect several CYP subfamilies in addition to CYP3A, which is reported to be up-regulated coordinately with P-gp by a CYP3A inducer.

Influence of gamma -rays on the mouse liver cytochrome P450 system and its modulation by phenothiazine drugs

Purpose : Phenothiazine drugs have been found to sensitize hypoxic cancer cells while offering protection to normal cells. Since phenothiazines are known to induce the cytochrome P450 system, its radiomodulation by phenothiazines has been examined. Materials and methods : Mice were administered phenothiazines intraperitoneally and irradiated with different doses of gamma -rays at 1.38 Gy/min. The activities of NADPH-cytochrome P450 reductase and NADH-cytochrome b5 reductase, the content of cytochrome P450 and b5, the extent of lipid peroxidation as well as the activities of LDH, XO, SOD, GST and DTD were determined in the liver. Results : The levels of different components of the cytochrome P450 system and antioxidant enzymes were enhanced up to 5Gy and decreased thereafter. However, a progressive increase was noticed in peroxidative damage and the activities of LDH and XO. Administration of phenothiazines enhanced the radiation effect on components of the cytochrome P450 system (except NADH-cytochrome b5 reductase) and the activities of SOD, GST and DTD. Concomitantly, phenothiazines inhibited lipid peroxidation, LDH and XO. Conclusions : Activation of the cytochrome P450 system by phenothiazines leading to the enhancement of antioxidant potential of animals and free-radical scavenging are attributes of the radioprotective action of phenothiazines.

Modeling drug-melanin interaction with theoretical linear solvation energy relationships.

The affinity of drugs and other xenobiotic agents for melanin is a well-known phenomenon, often occurring with serious physiological consequences. For example, the interaction of anti-psychotic drugs with neuromelanin may play a pivotal role in the induction of extrapyramidal movement disorders associated with the chronic administration of phenothiazine and other neuroleptic agents. Little, however, is known about the complete nature of melanin-drug binding and the impact of these interactions on the physico-chemical properties of melanin. Data, such as binding affinities, can be analyzed using recently developed computational methods that combine mathematical models of chemical structure with statistical analysis. In particular, theoretical linear solvation energy relationships provide a convenient model for understanding and predicting biological, chemical, and physical properties. By using this modeling technique, drug-melanin binding of a set of 16 compounds has been analyzed with correlation analysis and a set of theoretical molecular parameters in order to better understand and characterize drug-melanin interactions. The resulting correlation equation supports a charge transfer model for drug-melanin complex formation and can also be used to estimate binding constants for related compounds.

Excretion of Psychoactive Drugs into Breast Milk

The postpartum period is a time of great physical and emotional changes. The incidence of psychiatric illness is higher in this period than at any other time in a women's life. Therefore, the question of whether women receiving psychotropic drugs should continue breast feeding is an important one. Drug excretion in breast milk depends mostly on passive diffusion of the unionised unbound drug. Passive diffusion is affected mainly by the drug disposition in lactating mothers, by the physicochemical properties of the molecule and by the protein and lipid contents of breast milk. Indeed, breast milk can be considered as a compartment with bidirectional transfer rather than a reservoir into which drug accumulates. Benzodiazepines are the most prescribed psychotropic drugs. Generally there does not seem to be any contraindication to breast feeding after a single dose, provided the dose administered is relatively low. If higher doses are to be used or long term administration is required, then breast feeding should probably be discontinued, particularly with drugs with a long elimination half-life. On the basis of the average concentration of phenobarbital (phenobarbitone) in milk, breast feeding is not recommended. For glutethimide, breast feeding would appear to be safe for the infant when a single dose is taken occasionally. Zopiclone may also be prescribed on a short term basis to breast feeding mothers. Due to limited available data or to the large amount transferred to milk, administration of phenothiazines and nonphenothiazine tricyclic, butyrophenone, and benzamide antipsychotics to breast feeding mothers cannot be recommended. Breast feeding is not always considered an absolute contraindication to lithium therapy, but the mother should watch for signs of toxicity in her baby. Whether clomipramine should be contraindicated during breast feeding depends on the concentration of active metabolites in breast milk, and this has not yet been determined. It is probably safe for mothers to breast feed while receiving amitriptyline, but before more conclusive recommendations are made more infants should be studied. The available data suggest that the amount of doxepin and its metabolite in breast milk is small. However, the metabolite of doxepin may accumulate in the infant with risk of sedation and respiratory depression: therefore, an alternative antidepressant should be selected for breast feeding mothers.(ABSTRACT TRUNCATED AT 400 WORDS)

