Circadian rhythm of brain susceptibility to haloperidol during chronic administration

Circadian fluctuation has been reported to exist to the effects of haloperidol after acute administration. In an attempt to clarify the viability of chronotherapy with haloperidol, the antiapomorphine effect of haloperidol after chronic administration was investigated in the present paper. Haloperidol was administered once daily at the same time for 21 consecutive days to rats which were kept under 12 hr lighting conditions with light onset at 19:30. Then the chronology of the antiapomorphine effect was investigated. The antiapomorphine effect was significantly stronger in the group treated at 19:30 than that treated at 13:30. These data agreed with the results found after the acute administration of the drug. After chronic administration, no difference was found in the plasma and brain level of haloperidol due to the time of administration. These experimental results seem to suggest that a circadian rhythm in the brain susceptibility to haloperidol exists even during chronic administration.     

High dosage haloperidol therapy in chronic schizophrenic patients: A double-blind study of clinical response,side effects,serum haloperidol,and serum prolactin

In a 12-weeks double-blind study high dosage versus standard dosage haloperidol therapy was evaluated in 23 male, chronic schizophrenic inpatients. The patients were relatively treatment-resistant and, in spite of traditional neuroleptic medication, were characterized by a moderate to severe degree of illness. At the end of the trial the dose of haloperidol in the standard dosage group was 12–36 mg/day (mean 15), in the high dosage group 10–240 mg/day (mean 103). No significant difference in therapeutic effect was found between the two groups as measured by the Brief Psychiatric Rating Scale and global assessment. About half the patients in both groups improved during the trial. A greater incidence of side effects was noticed in the high dosage group than in the standard group, especially in the form of sedation (5 of 12 patients), aggressive episodes (three patients), muscular weakness and tendency to fall (two patients), and epileptic attacks (one patient). The incidence of extrapyramidal phenomena showed fewer differences between the two groups. In addition, the high dosage group showed a temporary rise in serum alkaline phosphatase and serum aspartate-aminotransferase. There was a positive correlation between the dose of haloperidol and serum haloperidol, and between the haloperidol dose of up to 80 mg/day and serum prolactin. At higher doses prolactin response leveled off. Neither serum haloperidol nor serum prolactin showed any correlation to clinical response. It is concluded (1) that very high doses of haloperidol in only a few cases show any therapeutic advantage over haloperidol in standard doses; (2) that high dosage treatment has a higher incidence of side effects; and (3) that the serum concentrations of a given neuroleptic and of prolactin are of very limited value in the monitoring of neuroleptic treatment.     

Differences between antipsychotic drugs in persistence of brain levels and behavioral effects

After a single dose of the butyrophenone neuroleptic haloperidol, behavioral effects and detectable drug levels in rat brain can last for several weeks. To determine if such persistence is a general property of neuroleptics, we compared drug levels and effects after IP administration of two butyrophenones (haloperidol and bromperidol), a high potency (fluphenazine) and a low potency (chlorpromazine) phenothiazine. Drug levels in brain tissue were measured by high pressure liquid chromatography and behavioral effects monitored as inhibition of apomorphine-induced stereotypy. Estimated near terminal elimination half-lives (t_1/2) from brain for acutely administered chlorpromazine (20 mg/kg) and fluphenazine (1 mg/kg) were 0.41 and 0.62 days, respectively, and neither drug was detectable after 4 days. Fluphenazine given daily for 5 days showed an only slightly slower elimination (t_1/2=1.1 days). In contrast, near-terminal elimination half-lives from brain for haloperidol and bromperidol (both at 1 mg/kg, IP) were much longer (6.6 and 5.8 days, respectively), and each was detectable for 21 days after dosing. Inhibition of apomorphine-induced stereotypy correlated highly (r=0.95) with brain levels of haloperidol. For fluphenazine, given once or repeatedly, early inhibition was replaced within 1 week by supersensitivity to apomorphine which persisted for up to 3 weeks. These findings, indicating marked differences in clearance and recovery times after dosing with butyrophenones and phenothiazines, have clear implications for studies of the effects of neuroleptic drugs in rats. While there are limits to the extrapolation of these findings to other species, our results and those from studies in human subjects suggest similarly persistent drug levels and effects may be seen when patients are withdrawn from neuroleptic drugs.     

