Acepromazine and Chlorpromazine as Pharmaceutical-grade Alternatives to Chlorprothixene for Pupillary Light Reflex Imaging in Mice.

Studies of visual responses in isoflurane-anesthetized mice often use the sedative chlorprothixene to decrease the amount of isoflurane used because excessive isoflurane could adversely affect light-evoked responses. However, data are not available to justify the use of this nonpharmaceutical-grade chemical. The current study tested whether pharmaceutical-grade sedatives would be appropriate alternatives for imaging pupillary light reflexes. Male 15-wk-old mice were injected intraperitoneally with 1 mg/kg chlorprothixene, 5 mg/kg acepromazine, 10 mg/kg chlorpromazine, or saline. After anesthetic induction, anesthesia maintenance used 0.5% and 1% isoflurane for sedative- and saline-injected mice, respectively. A photostimulus (16.0 log photons cm-2 s-1; 470 nm) was presented to the right eye for 20 min, during which the left eye was imaged for consensual pupillary constriction and involuntary pupil drift. Time to immobilization, loss of righting reflex, physiologic parameters, gain of righting reflex, and degree of recovery were assessed also. The sedative groups were statistically indistinguishable for all measures. By contrast, pupillary drift occurred far more often in saline-treated mice than in the sedative groups. Furthermore, saline-treated mice took longer to reach maximal pupil constriction than all sedative groups and had lower heart rates compared with chlorpromazine- and chlorprothixene-sedated mice. Full recovery (as defined by purposeful movement, response to tactile stimuli, and full alertness) was not regularly achieved in any sedative group. In conclusion, at the doses tested, acepromazine and chlorpromazine are suitable pharmaceutical-grade alternatives to chlorprothixene for pupil imaging and conceivably other in vivo photoresponse measurements; however, given the lack of full recovery, lower dosages should be investigated further for use in survival procedures.

Identification of chlorprothixene as a potential drug that induces apoptosis and autophagic cell death in acute myeloid leukemia cells.

Although acute myeloid leukemia (AML) is a highly heterogeneous malignance, the common molecular mechanisms shared by different AML subtypes play critical roles in AML development. It is possible to identify new drugs that are effective for various AML subtypes based on the common molecular mechanisms. Therefore, we developed a hypothesis-driven bioinformatic drug screening framework by integrating multiple omics data. In this study, we identified that chlorprothixene, a dopamine receptor antagonist, could effectively inhibit growth of AML cells from different subtypes. RNA-seq analysis suggested that chlorprothixene perturbed a series of crucial biological processes such as cell cycle, apoptosis, and autophagy in AML cells. Further investigations indicated that chlorprothixene could induce both apoptosis and autophagy in AML cells, and apoptosis and autophagy could act as partners to induce cell death cooperatively. Remarkably, chlorprothixene was found to inhibit tumor growth and induce in situ leukemic cell apoptosis in the murine xenograft model. Furthermore, chlorprothixene treatment could reduce the level of oncofusion proteins PML-RARα and AML1-ETO, thus elevate the expression of apoptosis-related genes, and lead to AML cell death. Our results provided new insights for drug repositioning of AML therapy and confirmed that chlorprothixene might be a potential candidate for treatment of different subtypes of AML by reducing expression of oncofusion proteins. DATABASE: RNA-seq data are available in GEO database under the accession number GSE124316.

Sertraline, chlorprothixene, and chlorpromazine characteristically interact with the REST-binding site of the corepressor mSin3, showing medulloblastoma cell growth inhibitory activities.

Dysregulation of repressor-element 1 silencing transcription factor REST/NRSF is related to several neuropathies, including medulloblastoma, glioblastoma, Huntington's disease, and neuropathic pain. Inhibitors of the interaction between the N-terminal repressor domain of REST/NRSF and the PAH1 domain of its corepressor mSin3 may ameliorate such neuropathies. In-silico screening based on the complex structure of REST/NRSF and mSin3 PAH1 yielded 52 active compounds, including approved neuropathic drugs. We investigated their binding affinity to PAH1 by NMR, and their inhibitory activity toward medulloblastoma cell growth. Interestingly, three antidepressant and antipsychotic medicines, sertraline, chlorprothixene, and chlorpromazine, were found to strongly bind to PAH1. Multivariate analysis based on NMR chemical shift changes in PAH1 residues induced by ligand binding was used to identify compound characteristics associated with cell growth inhibition. Active compounds showed a new chemo-type for inhibitors of the REST/NRSF-mSin3 interaction, raising the possibility of new therapies for neuropathies caused by dysregulation of REST/NRSF.

