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At least 19 recordsLinked to original sources
PubMed1996

Response in chronic schizophrenia correlated with chlorpromazine, 7-OH-chlorpromazine and chlorpromazine sulfoxide levels.

The relationship between chlorpromazine, six of its metabolites and therapeutic response in chronic schizophrenic patients was investigated in this study. Logistic regression revealed no correlation between therapeutic response and four metabolites viz. Nor1 chlorpromazine, Nor2 chlorpromazine, chlorpromazine-N-oxide and Nor2 chlorpromazine sulfoxide. A good correlation was seen between CPZ (P = 0.036), 7-hydroxychlorpromazine (P = 0.004), chlorpromazine sulfoxide (P = 0.002) and therapeutic response. Good therapeutic response was correlated to high levels of chlorpromazine and its 7-hydroxy metabolite while high levels of the sulfoxide metabolite appeared to have a negative effect on therapeutic response. Poor responders who had high levels of chlorpromazine also had high levels of the sulfoxide metabolite. This suggests that the difference in response may lie in the difference in the metabolism of the drug.

Adolescent↗
PubMed1995

Protein binding of chlorpromazine in vivo and in vitro: effect of chlorpromazine metabolite on chlorpromazine protein binding in rat.

The serum protein binding curve of chlorpromazine (CPZ) on the Scatchard plot in vitro was a two-phase downward curve. However, after i.v. administration of CPZ the curve was altered to an upward curve. To clarify the reasons for these in vivo changes, the influence of chlorpromazine S-oxide (CPZSO), chlorpromazine N-oxide (CPZNO), desmethylchlorpromazine (nor1-CPZ), chlorpromazine sulfone (sul-CPZ) and 7-hydroxychlorpromazine (7-OH-CPZ) on CPZ protein binding were studied in vitro. The results indicated that the characteristics of the CPZ protein binding are altered by the combination of CPZSO or CPZNO or by either of them. Since it was very difficult to explain the relationship between serum total and free concentrations of CPZ in vivo using mass-balance equations like Hill's equation or a competitive inhibition equation on the multiple binding sites for drug, the correlation between the ratio ot total concentration of CPZ metabolites and CPZ (CPZSO/CPZ or CPZNO/CPZ) and the free fraction of CPZ was examined using the in vitro and in vivo data. The correlation between the ratio of CPZSO/CPZ and the free fraction of CPZ was good in both the in vivo and the in vitro studies. There was no statistically significant difference between the population regression coefficient of the two studies. The values of the slope and the intercept became almost the same as those obtained using the in vivo studies when combined with CPZNO.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Chlorpromazine versus placebo for schizophrenia.

BACKGROUND: Chlorpromazine, formulated in the 1950s, remains a benchmark treatment for those with schizophrenia. OBJECTIVES: To evaluate the effects of chlorpromazine for schizophrenia in comparison to placebo. SEARCH STRATEGY: Electronic searches of Biological Abstracts (1982-1995), The Cochrane Library (1999, Issue 2), The Cochrane Schizophrenia Group's Register (October 1999), EMBASE (1980-1995), MEDLINE (1966-1995), PsycLIT (1974-1995) were undertaken. References of all identified studies were searched for further trial citations. Pharmaceutical companies and authors of trials were contacted. SELECTION CRITERIA: Randomised controlled trials relating to people with schizophrenia, and non-affective serious/chronic mental illness irrespective of mode of diagnosis evaluating chlorpromazine (any dose) versus placebo. Primary outcomes of interest were death, violent behaviours, overall improvement, relapse and satisfaction with care. DATA COLLECTION AND ANALYSIS: Citations and, where possible, abstracts were independently inspected by reviewers, papers ordered, re-inspected and quality assessed. Data were extracted by BT with CA and GA independently checking a 10% sample for reliability. Dichotomous data were analysed using random effects relative risk (RR) and the 95% confidence interval around this was estimated. Where possible the number needed to treat (NNT) or number needed to harm statistics (NNH) were calculated. Continuous data were excluded if more than 50% of people were lost to follow up, but, where possible, weighted mean difference was calculated. Sensitivity analyses have not been undertaken for this version of the review. MAIN RESULTS: Over 1000 electronic records were inspected. The review currently mentions 202 papers in its Excluded Studies section and 45 studies in its Included Studies table. Six papers await assessment. Chlorpromazine reduces relapse over six months to two years (RR 0.65 CI 0.5-0.9, NNT 3 CI 2.5-4) and there is convincing evidence from trials that it promotes a global improvement in a person's symptoms and functioning (RR 0.76 CI 0.7-0.9, NNT 7 CI 5-10) although the placebo response is also considerable (nearly 40%). Fewer people allocated to chlorpromazine leave trials early (RR 0.76 CI 0.6-1.1). There are many adverse effects. Chlorpromazine is clearly sedating (RR 2.4 CI 1.7-3.3, NNH 6 CI 4-8), it increases a person's chances of experiencing acute movement disorders (RR 3.1 CI 1.3-7.6, NNH 24 CI 14-77), parkinsonism (RR 2.6 CI 1.2-5.4, NNH 10 CI 8-16) and fits (RR 2.4 CI 0.4-16). Amongst other things it clearly causes a lowering of blood pressure with accompanying dizziness (RR 1.9 CI 1. 3-2.6, NNH 12 CI 8-22) and considerable increases in weight (RR 4.4 CI 2.1-9, NNH 3 CI 2-5). REVIEWER'S CONCLUSIONS: This review will confirm much that clinicians and recipients of care already know but provides quantification to support clinical impression. Despite the humbling 40% improvement rate in those who were allocated to placebo, chlorpromazine's global position as the 'benchmark' treatment of those with psychoses is not threatened by this review. Chlorpromazine, in common use for nearly half a century, is a well established but imperfect treatment. Judicious use of this best available evidence should lead to better informed decisions both by carers and those with psychotic illnesses.