Pharmacokinetics and effects of haloperidol in the isolated mouse

The pharmacokinetic behaviour of haloperidol (0.6 mg/kg s.c.) was studied in grouped and 4-week isolated male mice of the CF-1 strain (24 h observation; gas chromatography, NPFID). Maximal drug levels occurred in serum within 2 min and in whole brain after 15 min. The elimination from serum and brain was biphasic with larger t1/2 values for brain. There was an accumulation of haloperidol in brain up to 40 times of the serum level. Isolation resulted in a more rapid first phase of elimination from serum, provided the animals were tested for aggressivity immediately before the administration of the drug. The minimal effective (i.e. cataleptogenic) brain level of haloperidol was approximately 0.1 microgram/g wet weight. Haloperidol-induced catalepsy was (after 1 h) in isolated mice weaker than in grouped mice; this applied to animals of both the CF-1 and the NMRI strain. The catalepsy disappeared after 6 h. The antagonism by haloperidol of the stereotyped gnawing (induced by methylphenidate, 30 and 50 mg/kg, i.p., NMRI mice) likewise lasted for 6 h. Therefore, the cataleptic effects, but not the brain levels of haloperidol, are influenced by isolation and aggression in mice.     

Haloperidol and metabolite concentrations in the rat after concurrent isotretinoin administration: a preliminary report

Blood and tissue haloperidol concentrations can be altered by the concurrent administration of a number of other drugs. Here we describe effects of concurrent administration of the vitamin A metabolite, isotretinoin, on haloperidol and reduced haloperidol concentrations in the rat. Isotretinoin increased the concentrations of both haloperidol and reduced haloperidol in serum, red blood cells, and brain. However, the dose dependence and degree of the effect varied significantly across tissues. Further study is called for to elucidate the interaction of neuroleptics such as haloperidol with the vitamin A acids such as isotretinoin.     

Pharmacokinetics of maprotiline and its demethylated metabolite in serum and specific brain regions of rats after acute and chronic administration of maprotiline.

The concentrations of maprotiline (MAP) and its demethylated metabolite desmethylmaprotiline (DMAP) in the serum and specific brain regions were determined periodically after acute or chronic administration of 20 mg/kg of MAP in rats. MAP was eliminated in a biexponential manner from the serum and monoexponentially from the brain. The DMAP declined monoexponentially from the serum and brain regions. No significant difference was observed in elimination among the eight brain regions examined. In the brain, MAP distributed unevenly after chronic administration, whereas DMAP showed an even distribution. In the acute administration, the AUCbrain: AUCserum ratio of MAP was similar to that of DMAP, and the AUCDMAP: AUCMAP ratio in the serum was almost equal to that in the brain, indicating equivalent ability of MAP and DMAP to penetrate into the brain. After chronic administration, the AUCDMAP value in the serum increased 4.1 times, whereas no marked change was observed for MAP. There was no evidence of enhanced N-demethylation activity from in vitro metabolism study, suggesting that the enhanced AUCDMAP value was not attributable to the enhancement of drug metabolizing activity. Although the AUCMAP value in the brain, as well as in the serum, increased slightly, the AUCDMAP in the brain increased 2.3 times, showing less increase than that in the serum. These findings suggest inhibited distribution of DMAP into tissue, including brain regions, after chronic administration. The pharmacokinetics of the demethylated metabolite DMAP is affected more than that of MAP by chronic administration of MAP.     

Effects of minaprine, a novel antidepressant, on prolactin secretion in the rat

The effect of minaprine, a novel psychotropic drug with antidepressant properties, on prolactin secretion has been investigated in the rat. On intraperitoneal administration (10 and 20 mg kg-1) it significantly decreased basal prolactin levels. In contrast, both haloperidol (1 mg kg-1 i.p.) and morphine (20 mg kg-1 i.p.) increased serum prolactin levels and daily treatment with oestradiol (100 micrograms kg-1 s.c.) for 4 days also elevated the levels. Minaprine at a dose of 20 mg kg-1 failed to antagonize the elevation of serum prolactin levels induced by these drugs. The results imply that minaprine may not exert a direct inhibitory action on prolactin secretion at the pituitary gland.     

