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PubMed1985

[Haloperidol. Plasma monitoring and hormonal effects of treatment].

Therapeutic plasma monitoring of haloperidol, a major neuroleptic, measured by radioimmunoassay, has shown a rather good correlation between plasma level and dosage but with large interindividual variation in children as in adults; age seems not to have any effect on haloperidol metabolism. 80% of subjects present a concomitant prolactin levels variation, whereas in 20% no prolactin response is found. During acute kinetics of either a 10 mg oral haloperidol administration or a 250 mg intramuscular haloperidol decanoate injection, a parallel elevation of prolactin, cortisol, immunoreactive bêta-endorphin and bêta-lipotropin plasma levels occur, at the same time as haloperidol plasma levels. Those rise with a good equivalence between the two doses of the two forms.

Administration, Oral↗
PubMed1986

Investigation of the failure of parenterally administered haloperidol to antagonize dopamine released from micropipettes in the caudate.

An anomaly in the experimental data underlying the theory that neuroleptics act by blockade of dopaminergic neurotransmission is the repeatedly demonstrated failure in several laboratories of parenterally administered neuroleptics to antagonize electrophysiologic actions of locally applied dopamine (DA) in striatum. This failure is enigmatic since many investigators have successfully demonstrated antagonism when both dopamine and neuroleptic are applied directly to striatal neurons by microiontophoresis. We used multibarrel micropipettes to pressure-eject DA agonists onto rat caudate neurons while observing the ability of parenterally administered haloperidol to block the inhibitory actions of dopaminergic agonists on neuronal activity. Experiments performed at times of maximal behavioural effect of haloperidol did not demonstrate agonist-antagonist interaction. This result has been obtained by four other teams of investigators. A variety of pharmacologic manipulations were employed to help solve this enigma. Acute treatment with reserpine and alpha-methyl-paratyrosine, performed to minimize any possible interference by endogenous DA, did not permit blockade of dopamine by haloperidol. To see if this failure of antagonism could be generalized to other DA agonists, apomorphine, amphetamine, and phencyclidine (PCP) were also investigated. Although the direct dopaminergic agonist apomorphine was not antagonized by haloperidol, the indirect DA agonist PCP was successfully antagonized. Amphetamine, which has both direct and indirect actions when applied locally, was not antagonized. Antagonism of direct agonists was demonstrated in rats with unilateral 6-hydroxydopamine-induced lesions of the nigrostriatal pathway. In these preparations, parenterally administered haloperidol reversed the receptor-mediated supersensitivity to the inhibitory effects of locally applied DA and apomorphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine↗
PubMedDate not supplied

Serum haloperidol and neuroleptic receptor levels in chronic psychosis.

Serum haloperidol and serum dopamine blocking activity were measured, and steady state levels were compared in 22 chronic male schizophrenic patients. Haloperidol levels were measured by high pressure liquid chromatography (HPLC), and dopamine blocking activity was measured by a radioreceptor assay (NRRA). Clinical status was determined by the Brief Psychiatric Rating Scale (BPRS) and the Abnormal Involuntary Movement Scale (AIMS). Patients were stabilized on individual doses of haloperidol for at least three weeks and dosages ranged from five to 200 mg per day. All measures were determined on two occasions, one week apart. All measures (AIMS, BPRS, HPLC, and NRRA) showed a high degree of repeated test reliability. The behavioral measures showed a high degree of interobserver reliability on both occasions. There were significant correlations at both time points among haloperidol dosage, serum haloperidol levels, and dopamine blocking activity. Although the correlations between serum levels measured by HPLC and NRRA were positive and significant on both occasions, they never accounted for more than 58 percent (coefficient of variation) of the total variance.

Adult↗
PubMed1988

The role of a transmembrane pH gradient in uptake and release of imipramine and haloperidol in synaptosomes.