Antipsychotic Agents↗
PubMed1975

Chlorpromazine excretion in chronically dosed primates. I. Occurrence of a previously unreported class of chlorpromazine conjugates.

The use of tritiated chlorpromazine to correlate total excretion of radioactivity with characterization of the radioactive metabolites had shown a substantial discrepancy. While radioactivity was totally excreted and accounted for within three weeks, recognizable chlorpromazine metabolites represented only about two thirds of the radioactivity in any given sample. To rule out tritium exchange, 14C-labeled chlorpromazine was administered to Rhesus monkeys. The same discrepancy was observed, primarily in the conjugated drug fraction. Therefore, all unconjugated chlorpromazine metabolites were exhaustively extracted, and an alkaline hydrolysis performed. The aglycones liberated thereby were again carefully removed, and the residual aqueous fraction was subjected to an acid hydrolysis. This procedure yielded an additional group of known and unknown phenolic chlorpromazine aglycones, representing approximately one third of the radioactivity in the whole urine. Preliminary trials on urine pools of patients chronically dosed with chlorpromazine yielded essentially the same results. The structure of this new class of chlorpromazine conjugates has not yet been elucidated, nor is the ligand known at this time. A glucoside-type bond may characterize this significant class of chlorpromazine.

Animals↗
PubMed1991

Oxidation of chlorpromazine by methemoglobin in the presence of hydrogen peroxide. Formation of chlorpromazine radical cation and its covalent binding to methemoglobin.

The oxidation of chlorpromazine by methemoglobin plus H2O2 has been studied. The transient formation of the chlorpromazine radical cation in this reaction has been demonstrated by light absorption measurements. Under the experimental conditions complete conversion of chlorpromazine yields approximately 60% chlorpromazine sulfoxide. From studies with 3H-labeled chlorpromazine it appears that the remaining 40% is covalently bound to apohemoglobin. Upon reaction of methemoglobin with H2O2 a stable ferrylhemoglobin is formed. This ferrylhemoglobin is not the reactive species, which accepts the chlorpromazine electron, as its presence is not sufficient to induce chlorpromazine oxidation. For this the presence of H2O2 is a prerequisite. This indicates that a transient species in the formation of the stable ferrylhemoglobin is involved, whether this is a compound I analogue or a ferrylhemoglobin with a free radical on one of the apoprotein residues. Exposition of methemoglobin to H2O2 denatures hemoglobin and induces protein-heme crosslinks, as appears from changes in the visible absorption spectrum and heme retention by the protein after methyl ethyl ketone extraction. Reaction with CPZ partly protects against denaturation and crosslinking.

Chlorpromazine↗
PubMed1988

A kinetic study of chlorpromazine on the hyperglycemic response in rats. II. Effect of chlorpromazine on plasma glucose.

Kinetics of the pharmacologic effect of chlorpromazine was investigated in intact fed rats. After i.v. bolus administration of chlorpromazine (0.5, 2, 4 mg/kg), the time courses of plasma glucose, insulin, adrenaline and noradrenaline levels as well as serum and brain concentrations of the drug were determined. Since the hyperglycemic effect of chlorpromazine is known to be attributable to the endogenously released catecholamines, the effects of adrenaline and noradrenaline on the plasma glucose and insulin regulation system were also determined. The plasma glucose regulation system in rats was investigated by an i.v. glucose tolerance test. From the data obtained, a pharmacokinetic (PK)-pharmacodynamic (PD) model as well as the plasma glucose regulation model was constructed. The hyperglycemic effects of catecholamines during and after i.v. infusion were reasonably well correlated with the plasma concentrations of catecholamines using the PK-PD model. Since a quantitative relationship between plasma concentrations of catecholamines and the brain concentration of chlorpromazine was established in the previous report, the time course of hyperglycemic effect of chlorpromazine was analyzed. The result indicated that the hyperglycemic effect can be described quantitatively by a simple PK-PD model with plasma glucose regulation system, using brain concentrations of chlorpromazine in rats.