Diminished catalepsy and dopamine metabolism distinguish aripiprazole from haloperidol or risperidone

Catalepsy and changes in striatal and limbic dopamine metabolism were investigated in mice after oral administration of aripiprazole, haloperidol, and risperidone. Catalepsy duration decreased with chronic (21 day) aripiprazole compared with acute (single dose) treatment across a wide dose range, whereas catalepsy duration persisted with chronic haloperidol treatment. At the time of maximal catalepsy, acute aripiprazole did not alter neostriatal dopamine metabolite/dopamine ratios or homovanillic acid (HVA) levels, and produced small increases in dihydroxyphenylacetic acid (DOPAC). Effects were similar in the olfactory tubercle. Dopamine metabolism was essentially unchanged in both regions after chronic aripiprazole. Acute treatments with haloperidol or risperidone elevated DOPAC, HVA, and metabolite/dopamine ratios in both brain areas and these remained elevated with chronic treatment. The subtle effects of aripiprazole on striatal and limbic dopamine metabolism, and the decrease in catalepsy with chronic administration, illustrate fundamental differences in dopamine neurochemical actions and behavioral sequelae of aripiprazole compared to haloperidol or risperidone.     

The effect of the stereoisomers of butaclamol on neurotensin content in discrete regions of the rat brain

The prevailing hypothesis concerning the mechanism of antipsychotic drug action is principally based on the striking correlation between their clinical potency and their potency in blockade of D2 dopamine receptors. However, most of these compounds also have effects at serotonin, acetylcholine, histamine, and alpha-adrenergic receptors and have recently been shown to alter the concentrations of certain neuropeptides in the rat brain after chronic drug administration. One such neuropeptide that is increased in concentration in dopamine terminal regions by clinically effective neuroleptic drugs is neurotensin (NT). Neurotensin is closely associated with dopamine neurons, as demonstrated by evidence derived from anatomic, physiologic, and pharmacologic studies. In this report, we determined the effects of chronic administration of the potent D2 receptor antagonist (+)-butaclamol and its inactive (-) stereoisomer on regional brain NT content. Moreover, we sought to determine whether the effects of haloperidol on NT concentrations can be antagonized by concomitant administration of an indirect dopamine agonist, d-amphetamine. Neurotensin content in the caudate nucleus and nucleus accumbens of the rat were significantly increased by 3 weeks of daily injections of haloperidol or (+)-butaclamol, but not (-)-butaclamol. d-Amphetamine did not alter this effect of haloperidol on NT concentrations in either the nucleus accumbens or caudate nucleus. These data are concordant with the hypothesis that D2 receptor blockade is required for NT concentration increases after antipsychotic drug treatment and that the increase in synaptic cleft dopamine content produced by d-amphetamine cannot reverse this effect of dopamine receptor antagonists.     

Effect of haloperidol on a symbol digit substitution task in normal adult males

Two groups of normal male volunteers were administered oral haloperidol at two dose levels: 4 mg (n = 12), and 10 mg (n = 9). Subjects were administered the Symbol-Digit Substitution Test (SDST) prior to drug administration (0 hours) and at the following intervals after administration: 1, 3, 4, 6, 14, 24, and 36 hours. Overall performance of the 10-mg group was poorer than that of the 4-mg group. Both groups showed a significant time-dependent decrease in performance, with the effects for the 10-mg group being apparent earlier and lasting longer. The time course for this decrease corresponded to the time course of elevation of prolactin by haloperidol in these subjects. Performance on the Flexibility of Closure Test was unimpaired in subjects receiving 10 mg haloperidol, indicating that the impairment in performance on the SDST was not exclusively due to nonspecific factors such as sedation or psychomotor retardation. Extrapyramidal side effects could have contributed to impairment on the SDST, but the time course of these effects was different than that of performance impairment. Results indicate that haloperidol may have dose-dependent differential adverse effects on task performance when administered on a short-term basis, although little is known about the exact nature of these effects and their relationship to antipsychotic activity of the drug. Even though these effects may clear with repeated administration, their presence even for a short time may contribute adversely to the risk-benefit profile of neuroleptic medication.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of haloperidol and fluphenazine decanoates in chronic schizophrenia

