Phenothiazine Tranquilizers Research Articles

Simultaneous quantitation of eight tricyclic antidepressants in serum by high-performance liquid chromatography.

An analytical procedure has been developed for the simultaneous separation and quantitation of amitriptyline (AMI), imipramine (IMI), doxepin (DOX), trimipramine (TRI), desipramine (DES), nortriptyline (NOR), desmethyldoxepin (DMD), and protriptyline (PRO) in serum using N-propionylprocainamide (NPPA) as an internal standard. Serum samples were extracted using Bond Elute C-18 columns. A 5-mu Supelcosil LC-PCN column separated the analytes, using a mobile phase consisting of 10 mmol/L sodium phosphate (pH 7.0):acetonitrile:methanol (28:58:14) by volume at ambient temperature. Column effluents were monitored at 254 and 280 nm. Typical recoveries ranged from 81.8% to 94.0% at 50 ng/ml and from 92.0% to 102.6% at 200 ng/ml. Within-run variations were less than or equal to 10.1% at 50 ng/ml and less than or equal to 4.5% at 200 ng/ml, whereas day-to-day variations were less than or equal to 7.4% at 50 ng/ml and less than 4.8% at 200 ng/ml for n = 10. Calibration curves showed linearity over the concentration range of 25-1,000 ng/ml. Superior resolution (Rs greater than or equal to 1.0) was obtained with this column, which completely separated the eight tricyclic antidepressants (TCAs) and the internal standard in 16 min. Sensitivity limit is 25 ng/ml for all TCAs studied. Phenothiazine tranquilizers interfere with the quantitation of TCAs.

Tardive dyskinesia in Tourette syndrome

Three patients are reported who developed oral-buccal-lingual movements typical of tardive dyskinesia while being treated with stable doses of haloperidol for Tourette syndrome. In each case signs resolved within a number of weeks after medication was discontinued. One of the patients experienced recurrence of the dyskinesia during a challenge with phenothiazine tranquilizers. In each case the dose of haloperidol was well within the usual therapeutic range. A strong family history of movement disorders, including Tourette syndrome, was present in each family.

Comparative Effects of Selected PhenothiazineTranquilizers and Antihistaminics on BacterialCells and Possible Interactions with Antibiotics

Evaluation of the antibacterial effect of phenothiazine antihistaminics (trimeprazine, promethazine, and fonazine) and phenothiazine tranquilizers (promazine, chlorpromazine, triflupromazine, and propiomazine) on Staphylococcus aureus showed that tranquilizers were more active [minimum inhibitory concentration (MIC) 0.5–1.6 μg/mL] than antihistaminics (MIC > 1.6 μg/mL). The antibacterial activity was found to correlate with both the rate of adsorption of these drugs on the bacterial cells and the surface tension of their solutions. Phenothiazine tranquilizers caused rapid and extensive leakage of potassium ions from bacterial cells, while phenothiazine antihistaminics produced relatively slower leakage of these ions. A study of the effect of the phenothiazines on the antibacterial activity of some antibiotics showed that all phenothiazines produced a synergistic effect with erythromycin and an antagonistic effect with tobramycin. Variable effects were observed with chloramphenicol, and no effect was observed with penicillin. Results were explained on the basis of structural characteristics of the phenothiazines.

Cell cycle related phenothiazine effects on adriamycin transport

In P388 murine leukemic cells, the pheno-thiazine tranquilizer, chlorpromazine, causes a marked increase in intracellular drug retention. Laser excited flow cytometry shows that in log phase cultures this increase in drug retention is not uniform but confined to a sub-population. In cell cycle phase enriched populations of P388 cells obtained by centrifugal elutriation, the phenothiazine enhanced adriamycin retention is seen predominantly in cells in the late S, G 2 M part of the cell cycle.

Interactions of a phenothiazine tranquilizer with phosphatidylcholine and phosphatidylcholine/cholesterol membranes

Interactions of a phenothiazine tranquilizer with phosphatidylcholine and phosphatidylcholine/cholesterol membranes

Uptake of phenothiazine tranquilizers by lauromacrogol micelles in acidic solution.