Animals↗
PubMed1987

Chlorpromazine, but not chlorpromazine sulphoxide, stimulates transmitter release from motor nerve terminals.

Treatment of frog neuromuscular preparations with chlorpromazine (5 mumol/l) resulted in a marked rise in miniature endplate potential (MEPP) frequency of greater than 100% within 30 min, and an increase in evoked transmitter release (quantal content 5-15) of about 35%. Treatment with chlorpromazine sulphoxide (5 microM), a derivative of chlorpromazine with a much lower affinity for calmodulin, had very little effect on either form of transmitter release. It is concluded that stimulatory effects of calmodulin-binding drugs at the nerve terminal may well be exerted through calmodulin inhibition. The stimulatory effect of chlorpromazine on MEPP frequency was markedly reduced in preparations bathed in EGTA-containing Ca2+-free saline, but the response was largely restored by raising the temperature by 3-4 degrees C. It is argued that despite this partial dependence on [Ca2+]o, stimulation of transmitter secretion by chlorpromazine is likely to be mediated by inhibition of calmodulin-activated Ca2+-ATPases, and consequent elevation of [Ca2+]i.

Animals↗
PubMed1979

Effects of chlorpromazine hydrochloride on bile salt synthesis, bile formation and biliary lipid secretion in the rhesus monkey: a model for chlorpromazine-induced cholestasis.

We studied the acute effects of intravenous infusions of chlorpromazine hydrochloride on bile salt synthesis, bile formation and biliary lipid secretion in the alert female Rhesus monkey prepared with a total biliary fistula and in a steady bile salt secretory state. In twelve studies (three animals), five doses of radiolabelled chlorpromazine hydrochloride (1-10 mg identical to 2.8-28 mumol/kg) were infused intravenously for 1 h in random order. Cholestasis was induced within minutes in all experiments. The radiolabel appeared rapidly in bile, with similar recoveries in bile and urine and a 90% total cumulative output in 4 days. Both bile flow, bile salt and other biliary lipid outputs were inhibited in a dose related and reversible manner. The apparent bile salt independent bile flow was consistently abolished, and a prompt return to basal values occurred when biliary concentration of the drug and metabolities fell below 1-2 mM. When chlorpromazine hydrochloride was infused at three doses (2.5, 5.0 and 10.0 mg identical to 7-28 mumol/kg) during constant intravenous infusion of 14C sodium taurocholate (300 mumol/h), bile flow, total bile salt output and 14C taurocholate output decreased within minutes. This was accompanied by a progressive rise in the serum 14C taurocholate concentration. After 90 min the taurocholate specific activity in bile increased significantly indicating that bile salt synthesis was inhibited. Secretion of retained bile salts and reversal of inhibition of bile salt synthesis occurred with time: the course of both events was correlated with the dose of the drug. Thus, in monkeys, chlorpromazine hydrochloride induces reversible, dose related cholestasis suppression of the bile salt dependent and independent flow, inhibition of bile salt synthesis and impairment of biliary lipid secretion. We suggest that these effects are due to both bile salt-chlorpromazine interactions and the effect of the latter on canalicular and other membranes.

Animals↗
PubMed1992

A case of phenobarbital exacerbation of a preexisting maladaptive behavior partially suppressed by chlorpromazine and misinterpreted as chlorpromazine efficacy.

An adult female with developmental disability was prescribed chlorpromazine for the target behaviors of aggression and self-injurious behavior (SIB), and she was prescribed phenobarbital for seizures. Upon a chlorpromazine minimal effective dose reduction, target behaviors increased and dosage was returned to prior levels with the conclusion that chlorpromazine was controlling the target behaviors. Upon subsequent reduction and discontinuation of phenobarbital, however, chlorpromazine was able to be reduced with no increase in target behaviors. Ten years of behavioral data are presented to support the hypothesis that phenobarbital was exacerbating maladaptive behaviors. Given tardive dyskinesia (TD), clinicians and interdisciplinary teams should remain alert to the following client profile: (1) prescribed phenobarbital (or primidone), (2) prescribed neuroleptics, especially at high dosages, to control maladaptive behaviors, (3) failure of neuroleptic gradual minimal effective dose attempts, and (4) possible presence of behavioral procedures, especially intrusive procedures, to control maladaptive behaviors. This profile should trigger a "red flag" as to the possibility of phenobarbital behavioral side effects or exacerbation of preexisting maladaptive behaviors.