By using the methylamine method, the influence of a transmembrane pH gradient on the distribution of the antidepressant imipramine and the neuroleptic haloperidol was assessed in synaptosomes. Resting synaptosomes concentrated methylamine 8- to 9-fold at pH 7.4, as compared with a 400- to 600-fold concentration of the lipophilic weak bases imipramine and haloperidol. Ignoring compartmentation, the methylamine ratio is consistent with an internal pH of 6.5. Weak acid partition yielded an internal pH of 7.1. In agreement with the pH partition hypothesis, elevation of the internal pH by NH4Cl reduced whereas internal acidification enhanced imipramine and haloperidol uptake. Release of both drugs could also be elicited with excess K+ or veratridine. The underlying mechanism is a depolarization-induced rise of the internal pH by 0.12 to 0.25 units. In polarized synaptosomes, about 70% of the uptake of imipramine and haloperidol depended on the transmembrane pH gradient. A predominant localization in synaptic vesicles in situ is derived from the proportional release of methylamine, imipramine, and endogenous dopamine by nigericin. It is concluded that the acidic internal pH plays an important role for the passive concentration of lipophilic bases like imipramine and haloperidol in the brain, thereby profoundly influencing the extra- and intracellular free concentrations. Binding to cellular constituents contributes to internal accumulation. Especially high concentrations are attained in acidic vesicles.

Animals↗
PubMed1986

A comparison of parenteral loxapine and haloperidol in hostile and aggressive acutely schizophrenic patients.

In a parallel groups, double-blind study, 54 acutely psychotic schizophrenics were given loxapine or haloperidol parenterally for 24 to 72 hours, then orally for a total study period of up to 10 days. Dosage ratios of loxapine to haloperidol ranged from a minimum of 2.7:1 to a maximum of 4.4:1. Both groups showed significant and rapid improvement from baseline. Forty-eight percent of the loxapine patients and 33% of the haloperidol patients achieved and maintained a global severity of illness rating of mild or better. By the end of the study, 84% of the loxapine patients and 63% of the haloperidol patients had achieved an improvement rating of moderate or marked. This difference approached significance (p less than .10). The most frequently reported adverse experiences were dystonic reactions and akathisia. The number and severity of adverse experiences did not differ significantly between drug groups. Intramuscular loxapine was at least as effective as haloperidol in the initial management of hostile and aggressive schizophrenic patients. The maintenance of therapeutic response after conversion to oral concentrate was comparable with the two drugs.

Acute Disease↗
PubMedDate not supplied

[Use of very high doses of haloperidol in the treatment of acute psychotic episodes. Clinical and pharmacokinetic analysis apropos of 15 cases].

High-dosage haloperidol treatment was administered during three weeks in a rapid neuroleptization technique to fifteen patients suffering from acute psychotic episodes. Haloperidol plasma levels were determined by radioimmunoassay. The efficacy of such a therapeutic design seemed fairly good, particularly the rapid improvement during the first week. Yet, tolerance appeared to be low, with a high incidence of adverse effects, some of them unexpected. A very good correlation was observed between haloperidol plasma levels and haloperidol oral doses. By contrast, there was no correlation between plasma levels and clinical improvement. In the same way, the occurrence of adverse effects did not seem to be related to haloperidol plasma levels.

Acute Disease↗
PubMed1987

Further characterization of the leukemogenic activity of haloperidol in mice.

Haloperidol, a butyrophenon, is widely used for the treatment of psychotic disorders in man. Recently we reported that this drug causes, with high incidence, the development of monocytic-myeloid leukemias in male NMRI mice upon 5 X 5 mg/kg i.p. administration. Here we present evidence for the leukemogenic effect of haloperidol in two other strains of mice (XVII AKF1 hybrids, and the low leukemic BALB/c/BOM). The strain-dependent incidence of leukemias ranged both in males and females between 34% (AKR) and 69% (XVII AKF1) with average latencies between approximately 200 (AKR) and 600 (BALB/c) days. On the basis of cytological and cytochemical criteria the predominating type of leukemias was classified as monocytic-myeloid. These leukemic were serially transplantable. Cell-free extracts of leukemic tissues did not induce the disease indicating that no virus was activated by haloperidol. However, when the drug was administered to AKR mice after a suboptimal dose of nitrosomethylurea (NMU), a higher incidence of mixed-type leukemias was observed as with haloperidol alone. NMU alone induced lymphatic leukemias with proven viral involvement. The tumor promoter 12-0-tetradecanoylphorbol-13-acetate did not influence haloperidol-induced leukemogenesis.