Mechanistic considerations in chemical carcinogenesis

We studied the effects of two P-glycoprotein (P-gp) inducers, 2-acetylaminofluorene (2-AAF) and phenothiazine (PTZ), administered intraperitoneally, on the activities and content of hepatic cytochrome P-450 (CYP) subfamilies in hepatic microsomes of Sprague–Dawley rats. After 4-day administration of 2-AAF or PTZ, the P-gp content was increased. The total CYP content after PTZ treatment was significantly increased compared with that of controls. The CYP1A, CYP2B and CYP3A2 contents were induced, while the CYP2C6, CYP2C11 and CYP2E1 contents remained unaffected. A marked increase in CYP1A1 was found after administration of each compound. Ethoxyresorufin O-deethylase, pentoxyresorufin O-deethylase, and testosterone 6β hydroxylation activities showed a significant increase after both 2-AAF and PTZ treatments. In particular, ethoxyresorufin O-deethylase exhibited more than ten times greater activity than that of the controls after the treatments. These results suggest that P-gp inducers affect several CYP subfamilies in addition to CYP3A, which is reported to be up-regulated coordinately with P-gp by a CYP3A inducer.

Long-term phenothiazine administration and the eye in 100 Malaysians.

Seventy-three out of a hundred Malaysians on phenothiazines for more than 24 months had ocular pigmentation. Seventy-one had conjunctiva pigmentation. No pigmentary retinopathy or visual impairment was detected. Frequency of pigmentation increased with age and with higher total dosage prescribed, but there was no critical level below which pigmentation was not detected.

Phenothiazine-Induced Sleep Apneas and the Opioid System

In Reply.— Dr Sandyk suggests that the increased number of apneas seen in sleeping infants after the administration of phenothiazine could be related to an increase in endogenous opioids. If validated, this suggestion could be of interest for the understanding of the mechanisms inducing central and obstructive sleep apneas. As suggested naloxone could be tried in case of phenothiazine-induced apneas, but it seems advisable to systematically avoid the administration of phenothiazine-containing drugs to children younger than 2 years of age.

Phenothiazine-Induced Sleep Apneas and the Opioid System

To the Editor.— I was interested in the report by Kahn et al.1 demonstrating an increase in the number of central apneas following phenothiazine administration to infants. Administration of phenothiazines to infants less than 1 year of age could precipitate sudden death in apnea-prone subjects. Although the authors suggested several possible mechanisms linking the effects of phenothiazines with sudden infant death syndrome (SIDS), an apparent role of the opioid system has not been mentioned. The endogenous opioid system has been implicated in the central control of respiration.2

A cell membrane correlate of tardive dyskinesia in patients treated with phenothiazines.

Phenothiazine administration to psychiatric patients is associated with an increase in the "structural order" of platelet membranes as determined by steady-state fluorescence polarization measurements with 1,6-diphenyl-1,3,5-hexatriene (DPH), a fluorescent probe that localizes preferentially in the hydrocarbon region of cell membranes (Zubenko and Cohen 1984, 1985a, b). In this study, platelet membranes prepared from a group of psychiatric patients who developed tardive dyskinesia following chronic treatment with phenothiazines exhibited a significant elevation in DPH fluorescence polarization when compared to similar preparations from an otherwise matched group of patients who had no symptoms or history of tardive dyskinesia. The distribution of polarization values obtained for the tardive dyskinesia group displayed minimal overlap with that of an unmedicated, psychiatrically-healthy control group matched for age and gender. The fluorescence polarization of DPH-labelled platelet membranes was not significantly correlated with phenothiazine daily dose or serum cholesterol concentration in the phenothiazine-treated patient groups, or with dyskinesia severity (AIMS rating) in the tardive dyskinesia group. Patient gender and the presence of an affective disorder did not significantly correlate with DPH fluorescence polarization. The potential physiological and clinical significance of these findings is discussed.

Relation of graded ocular anterior chamber pigmentation to phenothiazine intake in schizophrenics--quantification procedures.

The fact that larger doses of phenothiazine medications cause more anterior chamber (lens and cornea) pigmentation in schizophrenics has been apparent since the introduction of these neuroleptic drugs nearly 30 years ago. The present study relates the extent of pigmentation to the dose and duration of phenothiazine administration in long-term schizophrenics. An investigation and analysis of the medication records of 272 pigmented schizophrenics show a statistically significant correlation between most of the pigmentation grades and the associated dose of medication. The results indicate that regular biomicroscopy examinations for pigmentation can help confirm medication history and classify schizophrenics.