In a double-blind comparison of haloperidol decanoate and fluphenazine decanoate given 4-weekly for 60 weeks as maintenance therapy in 38 chronic schizophrenic in-patients, plasma haloperidol, fluphenazine and prolactin levels were measured at regular intervals by radioimmunoassay. After the first injection, the mean plasma haloperidol level was highest at week 1 and fell gradually towards week 4. Mean pre-dose haloperidol levels changed little after week 8. Results suggested an absorption half-life of 4 weeks, although, in three cases steady state was only achieved after 11 monthly injections. Steady state levels of both haloperidol and fluphenazine correlated highly with dose. In two subgroups observed at steady state, both drugs produced a biphasic pattern of plasma drug concentration between injections, a rapid rise on day 1 followed by stable elevated levels and a gradual return to pre-injection concentration by the end of week 4. In the fluphenazine subgroup there was a second peak on day 7 and a steeper decline, so that the mean area-under-curve in week 4 was 64% of that in week 1. Drug injections at steady state induced an increase in prolactin secretion in all of the fluphenazine sub-group and in half of those receiving haloperidol. Plasma prolactin changes resembled those for drug concentrations, but differences in times of peaks on day 1 resulted in weak correlations. Fluphenazine appeared more potent than haloperidol in provoking prolactin secretion.     

Co-administration of haloperidol and drugs affecting the angiotensin pathway: effect on the extrapyramidal system

The present study investigates the extrapyramidal effects of co-administration of enalapril (angiotensin-converting enzyme inhibitor) or losartan (angiotensin receptor blocker) with haloperidol in mice. Enalapril/losartan (as a suspension in 1% gum acacia) was administered by oral gavage and haloperidol was administered as an intraperitoneal injection to all the animals for seven days. Catalepsy was measured 30?min after the administration of haloperidol (1?mg/kg i.p.) on days 1 and 7. Observations on day 1 constituted the acute study (single dose administration) and observations on day 7, constituted the chronic study (repeated dose administration). Both acute and chronic administration of enalapril/losartan produced an increase in the duration of haloperidol induced catalepsy at the highest dose (20?mg/kg). Enalapril produced a more pronounced increase in the duration of catalepsy as compared to losartan on both acute and chronic administration. Results of our study suggest that co-administration of anti-psychotics and drugs affecting the angiotensin system can lead to an increase in motor side effects and therefore should be used with caution in patients with these co-morbid conditions.     

Modulating role of lithium on dopamine turnover,prolactin release,and behavioral supresensitivity following haloperidol and reserpine

The effects of haloperidol, reserpine, and concomitant lithium were evaluated in biochemical, endocrine, and behavioral studies in the rat. Concomitant administration of a chronic regimen of haloperidol and lithium did not prevent the development of tolerance as noted by dopamine metabolites in the striatum or olfactory tuberculum. Nor did chronic lithium alter behavioral response in rats treated with reserpine and challenged with the dopamine agonist apomorphine. Additionally, prolactin release was increased by haloperidol, but was not altered by acute or chronic lithium treatment. These findings are discussed in the light of present knowledge of pre- and postsynaptic receptor changes and the effects of lithium.     

Pharmacokinetics and body distribution of amiodarone and desethylamiodarone in rats after oral administration