The uptake of the phenothiazine tranquilizers by lauromacrogol (PLE) micelles was studied in relation to ionic strength, pH and the chemical structure of the phenothiazines. The phenothiazine uptake could be described by a Langmuir type equation. The number of mol of chlorpromazine bound per mol of PLE at saturation, n, increased with increasing ionic strength, but the binding constant, K, changed in the opposite manner. The combined binding constant, nK, showed an almost constant value in the range of ionic strength up to 0.14 and then increased. There was no pH-dependency of the micellar uptake (pH 3.0-6.0) at constant ionic strength (μ=0.14), indicating that only the cationic form of the phenothiazine was involved in the interaction. The value of nK was fairly well correlated with the critical micelle concentration of the phenothiazines. The results obtained suggest that the phenothiazine cations were oriented in PLE micelles so as to form mixed micelles.

Calmodulin-Binding Drugs Affect Responses to Cytokinin, Auxin, and Gibberellic Acid

Trifluoperazine, a phenothiazine tranquilizer, and tetracaine, a local anesthetic, have been found to inhibit a variety of plant hormone responses at concentrations compatible with their known inhibition of Ca(2+)-calmod-ulin-dependent enzyme activities. Among these responses are cytokinin-dependent betacyanin synthesis and increase in fresh weight in Amaranthus tricolor cotyledons, auxin-dependent increase in length of wheat coleoptile segments and gibberellic acid-dependent induction of alpha-amylase synthesis in barley aleurone layers. The reversibility of some of these inhibitory effects has been demonstrated, indicating that, up to a point, a generalized membrane destruction can be ruled out. The evidence, taken in conjunction with numerous examples from the literature showing calcium involvement in the action of all of the plant hormones, support a unifying theory of hormone action.

Susceptibility of Bordetella species to growth inhibition and killing by chlorpromazine.

Chlorpromazine, the prototype phenothiazine tranquilizer, inhibited the growth and killed organisms of the genus Bordetella. There were striking differences, however, among the three Bordetella species. Bordetella pertussis was most susceptible, with some inhibition of growth at greater than or equal to 4 micrograms/ml and killing at 16 micrograms of chlorpromazine per ml. Bordetella parapertussis and Bordetella bronchiseptica were less susceptible, with killing at 32 and 256 micrograms/ml, respectively. Although the phenothiazines were inhibitory for Bordetella extracytoplasmic adenylate cyclase, the lethal effect occurred at a lower concentration and did not appear to involve modification of the enzyme activity. Exposure of B. pertussis to combinations of chlorpromazine and erythromycin resulted in impaired growth at concentrations lower than that of either drug alone, but there was no evidence that the two drugs interacted either synergistically or antagonistically.

ChemInform Abstract: SIDE‐CHAIN EFFECTS ON PHENOTHIAZINE CATION RADICAL REACTIONS

AbstractDie Reaktion von Radikalen der Phenothiazine (I) in wäßriger Lösung und der Einfluß der Radikalstruktur auf die Bildung von hydroxylierten und Sulfoxid‐Metaboliten werden untersucht.

The determination of propiopromazine in animal tissue.

A thin-layer chromatographic method for the determination of the veterinary tranquillizer propiopromazine (Combelen) in slaughter pigs is described. Propiopromazine residue depletion from the kidney occurs with different rates in sows and in castrated boars. In the liver residues increase over at least 24 h after intramuscular administration, in accordance with the distribution pattern of phenothiazine tranquilizers.

Side-chain effects on phenothiazine cation radical reactions.

The cation radical of each of the phenothiazine tranquilizers is a likely intermediate in the metabolism of the drugs to at least two of the three major metabolic classes, the sulfoxides and the hydroxylated derivatives. Previous work has shown that the reactions of the radical are highly dependent on the environment, particularly the presence of nucleophiles. The present report discusses the effect of cation radical structure on the formation of sulfoxide and hydroxylated metabolites in vitro. Cyclic voltammetry, spectrophotometry, and liquid chromatography were used to examine reactions of various phenothiazine radicals in aqueous buffers. A radical with a three-carbon aliphatic side chain (e.g., chlorpromazine) forms solely sulfoxide and parent unless amine nucleophiles are present, in which case hydroxylation occurs. A shorter side chain (e.g., promethazine) causes radical dimerization and pronounced hydroxylation, regardless of external nucleophiles. A piperazine side chain (e.g., fluphenazine) promotes hydroxylation, with some sulfoxide observed. The results indicate that a deprotonated amine is necessary for hydroxylation and that the amine may be present in the original drug rather than an external nucleophile. In addition to information about cation radical reactions, the redox properties of several different phenothiazines are presented.