Animals↗
PubMedDate not supplied

[Changes in the behavioral and biochemical effects of cerulein, an analog of cholecystokinin octapeptide, after prolonged administration of haloperidol].

In experiments on male mice and rats, long-term haloperidol administration (0.25 mg/kg twice a day during 15 days) significantly changed behavioural effects of caerulein, an agonist of CCK-8 receptors. As a rule, the effects of caerulein were reduced or inverted; only long-term antagonism with amphetamine motor excitation in rats increased after the cessation of haloperidol administration. The decrease or inversion of caerulein's effects was connected with reduction of high-affinity dopamine2- and low-affinity CCK-8 receptors' density, reflecting the inhibition of some interneurons' activity in subcortical forebrain structures after haloperidol treatment. A more pronounced inhibition of dopamine's release by caerulein was the reason for the increased antiamphetamine action after long-term haloperidol treatment. It seems possible that both above mechanisms are involved in the antipsychotic action of haloperidol.

Animals↗
PubMed1979

Modification of behavioral and neurochemical effects of cocaine by haloperidol.

Cocaine (20 mg/kg, i.p.) stimulated spontaneous motor activity (SMA) and induced stereotypy (ST) in rats. Haloperidol at 0.015 mg/kg, i.p. dose reduced or blocked cocaine-induced ST, but did not affect, drug-induced hyperactivity. At 0.03 mg/kg, i.p. dose of haloperidol, both behavioral effects were blocked. Cocaine decreased the norepinephrine (NE) and serotonin (5-HT) contents of diencephalon-midbrain (DM) and pons-medulla (PM) and increased dopamine (DA) contents in the DM and caudate nucleus (CN) at 20 min after its administration. Haloperidol (0.03 or 0.015 mg/kg) at 30 min postdrug produced opposite effects on the levels of NE, DA and 5-HT in the respective brain areas compared to cocaine. Given in combination, haloperidol reversed the effects of cocaine on the levels of NE, DA and 5-HT. Thus the cocaine-induced behavioral changes and their modification by haloperidol can be correlated to the neurochemical changes produced by these drugs alone or their combination.

Animals↗
PubMed1980

Anomalous behavioral response to imidazoleacetic acid, a GABA agonist, in animals treated chronically with haloperidol.

Short-term haloperidol treatment decreases the stimulant effects of drugs with dopaminelike actions, while withdrawal from long-term haloperidol treatment enhances the effects of such drugs. In the present study, we have shown that withdrawal from long-term haloperidol treatment decreases or eliminates the tendency for imidazole-4-acetic acid, a GABA agonist, to decrease the locomotor activity of mice. Acute haloperidol treatment did not duplicate these effects. It is suggested that chronic administration of haloperidol causes changes in a variety of systems in the brain, and that the GABA system in particular is profoundly altered by such treatment.

Animals↗
PubMed1983

Electroencephalogram and treatment of hospitalized aggressive children with haloperidol or lithium.

Electroencephalograms (EEGs) of 48 children ages 5.2 to 12.9 years were examined on baseline placebo and on optimal dosages of haloperidol, lithium, or placebo. These children represent a subgroup of 61 hospitalized aggressive and explosive patients diagnosed as Conduct Disorder, undersocialized, aggressive who completed a double-blind study comparing the efficacy of haloperidol, lithium, and placebo. EEGs were correlated across treatment groups with behavioral ratings, ratings of untoward effects, and optimal dosages of medication. During the baseline placebo period 58.3% of the children had abnormal EEGs. Children receiving haloperidol or lithium had a significant probability that their EEGs on optimal dose would worsen, and would be more likely to show paroxysmal or focal abnormalities than those children treated with placebo. It was possible to identify children treated with haloperidol, lithium, or placebo on the basis of EEG alone. Thus, despite limitations, visual evaluation of EEGs is of value. No statements can be made with confidence regarding associations between baseline EEGs and behavioral changes, side effects, or optimal dosages of haloperidol or lithium.

Aggression↗
PubMedDate not supplied

Behavioral and pharmacokinetic interaction between morphine and haloperidol in the rat.