Thioxanthenes, chlorprothixene and flupentixol inhibit proton currents in BV2 microglial cells.

The thioxanthene antipsychotic drugs chlorprothixene and flupentixol have anti-inflammatory and antioxidant properties. The reactive oxygen species produced by NADPH oxidase during microglia-mediated inflammatory responses cause neuronal damage, thereby contributing to various neurodegenerative diseases. Voltage-gated proton channels sustain the NADPH oxidase activity, and inhibition of the channels' activity reduces the production of reactive oxygen species. Herein, the effects of chlorprothixene and flupentixol on proton currents were investigated in BV2 microglial cells using the whole-cell patch-clamp method. Both drugs inhibited the proton currents in a concentration-dependent manner (IC50=1.7µM and 6.6µM, respectively). Chlorprothixene at 3µM slightly shifted the activation voltage toward depolarization. Both the activation and the deactivation kinetics of the proton currents were slowed by chlorprothixene 1.2- and 3.5-fold, respectively. Thus, the inhibition of proton currents may be partly responsible for the antioxidant effects of thioxanthene antipsychotic drugs.

Shape-based reprofiling of FDA-approved drugs for the H1 histamine receptor.

Reprofiling of existing drugs to treat conditions not originally targeted is an attractive means of addressing the problem of a decreasing stream of approved drugs. To determine if 3D shape similarity can be used to rationalize an otherwise serendipitous process, we employed 3D shape-based virtual screening to reprofile existing FDA-approved drugs. The study was conducted in two phases. First, multiple histamine H(1) receptor antagonists were identified to be used as query molecules, and these were compared to a database of approved drugs. Second, the hits were ranked according to 3D similarity and the top drugs evaluated in a cell-based assay. The virtual screening methodology proved highly successful, as 13 of 23 top drugs tested selectively inhibited histamine-induced calcium release with the best being chlorprothixene (IC(50) 1 nM). Finally, we confirmed that the drugs identified using the cell-based assay were all acting at the receptor level by conducting a radioligand-binding assay using rat membrane.

Non-antibiotics reverse resistance of bacteria to antibiotics.

BACKGROUND: Most clinical isolates that exhibit a multi-drug resistant phenotype owe that resistance to over-expressed efflux pumps. Compounds that are efflux pump inhibitors (EPIs) reduce or reverse resistance to antibiotics to which the bacterial strain is initially resistant. We have evaluated non-antibiotics to reduce resistance of commonly encountered bacterial pathogens to antibiotics. MATERIALS AND METHODS: The effect of non-antibiotics on the susceptibility of bacteria to antibiotics was conducted by minimum inhibition concentration determinations of the antibiotic in the absence and presence of the non-antibiotic. RESULTS: Non-antibiotics such as chlorpromazine, amitryptiline and trans-chlorprothixene are shown to reduce or reverse resistance of a variety of bacteria to antibiotics. CONCLUSION: The results suggest that non-antibiotics may serve as adjuncts to conventional antibiotics for the therapy of problematic antibiotic infections caused by bacteria that owe their resistance to over-expressed efflux pumps.

Chemiluminescent analysis of the antioxidant and immunomodulation effects of several psychotropic drugs on peritoneal macrophages.

The present study describes the application of several chemiluminescent (CL) methods for evaluation of antioxidant and immunomodulation effects of psychotropic drugs upon phagocytes: KO2-induced luminal-dependent CL for detection of superoxide anion radicals in a pure chemical system; PMA- and A23187-induced CL of peritoneal macrophages for detection of free radicals in cell suspension; and CL, produced by the luciferase-catalyzed luciferin + ATP reaction, for evaluation of cell viability before and after drug application. These methods provide also a way to investigate the location of drug action. It was found that the psychotropic drugs in fluence the 'oxidative burst' of macrophages through two mechanisms: by expression of drug antioxidant properties and/or by a direct immunomodulation effect.

Pharmacokinetic-pharmacodynamic modeling of tolerance to the prolactin-secreting effect of chlorprothixene after different modes of drug administration.

