RESERPINE AND CHLORPROMAZINE—Their Use in Alcoholic and Geriatric Patients

Although reserpine and chlorpromazine had tranquilizing effect on a number of geriatric and alcoholic patients in a state hospital, several complicating results were noted, some with a bearing on the patients'' health and others that might affect the assignment of personnel.Lipoprotein studies carried out on patients receiving reserpine seemed to indicate that a reduction in the blood levels of the denser lipoprotein molecules took place during therapy.Several elderly patients receiving chlorpromazine died of diseases that were not as sharply manifest by symptoms as they might be expected to be. Hence the need for closer observation than a limited staff could afford seemed a matter for consideration. Another consideration of the same order was the possible need for increased personnel for psychotherapy in light of the more receptive condition of the patients.     

Chlorpromazine alone and with reserpine; use in the treatment of mental diseases

One hundred psychiatric patients were treated with chlorpromazine, alone or combined with reserpine. Fifty-six per cent of patients with chronic schizophrenic reactions showed moderate or pronounced improvement when treated with chlorpromazine alone. The results of treatment with the combined drugs were not so good as that. Indications are that treatment of patients with chronic schizophrenic reactions is more efficacious with these drugs than with other forms of somatic therapy. Complications of treatment were far greater with combined use of chlorpromazine and reserpine. For this reason, the combination appears to have limited usefulness. The Parkinson syndrome was the most frequent complication of large doses of these drugs. It appears to be a toxic reaction, requiring reduction in dosage. Jaundice appears to be neither a frequent nor a serious complication of treatment.     

CHLORPROMAZINE ALONE AND WITH RESERPINE—Use in the Treatment of Mental Diseases

One hundred psychiatric patients were treated with chlorpromazine, alone or combined with reserpine. Fifty-six per cent of patients with chronic schizophrenic reactions showed moderate or pronounced improvement when treated with chlorpromazine alone. The results of treatment with the combined drugs were not so good as that. Indications are that treatment of patients with chronic schizophrenic reactions is more efficacious with these drugs than with other forms of somatic therapy.Complications of treatment were far greater with combined use of chlorpromazine and reserpine. For this reason, the combination appears to have limited usefulness. The Parkinson syndrome was the most frequent complication of large doses of these drugs. It appears to be a toxic reaction, requiring reduction in dosage. Jaundice appears to be neither a frequent nor a serious complication of treatment.     

Effects of chemically- and environmentally-induced hypothermia on micronucleus induction in rats

We investigated micronucleus induction in rats treated with chlorpromazine and reserpine, drugs that induce hypothermia. We administered chlorpromazine (31.3--250mg/kg) or reserpine (500--2000 mg/kg) intraperitoneally and measured temperature rectally. Chlorpromazine at 62.5-250mg/kg and reserpine at all doses significantly decreased rectal temperature, although the hypothermic response was weaker than previously reported in mice. Only chlorpromazine at 250mg/kg decreased rectal temperature transiently to <33 degrees C for 20h and induced a statistically significant increase in micronucleated polychromatic erythrocyte frequency. When rats treated with reserpine at 500mg/kg were exposed to an environmental temperature of 16 degrees C for 6, 12, or 24h to keep their body temperature under 33 degrees C, only the 24h treatment group significantly induced micronuclei. In addition, relatively large micronuclei (diameter of micronucleus> or = 1/4 diameter of cytoplasm) accounted for 33.0% of the induced micronuclei, suggesting that hypothermia affected the mitotic apparatus. The hypothermic response to chlorpromazine and reserpine was weaker in rats than in mice, and it was correspondingly more difficult to induce micronuclei in rats with those drugs.     

USE OF TRANQUILIZERS IN DISEASES OF THE SKIN—A Preliminary Report

Tranquilizing agents such as chlorpromazine and reserpine were used in various diseases of the skin in which the psychogenic factors were considered important etiologic agents. While a tranquilizing effect was obtained in the majority of instances, the side reactions and variation in response were so great as to render these agents unsatisfactory for routine use as tranquilizers. Meprobamate (marketed under the trade names Miltown and Equanil) was then used on a group of dermatologic patients with more consistent tranquilizing effect and comparatively little unpleasant side reactions. It is felt that further study of the use of meprobamate as a tranquilizing agent in dermatology is worth while.     

Use of tranquilizers in diseases of the skin; a preliminary report

Tranquilizing agents such as chlorpromazine and reserpine were used in various diseases of the skin in which the psychogenic factors were considered important etiologic agents. While a tranquilizing effect was obtained in the majority of instances, the side reactions and variation in response were so great as to render these agents unsatisfactory for routine use as tranquilizers. Meprobamate (marketed under the trade names Miltown and Equanil) was then used on a group of dermatologic patients with more consistent tranquilizing effect and comparatively little unpleasant side reactions. It is felt that further study of the use of meprobamate as a tranquilizing agent in dermatology is worth while.     