Tail-flick latencies and morphine concentrations in the blood serum, brain (without striatum) and spinal cord were measured in rats receiving 10 mg/kg ip morphine with or without haloperidol pretreatment (0.1 or 1 mg/kg sc). Haloperidol pretreatment dose-dependently potentiated the analgesic action of morphine and interfered with tissue morphine levels. Morphine levels in the spinal cord were similar to those in the blood serum and were dose-dependently increased by haloperidol pretreatment; in the brain the appearance of morphine was delayed, the levels lower than in the blood serum, and the effect of both doses of haloperidol (augmentation of morphine level) was similar. The results indicate that the analgesic effect of morphine in the tail-flick test is correlated better with the spinal than cerebral morphine levels and that potentiation of morphine analgesia by haloperidol is due, at least in part, to pharmacokinetic interaction.

Animals↗
PubMedDate not supplied

Haloperidol decanoate in schizophreniform disorders. Clinical and neuroendocrine aspects.

The recently synthesized depot neuroleptic haloperidol decanoate (HD) has been mainly used in the treatment of chronic schizophrenia. In this trial 23 outpatients, 11 male and 12 female, suffering from schizophreniform disorders, according to the DSM III, were treated with 50 mg to 250 mg of HD, every 4 weeks for 12 months. At the end of the trial, the mean dosage of HD administered and BPRS (Brief Psychiatric Rating Scale) mean scores were significantly lower than the initial ones (70.8 mg VS 108 mg, and 21.5 VS 45.7 respectively). In 10 male patients, plasma levels of haloperidol and PRL were evaluated during the first four weeks of treatment. A positive correlation between haloperidol levels and clinical improvement and a significant increase in PRL levels in correspondence with haloperidol plasma peaks, but not with clinical improvement, were observed. These data indicate a dissociation between the effect of haloperidol after HD injection on the limbic dopaminergic system and the effect at the level of the tubero-infundibular system.

Acute Disease↗
PubMed1983

Effects of haloperidol-induced dopamine receptor supersensitivity on kindled seizure development.

By using kindling by repetitive amygdala stimulation as a model of generalized seizure development in the rat, we have shown that dopamine receptor subsensitivity has been shown to occur in selected brain areas after the development of seizures. In the present study, the influence of initially altered dopamine receptor sensitivity on the development of seizures was examined by inducing receptor supersensitivity through chronic haloperidol injection before amygdaloid kindling stimulation. Rats injected with haloperidol (5 mg/kg i.p.) for 18 or 30 days were stimulated in the amygdala daily until full seizures were elicited. Starting 2 days after the last injection, rats treated with 5 mg/kg of haloperidol i.p. required significantly more stimulations than their respective control groups. The slowed rate of seizure development was not significant if the kindling stimuli were initiated 6 days posthaloperidol treatment nor if 10-mg doses of haloperidol were used for 30 days. [3H]Spiroperidol binding assays were performed on tissue from striatum and amygdala-pyriform cortex at various times after drug treatment. Increased receptor binding was observed in striatum and amygdala-pyriform cortex of all haloperidol treatment groups. These observations lend support to the hypothesis that dopamine plays a role in seizure suppression as an increased receptor sensitivity to dopamine delayed kindled seizure development.

Amygdala↗
PubMedDate not supplied

[Effect of fenamin and haloperidol on conditioned activity of neurons of the motor cortex and striopallidal system].

The activity of neurones in the motor cortex, caudate nucleus, putamen and globus pallidus was studied during elaboration of motor conditioned reflexes to time in rabbits, treated with 1-amphetamine and haloperidol. Mechanisms of reproduction of cells trace activity in the reflex to time at the omission of trials, reacted to 1-amphetamine by increasing the intensity of reactions in the motor cortex and inactivation in putamen cells. The curve of dynamics of intensity changes of trace discharges in the course of a series of trials omissions remained unaltered only in motor cortex; in the other structures it significantly differed from the norm of intact animals. Haloperidol depressed the mechanisms of reproduction of trace reactions of the globus pallidus cells, and made them almost fully inactive in the motor cortex; the putamen neurones reacted to haloperidol by an increase of trace reactions intensity. Against the background of the animal chronic 1-amphetamine intoxication, haloperidol normalized the dynamics and intensity of trace activity. "Therapeutic" effect of haloperidol was most distinctly expressed in the motor cortex and putamen cells, less--in the caudate nucleus and was completely absent in the globus pallidus.