The objective of this study was the construction of a pharmacokinetic-pharmacodynamic model to describe the effects of chlorprothixene on prolactin secretion and the time-dependent alterations in the concentration-effect relationship due to tolerance development. Prolactin and chlorprothixene serum concentrations were determined in eight healthy men for up to 72 h after the intravenous and oral administration of chlorprothixene. An integrated pharmacokinetic model and a physiological indirect pharmacodynamic/tolerance model were applied to describe the prolactin-secreting effect of chlorprothixene. A three-compartment model served as pharmacokinetic model. The pharmacodynamic and tolerance model accounted for the baseline effect, the effect induced by the drug, and the regulatory mechanism that opposes the effect of the drug. This model adequately characterized the prolactin response after intravenous and oral drug administration of each individual by the sensitivity (dissociation constant), the efficacy (maximal prolactin secretion rate), the extent, and the rate of tolerance development. We speculate that this approach improves the quality of neuroendocrine challenge tests to determine the subject's sensitivity to drugs and the time course of adaptation.

Effect of some psychotropic drugs on the activated macrophage-induced luminol-dependent chemiluminescence.

The effect of some psychotropic drugs on the activity of macrophages to produce superoxide radicals during phagocytosis was tested. Three-cyclic antidepressants, imipramine and amitriptyline, and the thioxanthene neuroleptic, chlorprothixene, were studied. The superoxide production was measured by luminol-dependent chemiluminescence. The drugs were investigated in the concentration range of 10(-7)-10(-4) mol/l. It was seen that all tested drugs caused a concentration-dependent decrease of the luminol-dependent chemiluminescence. The inhibitory effect of imipramine and amitriptyline on the macrophage superoxide production was moderate, while the effect of chlorprothixene was significantly stronger (a decrease more than 100 times that of macrophage chemiluminescence). Essentially, the luminol-dependent chemiluminescence reflects the level of superoxide radicals in the system. Therefore, the effect of drugs may be due to the possible activity for scavenging superoxide. In additional experiments with different systems of generations of O2- and different methods of registration, this possibility was discarded. Therefore, the effect of the drugs on the luminol-dependent chemiluminescence seems to be due to drug-induced decrease of the ability of activated macrophages to produce superoxide radicals.

Role of calcium channels in effects of antidepressant drugs on responsiveness to pain.

The effect of acute and chronic treatment with three antidepressant drugs on the cortical L-type calcium channel (measured as [3H]nitrendipine binding sites) and on the responsiveness to pain (assessed in the hot-plate test) was tested on the Wistar rat. Acute administration of antidepressants did not affect the characteristics of calcium channels and did not significantly prolong the hot-plate latency. However, a combination of antidepressants with nifedipine brought about analgesia. Chronic administration of imipramine did not significantly affect the characteristics of calcium channels but produced a moderate analgesic effect. In contrast, chronic administration of citalopram and chlorprothixene increased the density of [3H]nitrendipine binding sites and induced hyperalgesia, which was nullified by acute administration of nifedipine. The results confirm that calcium channels may be involved in analgesia and hyperalgesia and indicate that chronic treatment with some antidepressant may induce an increase in the density of cortical calcium channels.

[The effect of various non-ulcer pharmaceuticals on nocturnal gastric pH in healthy subjects]. / Die Wirkung verschiedener Nichtulkuspharmaka auf den nächtlichen Magen-pH gesunder Probanden.

The effects of 4 non-ulcer drugs and the M1-antagonist pirenzepine on the nocturnal intragastric pH were investigated in 12 healthy volunteers. We tested single doses of pirenzepine (100 mg), Chlorprothixene (30 mg), clonidine (75 micrograms), ketotifen (3 mg) and nifedipine (30 mg) in an randomized, single-blind, cross-over study. The nocturnal intraluminal pH is significantly elevated not only by pirenzepine but also by the other substances. As expected pirenzepine (mean nocturnal pH = 2.49 +/- 0.22) shows the most distinct effect, nifedipine (mean nocturnal pH = 1.72 +/- 0.20) the most sparsely effect. The other drugs are nearly half as effective as pirenzepine. The acid suppressive side effect of the non-ulcer remedies is considered to be important for the treatment of ulcer patients with concomitant diseases.

Effect of some drugs, experimental stress and estrus on unstable and fixed conditioned alimentary motor reflexes in cats. Meclophenoxate, chlorprothixen, caffeine, piracetam. Part VI.