The effects of some antipsychotic drugs, D-amphetamine, and reserpine on the concentration and rate of accumulation of tryptamine and 5-hydroxytryptamine in the mouse striatum

The mouse striatum contains about 2 ng/g of tryptamine and 600 ng/g of 5-hydroxytryptamine. No significant changes in mouse striatal tryptamine were observed after the administration of chlorpromazine, haloperidol, spiperone, or alpha-flupenthixol. The levels of 5-hydroxytryptamine were moderately reduced by chlorpromazine, spiperone, and alpha-flupenthixol but not by haloperidol. The administration of antipsychotic drugs to mice pretreated with a monoamine oxidase inhibitor (pargyline) produced an increase in the rate of accumulation of striatal tryptamine compared with that of pargyline-treated mice. In contrast, the rate of accumulation of 5-hydroxytryptamine after monoamine oxidase inhibition was reduced by chlorpromazine, spiperone, and alpha-flupenthixol but not haloperidol. D-Amphetamine administration did not change either tryptamine or its 5-hydroxyderivative while reserpine increased tryptamine and reduced 5-hydroxytryptamine. The results suggest that changes in striatal tryptamine may be controlled by the availability of tryptophan, the amino acid precursor of tryptamine.     

Skin Pigmentation and Corneal and Lens Opacities with Prolonged Chlorpromazine Therapy

Previously undescribed ocular and dermatologic complications of prolonged chlorpromazine therapy have been noted in 70 patients of a series of many thousands receiving similar therapy. All affected patients were women who had been receiving high doses of chlorpromazine, averaging 500 to 1500 mg. daily, for at least three to five years before the complications became apparent. Skin manifestations consisted of a peculiar purplish pigmentation of the skin of exposed areas of the face, neck and hands, characterized histologically by deposition of material with the staining properties of melanin in the superficial layers of the dermis, particularly in a perivascular distribution. Ocular complications consisted of granular opacity of the cornea and often of the lens as well, the latter producing a central stellate type of cataract.     

Changes in in vivo binding of 3H-Ro 15-1788 in mouse brain by reserpine

The effects of reserpine on the in vivo binding of ³H-Ro 15-1788, (Ro 15-1788: ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5a] [1,4]benzodiazepine-3-carboxylate) a selective benzodiazepine antagonist, in the mouse brain were investigated. The biodistributions of tracer amounts of ³H-Ro 15-1788 in mice were significantly altered by pretreatment with reserpine (2.5 or 5.0 mg/kg, 24 h before the tracer administration). The time courses of radioactivity in the brain and the blood following i.v. injection of ³H-Ro 15-1788 with carrier Ro 15-1788 were not changed by pretreatment with reserpine, which suggested that the specific binding process might be altered by reserpine. The degree of alteration in the in vivo binding of ³H-Ro 15-1788 seemed to be dependent upon the dose of reserpine and the duration after the treatment of reserpine. The maximum changes in the biodistribution of ³H-Ro 15-1788 were observed at 1 day after injection of reserpine. The body temperature and the brain monoamine contents (dopamine, norepinephrine and 5-hydroxytryptamine) in mice were measured as indicators of pharmacological effects of reserpine, and good relationships to the degree of changes in the biodistribution of ³H-Ro 15-1788 and either the body temperature or brain monoamine contents, were observed. Furthermore, the changes in the biodistribution of ³H-Ro 15-1788 in the reserpinized mice were significantly suppressed by antidepressant imipramine treatment. These results suggest that it would be possible to detect the in vivo drug interaction with brain benzodiazepine receptors in the living human brain using ¹¹C-Ro 15-1788 and positron emission tomography (PET).     

A comparison of the effects of chlorpromazine, 7-hydroxychlorpromazine and chlorpromazine sulfoxide on the activity of central dopaminergic neurons

