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  • 1
    Electronic Resource
    Electronic Resource
    Neuroleptic blood levels and therapeutic effect (1980)
    Springer
    Psychopharmacology 70 (1980), S. 191-193 
    Details
    ISSN: 1432-2072
    Keywords: Radioreceptor assay for neuroleptics ; Blood neuroleptic activity ; Therapeutic range
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Studies attempting to delineate a therapeutic range of blood levels for neuroleptics have yielded conflicting results. The reasons for this are briefly reviewed and a study is described in which a correlation is sought between blood levels of thioridazine and clinical efficacy. The study employs the radioreceptor assay for neuroleptics to detect both parent drug and active metabolites in blood. The results of the study indicate that while dose is a poor predictor of blood levels of medication, blood levels of neuroleptic activity in patients on thioridazine may be very highly correlated with antipsychotic effect.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00435313
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  • 2
    Electronic Resource
    Electronic Resource
    Atypical antidopaminergic properties of CI-686: A potential antipsychotic agent (1979)
    Springer
    Psychopharmacology 66 (1979), S. 23-27 
    Details
    ISSN: 1432-2072
    Keywords: Stereotyped behavior ; Radioreceptor assay ; Antipsychotic efficacy ; DOPAC/HVA ; Prolactin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of the antipsychotic/antidepressant drug CI-686 on apomorphine- and amphetamine-induced stereotypies, dopamine metabolism, neuroleptic binding, and serum prolactin levels were determined. CI-686 displayed profiles of activity in each of these systems that differs markedly from those of other antipsychotics. CI-686's unique preclinical profile suggests a mechanism of action other than dopamine antagonism which could have implications regarding current thinking on the pathophysiology of schizophrenia.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00431984
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    Paper (German National Licenses)
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  • 3
    Electronic Resource
    Electronic Resource
    In vitro effects of psychotropic agents on the microviscosity of platelet membranes (1984)
    Springer
    Psychopharmacology 84 (1984), S. 289-292 
    Details
    ISSN: 1432-2072
    Keywords: Platelet membranes ; Membrane fluidity ; Microviscosity ; DPH ; Fluorescence polarization ; Phenothiazines
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Normal platelet membranes were exposed in vitro to a variety of psychotropic agents, including chlorpromazine, fluphenazine, haloperidol, imipramine, and lithium. Changes in microviscosity of the hydrocarbon layer of the drug-exposed membranes were determined by steadystate fluorescence polarization measurements, employing the fluorescent probe 1,6-diphenyl 1,3,5-hexatriene (DPH). Concentrations of the phenothiazines chlorpromazine and fluphenazine above 200 nM produced significant increases in microviscosity, while haloperidol produced a small but consistent decrease in microviscosity in the concentration range of 200 nM to 200 μM. Imipramine and lithium were without effect. The phenothiazine-induced increase in microviscosity was apparently dependent upon the structure of the phenothiazine nucleus; side chain structure was less important to this effect.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00427463
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  • 4
    Electronic Resource
    Electronic Resource
    Effects of psychotropic agents on the physical properties of platelet membranes in vitro (1985)
    Springer
    Psychopharmacology 86 (1985), S. 369-373 
    Details
    ISSN: 1432-2072
    Keywords: Platelet membranes ; Membrane order ; Fluidity ; DPH fluorescence polarization ; Phenothiazines
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Normal platelet membranes were exposed in vitro to a variety of psychotropic medications commonly used in the treatment of patients with psychiatric disorders. Changes in structural order at the hydrocarbon region of the drug-exposed membranes were determined by steadystate fluorescence polarization measurements employing the fluorescent probe 1,6-diphenyl-1,3,5-hexatriene (DPH). Chlorpromazine, an aliphatic phenothiazine, produced a significant increase in DPH fluorescence polarization at concentrations from 2–200 μM. Thioridazine, a piperidine phenothiazine, and three piperazine derivatives, perphenazine, trifluoperazine, and fluphenazine, produced significant increases in this parameter at concentrations from 20–200 μM. The other agents tested, including thiothixene, lithium, antidepressants, anxiolytics, and anticonvulsants, were without effect in the concentration ranges examined. The phenothiazine-induced increase in DPH fluoresence polarization apparently depended on the structure of the phenothiazine nucleus; changes in side-chain structure appeared to modulate this effect, most likely by altering the inherent membrane solubility of the agents.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00432231
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  • 5
    Electronic Resource
    Electronic Resource
    A fixed dose study of the plasma concentration and clinical effects of thioridazine and its major metabolites (1989)
    Springer
    Psychopharmacology 97 (1989), S. 481-488 
    Details
    ISSN: 1432-2072
    Keywords: Thioridazine ; Metabolites ; Plasma concentration versus clinical effects ; HPLC ; Radioreceptor assay
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Fifty-three patients in an acute episode or exacerbation of psychosis were given thioridazine 200 or 400 mg daily for 2 weeks. Thioridazine and its active metabolites, mesoridazine and sulforidazine, were estimated in plasma by high performance liquid chromatography (HPLC) and radioreceptor assay (RRA). One week after institution of treatment, plasma concentrations of drug were stable in the morning 12 h after dosing. Drug levels varied widely between patients, but in all patients the relative level of thioridazine to mesoridazine was about one half and thioridazine to sulforidazine was about two fold. Estimates of neuroleptic activity by RRA and the weighted sum of thioridazine, mesoridazine and sulforidazine by HPLC were very similar. Plasma concentration of parent compound, metabolites, or the sum of active substances as estimated by HPLC or RRA, showed only modest correlations (r s=0.10–0.22, all NS) to the degree of improvement as measured by change on the Brief Psychiatric Rating Scale. Significant correlations were observed between plasma concentrations of drug and side effects, including dry mouth, blurred vision, or total rating on the Somatic Symptoms Scale. Even patients receiving the lowest dose and achieving the lowest plasma concentrations of drug showed considerable improvement. There was suggestive evidence that the patients achieving the highest plasma levels of drug did not have the best clinical outcome. These and similar observations from other studies suggest that currently used doses of neuroleptics may be excessive. Optimal drug effects as well as stronger relationships between dose, drug concentration, and clinical therapeutic effects might best be sought at doses below those in common use.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00439552