Effects of phenothiazine treatment on the physical properties of platelet membranes from psychiatric patients

Exposure of normal platelet membranes in vitro to clinically relevant concentrations of phenothiazines has been reported to result in an increase in the structural order of the hydrocarbon region of these membranes (Zubenko and Cohen 1984b,c). In this study, the order parameters (reciprocal of fluidity) of platelet membranes prepared from psychiatric patients receiving phenothiazine antipsychotic drugs were compared to those of an otherwise matched population of psychiatric patients who were not receiving medications that significantly affect this cell membrane property in vitro (Zubenko and Cohen 1984b,c). Membrane order was determined ex vivo by steady-state fluorescence polarization measurements employing 1,6-diphenyl 1,3,5-hexatriene, a fluorescent probe that localizes preferentially in the hydrocarbon region of cell membranes. Phenothiazine administration was associated with a significant increase in platelet membrane order and most likely results from a direct action of these agents on cell membranes. The platelet membrane order parameters of phenothiazine-free patients did not differ significantly from those of a matched group of unmedicated, normal controls. Platelet membrane order was not correlated with daily phenothiazine dose or serum cholesterol concentration. Patient gender did not significantly affect platelet membrane order in any of the groups studied. The potential physiological and clinical significance of phenothiazine-induced increases in cell membrane order is discussed.

Decreased concentration of high density lipoprotein cholesterol in schizophrenic patients treated with phenothiazines

In chronic schizophrenic patients treated with phenothiazines (Chlorpromazine, Levomepromazine, Perphenazine) for long periods (average = 8 years), high density lipoprotein cholesterol (HDL-C) levels were significantly lower ( P < 0.001) compared with normal controls. The HDL subfractions showed that HDL 3-C was significantly low ( P < 0.005) whereas HDL 2-C was not. Both serum apo A-I and apo A-II levels were also low ( P < 0.005 and P < 0.001 respectively) in schizophrenics treated with phenothiazines. The serum triglycerides (TG) level was significantly higher ( P < 0.05) in patients treated with phenothiazines than in controls. No significant differences in total cholesterol (TC), TG and HDL-C were found between users and nonusers of benzodiazepine in schizophrenic patients receiving phenothiazines. In addition to chronic schizophrenic patients, 8 new patients with schizophrenia and related diseases were studied. The serum HDL-C level decreased by 24% within 1 week following administration of phenothiazines. No significant differences were found in TC and TG levels for 10 weeks after initiation of phenothiazine administration.

Delta-9-tetrahydrocannabinol as an antiemetic

The use of delta-9-tetrahydrocannabinol (THC) as an antiemetic in patients undergoing cancer chemotherapy is reviewed. The pharmacokinetics of THC is discussed, and the agent's effects on the central nervous, cardiovascular, respiratory, gastrointestinal, immune, endocrine, and reproductive systems are presented. The toxicology, potential hazards, and adverse reactions of THC are reviewed. Also reviewed are studies of THC's use as an antiemetic. THC appears to be an effective antiemetic in cancer patients undergoing chemotherapy. The maximal antinauseant effects often correlate with the attainment of a "high". THC has been found consistently more effective than placebo and at least as effective as prochlorperazine. In phenothiazine-resistant patients, THC's effectiveness has exceeded that of the phenothiazines. Efficacy may depend on the chemotherapeutic agent causing emesis. Elderly patients do not tolerate the THC "high" well. Concurrent administration of phenothiazines with THC may block the "high" without reducing THC's antiemetic effectiveness. Because of variations in individual tolerance, absorption, and the form of chemotherapy, flexibility is necessary in establishing the correct dose of THC.

Concordance of Insulin-Induced Hypoglycemia and Phenothiazine-Induced Prolactin Secretion in Man*

Abstract Highly variable pituitary PRL responses have been reported after insulin-induced hypoglycemia in normal subjects. Thus, insulin hypoglycemia has not been widely utilized to ascertain hypothalamic-pituitary PRL reserve. To determine the clinical usefulness of measuring hypoglycemia-induced PRL secretion, serum PRL concentrations after standard insulin tolerance tests were compared to those after phenothiazine (perphenazine) administration in 12 normal subjects and in 24 euprolactinemic patients evaluated for possible hypothalamic-pituitary disorders. In normal subjects, mean PRL levels rose from 12.6 ± 1.0 to 42.6 ± 6.6 (1 SEM) ng/ml after insulin hypoglycemia and from 13.3 ± 1.7 to 52.2 ± 8.4 ng/ml after perphenazine ingestion. The mean maximum increment in PRL was 30.1 ± 6.7 ng/ml after hypoglycemia and 38.9 ± 8.8 ng/ml after perphenazine administration. In the 24 patients evaluated for hypothalamic-pituitary dysfunction, mean PRL concentration rose from 9.6 ± 1.3 to 32.0 ± 5.5 ng/ml after insul...

Schizophrenia following Withdrawal from Chronic Phenothiazine Administration: A Case Report

The chronic administration of phenothiazines has come under increasing scrutiny recently, and the uncritical use of this form of treatment has been criticized. A case is presented illustrating the development of schizophrenia in a young adult following withdrawal from phenothiazines. As far as could be ascertained ther was no evidence of schizophrenia prior to withdrawal of phenothiazines. The possibility that withdrawal of phenothiazines may have aetiological significance in this case is discussed.