The pharmacokinetics and body distribution of amiodarone and desethylamiodarone were studied in rats after single oral administration of 100 mg/kg and 200 mg/kg of amiodarone. The time-course of the concentrations of the drug and its main metabolite was determined by high performance liquid chromatography in serum and tissues up to 24 h. The mean absorption half-life of amiodarone was 1.83 h for both dosages and the mean elimination half-life was 15 h after the 100 mg/kg dosage and 105 h after the 200 mg/kg dosage. The mean bioavailability of oral amiodarone ranged from 17% to 60% with an average of 39%. Desethylamiodarone, the major metabolite of amiodarone, was present over the 24 h period of observation in relatively low levels of 30 to 60 ng/ml after the 100 mg/kg dose and 50 to 110 ng/ml after the 200 mg/kg dose respectively, which is circa 4% and 7% of the corresponding parent drug level. Amiodarone is preferentially distributed in decreasing order in lung, liver, thyroid gland, kidney, heart, adipose tissue, muscle tissue and brain. The metabolite desethylamiodarone exhibited a distribution pattern comparable to the parent drug. However, its maximum concentrations in serum and tissues were consistently lower than the corresponding amiodarone concentrations and varied from 18 to 55% (mean 27%), depending on the acute oral dose applied and on the kind of tissue. The amiodarone tissue/serum concentration ratios were high in lung tissue (60-100) and moderate to high in the other tissues except brain (3-60), and indicate an extensive distribution of the drug with the lung as an organ with specific binding sites or uptake mechanisms and adipose tissue as a reservoir with a large storage capacity. The metabolite tissue/serum concentration ratios were very high in lung tissue (500-800), high in renal, thyroid, liver and adipose tissue (80-200) and moderate in the other tissues except for brain (20-60); they indicate a very extensive distribution of desethylamiodarone with, primarily, lung and to some lesser extent kidney, liver and thyroid gland as organs with sites of metabolism and/or specific binding sites or uptake mechanisms and fat as a reservoir for the drug. A marked increase in the accumulation of amiodarone and desethylamiodarone was observed in adipose tissue after chronic oral administration, whereas the rise in kidney and brain was less pronounced and in the remaining tissues it was insignificant. Our data suggest that the rat is a good model for describing the single oral dose pharmacokinetics and body distribution of amiodarone and desethylamiodarone in man.     

The pharmacokinetics of perindopril and its effects on serum angiotensin converting enzyme activity in hypertensive patients with chronic renal failure.

1. Perindopril, an orally active angiotensin converting enzyme inhibitor, was given to 23 hypertensive patients with stable chronic renal failure for 15 days. The dose of perindopril was 2 or 4 mg once a day according to the degree of renal failure. The creatinine clearance of the patients ranged from 6 to 67 ml min-1 1.73 m-2. The pharmacokinetics of perindopril and perindoprilat, its active metabolite, were studied after acute and chronic administration of perindopril. 2. The drug was well tolerated and creatinine clearance was unaltered by treatment. 3. In both groups, steady-state was reached within 3 days of chronic treatment. 4. After both acute and chronic drug administration renal impairment had no effect on perindopril pharmacokinetics but the pharmacokinetics of perindoprilat were altered significantly. After chronic administration the serum accumulation ratio was 1.81 in patients with mild renal failure and 5.35 in patients with severe renal failure. Chronic administration did not modify the renal clearance of perindoprilat nor its elimination half-life. 5. A significant correlation between the renal clearance of perindoprilat and creatinine clearance was observed (r = 0.87 first dose, r = 0.83 last chronic dose). 6. A non-linear relationship between serum perindoprilat concentration and inhibition of angiotensin converting enzyme was described by a modified Hill equation. Values of IC50 were 1.11 +/- 0.07 micrograms I-1 (mean +/- s.d.) in patients with severe renal failure and 1.81 +/- 0.20 micrograms l-1 in patients with moderate renal failure. Chronic administration increased maximal inhibition and decreased the time to maximal inhibition only in patients with severe renal failure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Stability of serum neuroleptic and prolactin concentrations during short- and long-term treatment of schizophrenic patients

The potential importance of neuroleptic activity measures in the management of schizophrenia warrants attention to the methods for assessing neuroleptic bioactivity and stability of neuroleptic bioactivity over time. We have carried out measurements of serum neuroleptic and prolactin concentrations in 18 schizophrenic patients treated with haloperidol or thioridazine for up to 1 year. Serum neuroleptic levels were measurd by a radioreceptor assay using porcine striatum. The lower limit of sensitivity of the assay was 0.6 ng haloperidol/ml, the intra- and interassay coefficients of variation 3 and 9%, respectively. A linear correlation was observed between haloperidol dose (5–30 mg/d) and serum neuroleptic activity (r=0.706, P<0.001) and a curvilinear relationship between thioridazine dose (50–600 mg/d) and serum neuroleptic activity in schizophrenic outpatients. There was a positive correlation between serum neuroleptic and prolactin concentrations for the patients taking haloperidol (r=0.620, P<0.001) or thioridazine (r=0.542, P<0.001). In patients taking a constant dose of haloperidol or thioridazine for up to 1 year serum neuroleptic activity remained stable, suggesting the absence of metabolic tolerance; the observation of a decrease of 38±16% (mean ± SD) in serum prolactin concentrations in patients treated with haloperidol but no prolactin decrease with thioridazine suggests that under certain neuroleptic treatment conditions a functional tolerance develops in the tuberoinfundibular dopamine system.     