Plasma membrane Ca2+ transport: antagonism by several potential inhibitors.

Inside-out vesicles prepared from human red blood cells took up Ca2+ by an active transport process. Membranes from the same red blood cells displayed Ca2+-activated, Mg2+-dependent adenosine triphosphatase activity. Both the initial rate of Ca2+ transport and the (Ca2+ + Mg2+)-adenosine triphosphatase activity were increased approximately twofold by the calcium binding protein, calmodulin. Activities in the absence of added calmodulin were termed basal activities. Calmodulin-activated Ca2+ transport and adenosine triphosphatase activities could be antagonized in a relatively selective fashion by the phenothiazine tranquilizer drug, trifluoperazine. High concentrations of trifluoperazine also inhibited basal Ca2+ transport and adenosine triphosphatase activity. By contrast, calmodulin binding protein from beef brain selectively antagonized the effect of calmodulin on Ca2+ transport with no inhibition of basal activity. Ruthenium red antagonized calmodulin-activated and basal activity with equal potency. The results demonstrate that although phenothiazines can act as relatively selective antagonists of calmodulin-induced effects, other effects are possible and cannot be ignored. Calmodulin-binding protein may be a useful tool in the analysis of calmodulin functions. Ruthenium red probably interacts with Ca2+ pump adenosine triphosphatase at a site not related to calmodulin.

ChemInform Abstract: EFFECT OF STRUCTURE ON PHENOTHIAZINE CATION RADICAL REACTIONS IN AQUEOUS BUFFERS

The reactions of the cation radicals of 11 phenothiazine tranquilizers were examined in mildly acidic aqueous buffers. Of the 11, those having an aminopropyl side chain in the 10 position reacted to form 0.5 mol of sulfoxide and 0.5 mol of parent drug per mole of initial radical. Cation radicals with different side chains react to form additional products, which remain to be identified but probably result from hydroxylation of the phenothiazine ring. The decay kinetics of three of the cation radicals undergoing reactions with known stoichiometry, namely, chloropromazine, promazine, and triflupromazine, were studied in detail, and it was concluded that they all react via the same mechanism. The mechanism involves attack of the cation radical by a nucleophile, and radicals with electron-withdrawing groups in the 2 position react more quickly. Since the cation radicals with faster reaction rates with nucleophiles are more pharmacologically active, it is hypothesized that the cation radical-nucleophile interaction may be responsible for binding of phenothiazines to receptor proteins.

Drug analysis by direct liquid introduction micro liquid chromatography mass spectrometry.

The analytical capabilities of a micro high performance liquid chromatograph interfaced to an unchanged quadrupole mass spectrometer are presented. Continuous monitoring of the total micro liquid chromatographic effluent allows full scan chemical ionization mass spectra of from one to five nanograms of drugs and their metabolites to be recorded. The interface is a simple, inexpensive device which can be assembled from commercially available components. An eight microliter per minute flow rate of the micro liquid chromatographic eluant allows separation and identification of biologically important substances not amenable to gas chromatography mass spectrometry techniques. The sensitivity of micro liquid chromatography mass spectrometry performed as described is comparable with gas chromatography mass spectrometry and is achieved by introducing the total micro liquid chromatographic effluent into the chemical ionization ion source of the mass spectrometer. Selected ion monitoring provides 20 pg detection limits of phenothiazine tranquilizers injected on column.

Chlorpromazine and its metabolites alter polymerization and gelation of actin.

Hepatic hydroxylated metabolites of chlorpromazine (10(-5)M to 10(-4)M), a frequently used phenothiazine tranquilizer, produce solid gel formation with filamentous actin, but the less toxic chlorpromazine sulfoxide metabolite does not. At higher concentrations (5 x 10(-4)M) chlorpromazine inhibits actin polymerization. These dose-response relationships parallel the drug's hepatic toxicity in vivo and suggest that interactions between chloropromazine or chlorpromazine metabolites and actin could be an underlying mechanism of cell injury.

Effect of structure on phenothiazine cation radical reactions in aqueous buffers.