Amphetamine↗
PubMed1981

Neuroleptic treatment of oligophrenic patients. A double-blind clinical multicentre trial of cis(Z)-clopenthixol and haloperidol.

One hundred mentally retarded patients from five Finnish institutions took part in a double-blind, double-dummy 12-week trial assessing the therapeutic effect of cis(Z)-clopenthixol and haloperidol. Assessments including CGI by psychiatrists and ward personnel as well as a 4-item target symptom scale was done at weeks 0, 4, 8, and 12. Improvement was registered by the psychiatrists in 16, 21, and 24 cis(Z)-clopenthixol patients and in 11, 6, and 7 haloperidol patients at weeks 4, 8, and 12, respectively--the difference between the two drugs being significant at weeks 8 and 12. The ratings of CGI by the personnel and the 4-item scale by the psychiatrists showed less improvements and no significant differences between the two drugs. While the overall impression of interference of patients' functioning by side-effects were in the favour of haloperidol the number of single side effects increased more with haloperidol than with cis(Z)-clopenthixol during the 12 weeks. Average doses administered at week 12 were 34 mg cis(Z)-clopenthixol and 5 mg haloperidol.

Adult↗
PubMed1982

Age effects on haloperidol pharmacokinetics in male, Fischer-344 rats.

Biodisposition of haloperidol was examined in male, Fischer-344 rats in four age groups, 3 to 4, 11 to 12, 23 to 24 and 32 to 34 months. Haloperidol was administered i.p. as a bolus (0.50 mg/kg) or continuously during 4 days from an implanted osmotic minipump (0.15 mg/day). Plasma and regional brain concentrations of haloperidol were determined by gas chromatography with a nitrogen-phosphorus detector. After a bolus administration, plasma and brain concentrations were significantly higher at later time points, the plasma elimination half-life was significantly longer and the estimated plasma clearance was lower in 32- to 34- than in 3- to 4-month-old animals. The plasma and regional brain concentrations 6 hr after a bolus increased as a function of age, up to 23 to 24 months. At a steady state after continuous infusion, plasma and brain concentrations also rose with age up to 23 to 24 months. After either bolus or continuous infusion, the brain/plasma concentration ratios were lower at 11- to 12- and 23- to 24-months-of-age than at either of the other age groups. The results indicate that a reduced apparent plasma clearance of haloperidol is primarily responsible for higher plasma and brain concentrations of haloperidol in the older animals and that plasma concentrations are not always predictive of brain concentrations.

Aging↗
PubMed1982

Studies on the melanin affinity of haloperidol.

The general distribution of 3H-haloperidol was studied in mice by means of whole body autoradiography. Extensive accumulation and retention was observed in the melanin containing tissues. In the albino animals uptake was low in the corresponding tissues. Impulse counting of excised tissue pieces showed a maximum concentration in the pigmented eyes 24 hr after a single intravenous injection. In the pigmented eyes, about 1/5 of the radioactivity at 24 hr still remained 90 days after administration. In vitro, haloperidol was found to be bound to beef-eye melanin and dopamine melanin (structurally similar to the melanin present in the pigmented nerve cells in the human substantia nigra). The total binding capacity of beef-eye melanin was approximately twice that of dopamine melanin. Beef-eye melanin bound haloperidol to an extent twice that earlier reported for chlorpromazine and chloroquine, while the binding strengths were of about the same magnitude. Due to its high melanin affinity it is most probable that haloperidol accumulates extensively in the pigmented neurons of the substantia nigra in patients on long term therapy. Other compounds with melanin affinity such as phenothiazine derivatives and manganese are known to produce irreversible extrapyramidal disorders, degeneration and depigmentation of the pigmented nerve cells in the substantia nigra. In conclusion the melanin affinity may be an important factor in the pathogenesis of haloperidol induced tardive dyskinesia.

Animals↗