A group of 10 cats, both sexes, were studied for the effect of peroral administration of the meclophenoxate (Cetrexin, Léciva, 1.5 mg kg-1) + chlorprothixen (Chlorprothixen, Spofa, 0.045 mg kg-1) + caffeine (Coffeinum natrium benzoicum, Spofa, 0.15 mg kg-1) combination upon the fixation of conditioned alimentary motor reflexes to a sound signal in the course of a 10-week experiment. The mentioned combination of drugs demonstrated a beneficial protective influence on the fixed alimentary motor reflexes against laboratory stress. The results were compared with the earlier fixation of the same reflexes in another group of 11 cats under piracetam (Nootropil, U.C.B. 20 mg kg-1, s.c.). In both groups of animals, the development of reflexes was performed in regular alterations of experiments under the effect of the drugs and control experiments. The drugs were administered 1 hour before the experiments. Both groups of animals showed significantly fewer intersignal and other incorrect motor reactions on the days they were given the drugs than the controls did. The number of fixed correct reactions and their latencies displayed only moderate insignificant differences between the pharmacological trials and the controls. The conclusions is that the actual development of conditioned alimentary motor reflexes was not found to be influenced by the action of the mentioned drugs modifying psychological functions and mental states.

Chlorprothixene-induced hypouricemia: a biologic indicator of drug compliance.

Chlorprothixene is a neuroleptic as well as a potent uricosuric drug that consistently lowers the levels of plasma uric acid (PUA). The usefulness of this relative hypouricemia as an indicator of compliance with treatment was evaluated in 17 outpatients treated from 120 to 600 days. Plasma uric acid values were substantially reduced in all patients with all doses within the therapeutic range. Low levels of PUA remained stable as long as the patients were treated and returned to normal within 7 days after treatment was terminated. The authors discuss the advantages and the limitations of PUA as an indicator of chlorprothixene treatment compliance.

[Effect of drugs possessing antialcoholic activity on ethanol pharmacokinetics]. / Vozdeistviia preparatov s protivoalkogol'noi aktivnost'iu na farmakokinetiku étanola.

Furazolidone, lithium carbonate, chlorprotixen and pyrroxan exert different effects on ethanol pharmacokinetics. Furazolidone decreases clearance of ethanol, increases its half-life with a simultaneous reduction of blood acetaldehyde concentration. Pyrroxan increases clearance and maximal concentration of ethanol. Chloprotixen effect is characterized by a concurrent increase of ethanol and acetaldehyde concentrations in the first hours after ethanol administration. Lithium carbonate produces no significant changes in ethanol pharmacokinetic parameters.

Anticholinergic effects of cis-chlorprothixene characterized in rat parotid acini.

The anticholinergic effects of the antipsychotic drug, cis-chlorprothixene, on the secretory events underlying the formation of primary saliva were investigated. The neuroleptic, cis-chlorprothixene, is used extensively as a major tranquillizer but shares side-effects such as xerostomia with most antidepressants. The inhibitory effects of cis-chlorprothixene upon the cholinergic-induced rise in Ca2+ as well as on O2 consumption and Cl- loss were investigated in isolated rat parotid acini in order to characterize its anticholinergic effects quantitatively. The cholinergic-induced rise in cytosolic, free Ca2+ was inhibited by cis-chlorprothixene with half-maximal effect at 1.9 microM and maximal inhibition at 10 microM. When the cytosolic, free Ca2+ was enhanced in the presence of 10 microM cis-chlorprothixene by means of the Ca2+ ionophore A23187, a loss of Cl- was observed similar to that observed during cholinergic stimulation in the absence of cis-chlorprothixene. The findings are consistent with the possibility that cis-chlorprothixene exerts its effects on the steps leading from agonist binding to the acetylcholine receptor and to the increase of cytosolic free Ca2+. Thus, measurement of the stimulation-induced rise in cytosolic, free Ca2+ in the presence of neuroleptics such as the thioxanthenes represents a fast and reliable method for detecting inhibitory effects on autonomic receptor activation.

Penfluridol, chlorprothixene and haloperidol block fast axonal transport in an order of potency consistent with a mechanism related to inhibition of calmodulin.