Using single unit recording techniques, chlorpromazine and two of its naturally occuring metabolites in man, 7-hydroxychlorpromazine and chlorpromazine sulfoxide, were tested for their ability to reverse amphetamine-induced depression of rat dopaminergic ventral tegmental neurons (A10). Small equivalent doses of chlorpromazine and 7-hydroxychlorpromazine were found to readily reverse amphetamine-induced depression of these cells. Chlorpromazine sulfoxide was found to be 50–100 times less potent in this regard. Previous findings have demonstrated that only phenothiazines with antipsychotic properties reverse amphetamine-induced depression of A10 neurons. Thus, we would predict that 7-hydroxychlorpromazine would have anti-psychotic properties whereas chlorpromazine sulfoxide would not. A preliminary study by Sakalis et al., suggests that plasma levels of chlorpromazine and 7-hydroxychlorpromazine are possibly correlated with the therapeutic effects of chlorpromazine in schizophrenia. Chlorpromazine sulfoxide levels, on the other hand, are reported to be high in chlorpromazine treated non-responders. Thus there is a direct parallel between predictions of antipsychotic efficacy based on our test model and the possible clinical importance of these chlorpromazine metabolites. Both findings suggest that 7-hydroxychlopromazine might be a good antipsychotic agent.     

The effect of chlorpromazine on SCE frequency in human chromosomes: An in vitro and in vivo study

Schizophrenic patients who were receiving, or who had received chlorpromazine showed SCE levels similar to those in a normal control population. Of 8 normal individuals whose lymphocytes were exposed in vitro to chlorpromazine (0.05–2.00 μg/ml) for two cell cycles, 4 showed a significant increase in SCE, 3 showed no increase and 1 a decrease compared with untreated lymphocytes. Lymphocytes from a further 8 donors treated with 2.0 μg/ml chlorpromazine prior to mitogen stimulation (G₀ lymphocytes) showed a similar SCE response. Only 3 of the 8 donors showed a significant increase in SCEs over the baseline level. When proliferating lymphocytes were exposed to chlorpromazine 38 h after culture initiation and prior to the addition of BrdUrd to the culture medium, metaphase chromosomes from only 3 of the 8 individuals studied showed increased levels of exchange. These results indicate that chlorpromazine can induce SCEs in vitro but that there is considerable variation in SCE response among individuals. Furthermore, our data emphasises the importance of using more than 1 or 2 donors when analysing SCE response in human chromosomes.     

Displacement of cell-surface associated calcium inhibits phagocytosis and Ca-ATPase activity in amoeba

Displacement of calcium from the cell surface region was observed in cells treated with either chlorpromazine or reserpine with chlorotetracycline being used as a calcium-fluorescent probe. The drugs also significantly inhibit the intensity of phagocytosis and Ca-ATPase activity. The possible role of Ca associated with the cell surface region in regulation of both phagocytosis and Ca-ATPase was discussed.     

RESERPINE IN WEIGHT REDUCTION—The Effect in Obese Patients on 1,000-Calorie Diets: A Controlled Study

In a controlled study (the control group receiving pyribenzamine) it was observed that reserpine, in the dosage used, had no effect on weight loss in patients receiving d-amphetamine sulphate (Dexedrine®) and methyl cellulose (Cellothyl®) while on 1,000-calorie diets as compared with the control group.There was no observable difference in subjective feelings of the patients in the two groups.Reserpine had no effect on the length of time the patients remained on their diets.     

Photodynamic action of chlorpromazine on adenovirus 5: Repairable damage and single strand breaks

Chlorpromazine, a substituted phenothiazine, commonly used as a sedative, has been found to photosensitize the inactivation of human adenovirus 5 to wavelengths of light between 330 and 390 nm. The slope of the inactivation curve is three fold greater when fibroblasts from people having xeroderma pigmentosum (XP) were used as viral hosts than when normal fibroblasts were used, showing that at least two-thirds of the damage produced in the virions is repairable by normal human fibroblasts. The phototreatment of chlorpromazine sensitized virions also results in the production of DNA strand breaks, which correlate fairly well with the production of lethal viral damage as measured in XP fibroblasts. These findings suggest that the photosensitization of the skin observed in patients treated with chlorpromazine might be due to DNA damage.     

Radioimmunoassay for reserpine

Antisera against reserpine have been developed in rabbits immunized with reserpine conjugated to bovine serum albumin. These antisera were used in a radioimmunoassay procedure for reserpine. No appreciable cross-reactivity was observed either with reserpine metabolites or with other drugs commonly used in conjunction with reserpine for the treatment of hypertension. The assay was able to detect as little as 150 pg of reserpine in serum (15 ng/ml), without the need for an extraction procedure. Serum concentrations were measured in rats following the oral and intravenous administration of 1 mg/kg of reserpine.     