Adult↗
PubMed1988

A kinetic study of chlorpromazine on the hyperglycemic response in rats. I. Effect of chlorpromazine on plasma catecholamines.

The effect of chlorpromazine (0.5 and 4 mg/kg) on plasma catecholamines (adrenaline and noradrenaline) concentrations was investigated in rats. After an i.v. bolus administration of chlorpromazine, plasma adrenaline and noradrenaline concentrations showed a dose dependent increase. In order to clarify the pharmacokinetics of catecholamines in plasma, i.v. infusion of adrenaline or noradrenaline was also carried out. Plasma catecholamines after i.v. infusion showed typical characteristics of a one compartment model with a zero order production rate of endogenous catecholamines. From the data observed, a mathematical model was constructed to elucidate the relationship between the pharmacokinetics (brain concentrations) and the pharmacologic effect (plasma catecholamines concentrations) of chlorpromazine in rats. The results indicated that the time courses of plasma adrenaline and noradrenaline concentrations after an i.v. administration of chlorpromazine were described reasonably well by a simple pharmacokinetic-pharmacodynamic model.

Animals↗
PubMed1993

[Comparison between electro-acupuncture with chlorpromazine and chlorpromazine alone in 60 schizophrenic patients].

60 schizophrenia patients were treated with electro-acupuncture and chlorpromazine therapy in comparison with chlorpromazine therapy alone, 30 patients for each group, and their curative effects evaluated according to the brief psychiatric rating scale (BPRS). The result showed the total curative effects of the two groups were similar. However, the marked effects appeared earlier in combined therapy than that of using chlorpromazine alone, less chlorpromazine was needed, hence displayed fewer side-effects.

Case-Control Studies↗
PubMed1991

Metabolic activation of chlorpromazine by stimulated human polymorphonuclear leukocytes. Induction of covalent binding of chlorpromazine to nucleic acids and proteins.

Human polymorphonuclear leukocytes (PMNs) have been stimulated with either phorbol 12-myristate 13-acetate (PMA), calcium ionophore A23187 or a combination of both to induce the respiratory burst and myeloperoxidase (MPO) release. Chlorpromazine (CPZ) but not chlorpromazine sulfoxide (CPZSO) inhibited the respiratory burst as measured with lucigenin chemiluminescence. The inhibition was due to interference with processes in the cell leading to the respiratory burst and not to scavenging of produced oxygen radicals that provoke the luminescence. CPZ was metabolized by stimulated PMNs. HPLC analysis revealed formation of CPZSO and an unidentified product. Both products result from decay of chlorpromazine radical cation (CPZ+.), indicating formation of this radical intermediate in CPZSO oxidation by stimulated PMNs. CPZ conversion correlated with H2O2 production and MPO release. The largest CPZ conversion was observed with phorbol ester plus A23187 stimulation. The conversion was reduced by catalase and sodium azide, an inhibitor of MPO, with 70% and 40%, respectively. This indicates only partial involvement of extracellularly released MPO in CPZ metabolism by PMNs. Considerable covalent binding of [3H]CPZ to nucleic acids and proteins of intact stimulated PMNs was observed. This binding was larger upon co-stimulation with phorbol ester and A23187. Azide did not reduce covalent binding. This indicates that covalent binding is not mediated by extracellularly released MPO and that CPZ is probably activated intracellularly. Activation of PMNs and production of H2O2 is a prerequisite for both CPZ conversion and covalent binding. This study demonstrates that phagocytic cells might contribute to drug metabolism and drug-induced toxicity.

Biotransformation↗
PubMed1986

Therapeutic monitoring of chlorpromazine. III: Minimal interconversion between chlorpromazine and metabolites in human blood.

Chlorpromazine (CPZ), chlorpromazine sulfoxide (CPZSO), and chlorpromazine N-oxide (CPZNO) were each incubated (37 degrees C), for various timed intervals up to 60 min, with pooled human whole blood. Plasma and red blood cells were then separated and analyzed by a high performance liquid chromatographic method that avoids the use of alkaline extraction procedures. It was found that CPZ, CPZSO, and CPZNO were remarkably stable in whole blood under physiological conditions. CPZ was converted into CPZSO to a small extent (1%). Reports of 15-50% conversion of CPZ into CPZSO are largely due to artifacts, which result when red blood cell materials come into contact with alkali. CPZNO was recovered (85%) unchanged from the plasma. A small portion (1%) of the CPZNO was reduced to CPZ in the red blood cells. Thus, on the basis of these in vitro data, blood does not appear to be an important tissue for the metabolism of CPZ, CPZSO, or CPZNO.

Biotransformation↗