Effects of prenatal treatment of rats with haloperidol due to altered drug distribution in neonatal brain

Maternal exposure to haloperidol during gestation produced decreased behavioral responsiveness to apomorphine in rat offspring at 10 days after birth, but not at 15 or 30 days. An apparent decrease in the affinity of specific binding of [³H]piroperidol to striatal tissue of rats so treated was observed at 7 days after birth, with no difference in receptor affinity or total binding capacity at 15 or 30 days. Because these effects could result from the continued presence of haloperidol after birth, the distribution and clearance of small quantities of [³H]aloperidol were studied in neonates, older controls, and mothers, up to 10 days after drug administration. The concentration of labelled drug in the brains of the neonates was consistently more than three times higher than in adults, although serum and liver concentrations, and apparent rates of elimination from brain tissue were approximately equal. Postpartum persistence of prenatally administered neuroleptics may account for transient behavioral and biochemical alterations.     

Radioreceptor assay of haloperidol tissue levels in the rat

The levels of apparent haloperidol-like biological activity in serum and brain were estimated by a radioreceptor assay (RRA) involving competition for binding of [³H]-spiroperidol to a membrane preparation of calf caudate nucleus. The RRA was found to be capable of measuring haloperidol sensitively to 3 pmol/ml serum and 140 pmol/g brain. With the RRA technique, recovery of haloperidol from serum or brain was 90–100%. Excellent correlations were found among results obtained with the RRA, by a corroborative gas chromatography-mass spectrometry method, and by radioimmunoassay. Correlations between serum and brain levels in individual animals were quite close, and dose versus tissue level and time course versus tissue level relationships were demonstrated. Since the binding assay method is simple and evidently reliable, it provides a highly versatile addition to chemical assay methods. It is particularly well suited to experiments which attempt to correlate tissue drug levels with behavioral or clinical effects.     

Possible role of prolactin in the modification of medial basal hypothalamic glutamic acid decarboxylase activity

The effects of acute and chronic injections of haloperidol, sulpiride and apomorphine on serum prolactin (PRL) levels and medial basal hypothalamus (MBH) glutamic acid decarboxylase (GAD) activity were investigated in male rats. Parallel changes in PRL and GAD activity were observed in acutely treated animals. Conversely, a return to normal of the GAD activity associated with high plasma PRL levels was induced by chronic haloperidol and sulpiride treatment. Results are discussed in the light of the possible existence of a hypothetical PRL-γ-aminobutyric acid (GABA) subsidiary feedback loop.     

Haloperidol-induced changes in glutathione and energy metabolism: effect of nicergoline

The aim of this study was to evaluate the possible effects of nicergoline, a semisynthetic ergot derivative, on the biochemical changes observed during chronic treatment with haloperidol in male Sprague-Dawley rats. Chronic treatment with haloperidol induced a significant decrease in the cellular glutathione (GSH) content in selected areas of the brain (cerebellum, striatum and cortex) and in the liver. Prolonged nicergoline administration was able to antagonize the haloperidol-induced GSH decrease, maintaining the GSH concentration at levels comparable to those observed in the control group. Analysis of the energy charge revealed changes similar to those observed for GSH: haloperidol induced a significant decrease in ATP and energy charge that was completely reversed by repeated nicergoline administration. In conclusion, chronic treatment with the classical antipsychotic haloperidol induces profound biochemical changes in the brain and in the liver. Nicergoline treatment is able to counteract the haloperidol-induced decrease in GSH levels and energy charge, suggesting a potential role of the drug in the treatment of neuroleptic-induced side effects.