The effects of the inhibitors of calmodulin penfluridol, chlorprothixene and haloperidol on fast axonal transport, the content of adenosine triphosphate and creatine phosphate and the density of axonal microtubules, were measured in spinal nerves of the bullfrog in vitro. These drugs inhibited the fast orthograde transport of [3H]leucine-labelled proteins: 35 microM penfluridol, 70 microM cis-chlorprothixene, and 200 microM haloperidol were needed to produce and approximately 50% inhibition of transport, and the order of potency was, therefore, penfluridol greater than cis-chlorprothixene greater than haloperidol; the trans isomer of chlorprothixene was as effective as the cis isomer-of chlorprothixene in inhibiting fast axonal transport. None of these drugs significantly reduced the density of microtubules in unmyelinated axons of nerves, incubated as for a transport experiment. Exposure to the concentration of these drugs which inhibited transport did not reduce significantly the content of adenosine triphosphate of the nerves, except for a 22% reduction by trans-chlorprothixene, and they had no significant effect on the content of creatine phosphate except for a 27% reduction by penfluridol and a 20% reduction by trans-chlorprothixene. The inhibition of axonal transport by these drugs can therefore not be explained either by an interference with oxidative metabolism or by disruption of microtubules. The order of potency of penfluridol, chlorprothixene and haloperidol as inhibitors of fast axonal transport parallels their known order of potency as antagonists of calmodulin; inhibition of axonal transport may therefore be related to inhibition of the function of calmodulin by these drugs.

Topographic brain mapping of EEG in neuropsychopharmacology--Part II. Clinical applications (pharmaco EEG imaging).

Multi-lead analysis of drug-induced changes in human brain function as monitored by the scalp-recorded electroencephalogram (EEG) and subsequent imaging of topographic pharmaco-EEG maps has become possible and practical with the advent of modern mini- and micro-computers. The present paper gives a survey about topographic analyses of pharmaco-EEG data obtained in systematic double-blind, placebo-controlled studies in normal healthy volunteers involving representative drugs of 5 different psychopharmacological classes, such as neuroleptics (chlorprothixene), antidepressants (imipramine), tranquilizers (diazepam), psychostimulants (caffeine), and antihypoxidotics/nootropics (pyritinol). The determination of cerebral bioavailability utilizing time- and dose-efficacy relations, as well as the evaluation of bioequipotency of different formulations of compounds is shown. Topographic pharmaco-EEG seems not only to confirm our previous knowledge that quantitative analysis of the human EEG in combination with certain statistical procedures ("quantitative pharmaco-EEG") is a valuable method to determine if, how, when and at which dosage a drug will be centrally effective, but also to have the potential to show effects of psychotropic drugs on the target organ--the human brain--which could not be previously picked up by single lead recordings. Topographic pharmaco-EEG imaging can be viewed as an enlargement of our armamentarium to better understand the mode of action of psychotropic drugs in human neuropsychopharmacology, as well as to monitor and (eventually) predict therapeutic efficacy in patients.

The influence of chronic treatment with antidepressant neuroleptics on the central serotonin system.

Chronic administration of antidepressant neuroleptics chlorprothixene (CPX) and levomepromazine (LMZ) increases the sensitivity of one kind of serotonergic receptors in CNS-5-HT2 receptors (which are involved in such behavioral responses as head-twitches and hyperthermia in heat adapted rats), but do not change 5-HT1 receptor population (responsible for the rate of serotonin synthesis). These results confirm once more the hypothesis about the existence of at least two types of serotonin receptors in the CNS. They also indicate that antidepressant neuroleptics, which are potent serotonin 5-HT2 and alpha 1-adrenergic blocking agents, after chronic administration affect the serotonin system in a manner similar to that produced by chronic treatment with classical antidepressant drugs.

SCH 23390 dissociated from conventional neuroleptics in apomorphine climbing and primate acute dyskinesia models.

SCH 23390 induced only a negligible incidence of the acute dyskinetic syndrome, a predictor of neuroleptic-induced extrapyramidal liability, in squirrel monkeys. However, haloperidol-induced dyskinesias were potentiated by SCH 23390 and were blocked by the D-1 agonist, SKF 38393. When administered orally or intraperitoneally to mice, SCH 23390 showed a considerably wider dose separation than did conventional neuroleptics between antagonism of apomorphine climbing and antagonism of stereotyped sniffing. Clinically relevant distinctions may exist between D-1 and D-2 antagonists, with D-1 antagonists (exemplified by SCH 23390) showing lower, although possibly not negligible, potential to cause extrapyramidal side effects.