Chlorpromazine oligomer is a potentially active substance that inhibits human D-amino acid oxidase, product of a susceptibility gene for schizophrenia

D-amino acid oxidase (DAO), a potential risk factor for schizophrenia, has been proposed to be involved in the decreased glutamatergic neurotransmission in schizophrenia. Here we show the inhibitory effect of an antipsychotic drug, chlorpromazine, on human DAO, which is consistent with previous reports using porcine DAO, although human DAO was inhibited to a lesser degree (K(i) = 0.7 mM) than porcine DAO. Since chlorpromazine is known to induce phototoxic or photoallergic reactions and also to be transformed into various metabolites, we examined the effects of white light-irradiated chlorpromazine on the enzymatic activity. Analytical methods including high-resolution mass spectrometry revealed that irradiation triggered the oligomerization of chlorpromazine molecules. The oligomerized chlorpromazine showed a mixed type inhibition with inhibition constants of low micromolar range, indicative of enhanced inhibition. Taken together, these results suggest that oligomerized chlorpromazine could act as an active substance that might contribute to the therapeutic effects of this drug.     

Comparative effects of 6-hydroxy-dopamine and of reserpine on quabain toxicity in the rat

The toxic effects of ouabain were compared in normal, and in 6-OH-DA and reserpine pretreated rats. Reserpine significantly reduced the lethality of intravenous ouabain. This effect does not seem related to depletion of peripheral catecholamines, since 6-OH-DA did not reduce mortality significantly. Since reserpine, but not 6-OH-DA, does cross the blood brain barrier it is suggested that the protective effect of reserpine might be related to its action on the central nervous system.     

Pre- and postsynaptic adrenergic activation by norepinephrine reuptake inhibitors in the field-stimulated rat vas deferens

Desipramine (DMI), protriptyline, chlorpromazine, amitriptyline and cocaine, alone or in the presence of prazosin, produced a dose-related inhibition of contractions induced by field stimulation of the rat vas deferens. The inhibition of contractions was readily reversed by yohimbine. In contrast, when yohimbine was first added to the bath, all agents, except chlorpromazine, produced a dose-related enhancement of contractions which were readily reversed by prazosin. The potencies of these agents for induction of contractile inhibition, after prazosin, and contractile enhancement, after yohimbine, were similar. Both of the latter contractile responses of DMI were markedly attenuated or absent in tissues taken from rats pretreated with reserpine and alpha-methyl-para-tyrosine. The data indicate that, in the rat vas deferens, inhibition of norepinephrine reuptake results primarily in presynaptic (α₂) receptor activation. Postsynaptic (α₁) adrenergic activation by inhibition of norepinephrine reuptake can be demonstrated in this tissue only after presynaptic (α₂) receptor blockade. The possible implications of the present studies to the delayed clinical onset of action of tricyclic antidepressants is discussed.     

Chlorpromazine oligomer is a potentially active substance that inhibits human D-amino acid oxidase,product of a susceptibility gene for schizophrenia

D-Amino acid oxidase (DAO), a potential risk factor for schizophrenia, has been proposed to be involved in the decreased glutamatergic neurotransmission in schizophrenia. Here we show the inhibitory effect of an antipsychotic drug, chlorpromazine, on human DAO, which is consistent with previous reports using porcine DAO, although human DAO was inhibited to a lesser degree (K_i = 0.7 mM) than porcine DAO. Since chlorpromazine is known to induce phototoxic or photoallergic reactions and also to be transformed into various metabolites, we examined the effects of white light-irradiated chlorpromazine on the enzymatic activity. Analytical methods including high-resolution mass spectrometry revealed that irradiation triggered the oligomerization of chlorpromazine molecules. The oligomerized chlorpromazine showed a mixed type inhibition with inhibition constants of low micromolar range, indicative of enhanced inhibition. Taken together, these results suggest that oligomerized chlorpromazine could act as an active substance that might contribute to the therapeutic effects of this drug.     

Gastrointestinal Disturbances Associated with Withdrawal of Ataractic Drugs

The psychological effects of abrupt withdrawal of ataractic drugs have been studied by others. Physical symptoms also occur under such circumstances and include abdominal pain, nausea and vomiting. Forty patients were divided into four groups of 10, each group receiving one of the following drugs: chlorpromazine, thioridazine, perphenazine or chlorprothixene. This medication was then suddenly withdrawn. In each of the chlorpromazine and thioridazine groups, three patients had gastrointestinal symptoms within 48 hours, lasting one to eight days. One patient on chlorprothixene, 450 mg. daily, experienced symptoms for six days. Perphenazine withdrawal produced no such symptoms. Thioridazine has little antiemetic action but perphenazine is prescribed for vomiting; hence it seems unlikely that the reported symptoms are due to a rebound action on the vomiting centre.These findings are relevant to the situation of withdrawal of ataractics prior to administration of anesthetics and to drug studies involving cross-over from an active compound to a placebo. The increasing use of ataractics suggests that this additional diagnostic possibility should be considered in the presence of obscure gastrointestinal symptoms.