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  • 6
    Electronic Resource
    Electronic Resource
    In vivo effects of psychotropic agents on the physical properties of cell membranes in the rat brain (1985)
    Springer
    Psychopharmacology 86 (1985), S. 365-368 
    Details
    ISSN: 1432-2072
    Keywords: Phenothiazines ; Membrane structural order ; Membrane function ; DPH fluorescence polarization
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Marked changes in biophysical properties, including structural order, have been observed in the hydrophobic core of cell membranes exposed to phenothiazines in vitro. In this study, similar changes are reported in vivo in cell membranes from the brains of rats treated with phenothiazines at doses thought to yield tissue concentrations approximating those attained in the clinical treatment of psychiatric patients. The membrane structural order parameter was estimated ex vivo by steady-state fluorescence polarization determinations using 1,6-diphenyl 1,3,5-hexatriene (DPH), a fluorescent probe that localizes preferentially to the hydrocarbon region of cell membranes. In these preliminary studies, rats received chlorpromazine (20 mg/kg), fluphenazine (1 mg/kg), haloperidol (1 mg/kg), and imipramine (1 mg/kg) in single or multiple dose protocols. As in earlier in vitro studies, exposure to the phenothiazine antipsychotics led to an observed increase in DPH fluorescence polarization ex vivo and a presumed increase in structural order. As predicted from the in vitro experiments, the effect of chlorpromazine was greater than that of fluphenazine, probably because chlorpromazine was given at higher doses. The magnitude of the effects seen was great enough to imply that physiologically significant changes in cell membrane characteristics may be produced in patients receiving phenothiazines.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00432230
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  • 7
    Electronic Resource
    Electronic Resource
    A cell membrane correlate of tardive dyskinesia in patients treated with phenothiazines (1986)
    Springer
    Psychopharmacology 88 (1986), S. 230-236 
    Details
    ISSN: 1432-2072
    Keywords: Tardive dyskinesia ; Fluorescence polarization ; Phenothiazines ; Platelet membranes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Phenothiazine administration to psychiatric patients is associated with an increase in the “structural order” of platelet membranes as determined by steady-state fluorescence polarization measurements with 1,6-diphenyl-1,3,5-hexatriene (DPH), a fluorescent probe that localizes preferentially in the hydrocarbon region of cell membranes (Zubenko and Cohen 1984, 1985a, b). In this study, platelet membranes prepared from a group of psychiatric patients who developed tardive dyskinesia following chronic treatment with phenothiazines exhibited a significant elevation in DPH fluorescence polarization when compared to similar preparations from an otherwise matched group of patients who had no symptoms or history of tardive dyskinesia. The distribution of polarization values obtained for the tardive dyskinesia group displayed minimal overlap with that of an unmedicated, psychiatrically-healthy control group matched for age and gender. The fluorescence polarization of DPH-labelled platelet membranes was not significantly correlated with phenothiazine daily dose or serum cholesterol concentration in the phenothiazine-treated patient groups, or with dyskinesia severity (AIMS rating) in the tardive dyskinesia group. Patient gender and the presence of an affective disorder did not significantly correlate with DPH fluorescence polarization. The potential physiological and clinical significance of these findings is discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00652246
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  • 8
    Electronic Resource
    Electronic Resource
    Differences between antipsychotic drugs in persistence of brain levels and behavioral effects (1992)
    Springer
    Psychopharmacology 108 (1992), S. 338-344 
    Details
    ISSN: 1432-2072
    Keywords: Haloperidol ; Brain levels ; Bromperidol ; Chlorpromazine ; Fluphenazine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract 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 (t1/2) 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 (t1/2=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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02245121
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  • 9
    Electronic Resource
    Electronic Resource
    Cocaine decreases relative cerebral blood volume in humans: a dynamic susceptibility contrast magnetic resonance imaging study (1998)
    Springer
    Psychopharmacology 138 (1998), S. 76-81 
    Details
    ISSN: 1432-2072
    Keywords: Key words Functional MRI ; Cocaine ; Cerebrovascular circulation ; Dynamic susceptibility contrast MRI
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Cocaine has substantial effects on cerebral hemodynamics which may partly underlie both its euphorigenic and toxic effects. Dynamic susceptibility contrast magnetic resonance imaging (DSC–MRI) was used to determine whether a dose-effect relationship could be detected between cocaine administration and cerebral blood volume reduction in human brain. Twenty-three healthy and neurologically normal adult males with a history of recreational cocaine use (3–40 lifetime exposures) participated. Subjects underwent DSC-MRI measurements of relative cerebral blood volume (rCBV) at baseline and 10min after IV double-blind placebo or cocaine (0.2 or 0.4 mg/kg) administration. Placebo administration resulted in superimposable rCBV curves with post-placebo CBV averaging 104 ± 4% (mean ± SE) of baseline, indicating no CBV change. Both cocaine doses induced CBV decreases which were statistically equivalent and post-cocaine CBV averaged 77 ± 4% of baseline (P 〈 0.002), when measured 10 min following drug administration. These data suggest that DSC-MRI can detect cocaine-induced CBV reductions indicative of vasoconstriction, and that it may be useful for evaluating treatments designed to reduce the cerebrovascular effects of cocaine.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s002130050647
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