The reactions of the cation radicals of 11 phenothiazine tranquilizers were examined in mildly acidic aqueous buffers. Of the 11, those having an aminopropyl side chain in the 10 position reacted to form 0.5 mol of sulfoxide and 0.5 mol of parent drug per mole of initial radical. Cation radicals with different side chains react to form additional products, which remain to be identified but probably result from hydroxylation of the phenothiazine ring. The decay kinetics of three of the cation radicals undergoing reactions with known stoichiometry, namely, chloropromazine, promazine, and triflupromazine, were studied in detail, and it was concluded that they all react via the same mechanism. The mechanism involves attack of the cation radical by a nucleophile, and radicals with electron-withdrawing groups in the 2 position react more quickly. Since the cation radicals with faster reaction rates with nucleophiles are more pharmacologically active, it is hypothesized that the cation radical-nucleophile interaction may be responsible for binding of phenothiazines to receptor proteins.

Photomutagenesis by chlorinated phenothiazine tranquilizers.

Phenothiazine tranquilizers are widely used pharmaceuticals that have been associated with side effects, such as formation of cataracts, that seem related to light exposure. Because patients may use them over extensive time periods, it is important to determine what deleterious cellular effects these drugs may cause and, if possible, to select or design drugs that do not cause such effects. The results reported here demonstrate that chlorinated phenothiazine drugs can be photoactivated to mutagenic species, whereas the nonchlorinated analogues do not possess this characteristic. None of the phenothiazines tested is mutagenic in the dark. Mutagenicity was observed only in strains of Salmonella typhimurium that lacked excision repair of DNA, and the mutagenicity was elevated in strains that contained the plasmid pKM101, which may enhance error-prone repair.

Penetration of trifluoperazine into mixed monolayers of dipalmitoyl lecithin and cholesterol (author's transl)

Penetration of trifluoperazine (TFPeZ), a phenothiazine tranquilizer, into mixed monolayers of dipalmitoyl lecithin (DPL) and cholesterol (CH) was studied by measurement of surface pressure (F)-mean molecular area (A^^-34) curves. The amount of penetration (or adsorption) by TFPeZ was calculated by the modified Gibbs adsorption equation. Adsorption isotherms at a constant A^^-34 showed a type of Langmuir adsorption. Saturated amount of adsorption (Γ∞2) and Langmuir constant (k) were obtained by Langmuir plots. Correlation between those parameters and A^^-34 at various mixing ratios of DPL and CH were discussed. With decreasing A^^-34, Γ∞2 decreased in any DPL-CH mixed monolayer. The relation between Γ∞2 and composition of the monolayer at a constant A^^-34 corresponded well with the state of mixed monolayer, i.e. Γ∞2 is small in expanded monolayer rich in DPL (XDPL>XCH), and increases with decreasing XDPL down to XDPL=0.5. This increase corresponds to changes of the mixed monolayer state, from liquid expanded to solid condensed state. Below XDPL=0.5, in which the mixed monolayer is fully solid, Γ∞2 level is independent of the monolayer composition. Miscibility of penetrated TFPeZ with insoluble components, DPL and CH, was also discussed.

Local anesthetics and phenothiazine tranquilizers induce parthenogenetic activation of the mouse oocyte

Incubation of recently ovulated mouse oocytes in various concentrations of local anesthetics and phenothiazine tranquilizers initiates the completion of meiosis and the formation of pronuclei. The potency with which these drugs induce oocyte activation is comparable to their relative ability to displace Ca 2+ from artificial lipid membranes. Oocyte activation induced by these drugs is inhibited by Ca 2+. Perturbation of the plasma membrane of the oocyte by these drugs may displace Ca 2+, which is responsible for the integrity of the microtubule-microfilament system that normally maintains the ovulated mammalian oocyte blocked at the Metaphase II of meiosis until sperm penetration.

Cytological effects of phenothiazine tranquilizing agents on barley meristems.

A growth reduction of 30--40% was noted in barley plants grown in two phenothiazine tranquilizers. Similar reductions were noted in the number of mid-anaphase cells, indicating the reduced growth could have been the result of a reduced mitotic rate. Also observed were several types of chromosomal aberrations. Electron microscopy revealed less endoplasmic reticulum and cytoplasmic organelles in the treated cells than in untreated cells. Various sized discontinuities in the nuclear membrane was the most frequent abnormality observed in the electron micrographs. The abnormal nuclear membrane was possibly a result of enzyme degradation.