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At least 505 records · Page 28Linked to original sources
PubMed2006

Determination of phenothiazines in pharmaceutical formulations and human urine using capillary electrophoresis with chemiluminescence detection.

A CE instrument coupled with chemiluminescence (CL) detection was designed for the determination of promethazine hydrochloride (PTH) and promazine hydrochloride (PMH) in real samples. An important enhancement of the CL emission of luminol with potassium ferricyanide was observed in the presence of these phenothiazines; so this system was selected for their detection after CE separation. Parameters affecting the electrophoretic separation were optimized in a univariate way, while those affecting CL detection were optimized by means of a multivariate approach based on the use of experimental designs. Chemometrics was also employed for the study of the robustness of the factors influencing the postcolumn CL detection. The method allows the separation of the phenothiazines in less than 4 min, achieving LODs of 80 ng/mL for PMH and 334 ng/mL for PTH, using sample injection by gravity. Electrokinetic injection was used to obtain lower LODs for the determination of the compounds in biological samples. The applicability of the CE-CL method was illustrated in the determination of PTH in pharmaceutical formulations and in the analysis of PMH in human urine, using a previous SPE procedure, achieving an LOD of 1 ng/mL and recoveries higher than 85%.

Antipsychotic Agents↗
PubMed1977

Characterization of a depolarizing dopamine response in a vertebrate neuronal somatic cell hybrid.

The physiology and pharmacology of a depolarizing dopamine response was studied in the vertebrate neuronal somatic cell hybrid TCX11. The average resting membrane potential was -50 mV (S.D.=+/-7) with a membrane resistance of 40.5 mOhms (S.D.=+/-8) as determined from intracellular recordings. Depolarizing current pulses did not elicit an action potential. Cells displayed a linear current-voltage relationship when artificially depolarized up to +30 mV. Iontophoretically applied dopamine elicited a depolarizing response with a conductance increase and a reversal potential of -15 mV (S.D.=+/-4.7). Experiments altering medium ion concentrations demonstrated the conductance increase was to sodium and most likely potassium. The dopamine agonist ET495 (Piribedil) and the analogue epinine mimicked dopamine, while closely related biogenic amines, with the exception of noradrenaline, elicited no response. Apomorphine also elicited a depolarizing response but was much less efficacious than Piribedil. Noradrenaline was less potent than dopamine and appeared to act at the dopamine receptor. Methylation (3-methoxytyramine) or absence of the 3-hydroxy group (tyramine) of dopamine resulted in total loss of activity. The dopamine antagonists chlorpromazine, trifluoperazine, promazine, and bulbocapnine reversibly blocked the response to dopamine at medium concentrations less than 5 micronM. The adrenergic antagonist phentolamine blocked the response while phenoxybenzamine only reduced the response at higher concentrations. The acetylcholine antagonists alpha-bungarotoxin, hexamethonium, and scopolamine did not block the dopamine response. Both d-tubocurarine and atropine acted as antagonists. Collectively, these results demonstrate the presence of a receptor on a cultured cell line that is specific for dopamine, mediates a depolarizing and conductance increase response to dopamine, and displays the pharmacology most closely associated with dopamine receptors.

Acetylcholine↗
PubMed1992

Influence of hypothalamic-pituitary-adrenocortical hormones on reproductive hormones in gray wolves (Canis lupus).

The release of hypothalamic-pituitary-adrenocortical hormones was studied in intact and neutered gray wolves (Canis lupus) to determine how these hormones interact and affect reproductive hormones. Experiments were performed on adult wolves anesthetized with 400 mg ketamine and 50 mg promazine. Intravenous (i.v.) injections with 50 micrograms ovine corticotropin releasing factor (oCRF) significantly increased adrenocorticotropin (ACTH; P < or = 0.01), cortisol (CORT; P < or = 0.004), and progesterone (P < or = 0.036), but not beta-endorphin (P > or = 0.52). Since neutered wolves demonstrated dose-dependent elevations in response to ACTH, it was concluded that the progesterone was secreted from the adrenal gland. Basal luteinizing hormone (LH) concentrations in neutered wolves were similar before and 60 min after i.v. injection of 1, 5, or 25 IU ACTH (P > or = 0.36) or 2.2 mg/kg cortisol (P = 0.42). Neither 25 IU ACTH (P = 0.55) nor 0.22 mg/kg dexamethasone (P = 0.49) altered the LH response to injection of LH releasing hormone in neutered wolves. Chronic administration of 0.22 mg/kg/day dexamethasone for 3 d did not alter baseline LH concentrations (P = 0.75). Injection of 1.0 mg/kg naloxone (NAL), however, increased LH concentrations relative to baseline values in both intact (P = 0.032) and neutered (P = 0.0005) female wolves, but not in intact (P = 0.19) or neutered males (P = 0.07). These results indicated that in gray wolves (1) oCRF stimulated the release of pituitary and adrenal hormones in a fashion similar to that of other mammals; (2) the adrenal cortex was capable of secreting progesterone into the systemic circulation; (3) exogenous glucocorticoids did not alter LH concentrations; and (4) endogenous opioids may modulate LH secretion in female wolves.

Adrenal Cortex Hormones↗
PubMed2002

Partition of N-monodemethylated phenothiazine drugs to phosphatidylcholine bilayer vesicles studied by second-derivative spectrophotometry.

The partition coefficients (Kps) of three N-monodemethylated metabolites of phenothiazines (chlorpromazine (CPZ), triflupromazine, and promazine) between phosphatidylcholine (PC) vesicles (SUV) and water were determined to evaluate their affinity to biomembranes by second-derivative spectrophotometry without any separation procedures. The second derivative spectra showed distinct derivative isosbestic points confirming the entire elimination of the residual background signal effects of the SUV, which were observed in the absorption spectra. From the relationship between PC SUV concentration and the derivative intensity change (DeltaD) of each metabolite induced by its interaction with the PC bilayer, the Kp values were calculated and could be obtained with the R.S.D. of below 10% (n = 5) proving an accuracy of the derivative method. The obtained Kp values were similar to those of the parent drugs (the relative differences were within 15%), although the partition coefficient of N-monodemethylated CPZ measured in an octanol/buffer system was reported to be about 1/18 of CPZ. The results obtained from the PC liposome/buffer system do not contradict with psychoactivity and brain accumulation of N-monodemethylated metabolites of phenothiazines, in contrast to the results of the octanol/buffer system.

Antipsychotic Agents↗
PubMed1975

Binding study of sulfonylureas and phenothiazines to bovine serum albumin using difference spectrophotometry.

2-(4'-Hydroxybenzeneazo)benzoic acid is a spectrophotometric probe which shows absorption spectrum changes upon binding to protein. Difference absorption spectra of this probe were used as an indirect measurement of the binding of selected sulfonylurea and phenothiazine drugs to bovine serum albumin. The results obtained using the spectrophotometric probe were similar to data obtained from other methods, especially fluorescent methods. Of the four sulfonylureas studied, tolbutamide showed the highest binding affinity, followed by glyburide, glipizide, and acetohexamide, in that order. The data collected for phenothiazine drugs indicated that chlorpromazine has the highest affinity, followed in order by trifluoperazine, perphenazine, fluphenazine, and promazine. Correlation of these results with chemical composition indicated that the interaction of phenothiazine drugs with bovine serum albumin was of a hydrophobic nature.

Animals↗
PubMed1976

Comparative plasma concentrations of quinidine following administration of one intramuscular and three oral formulations to 13 human subjects.

A GLC method, based on flame-ionization detection, was developed for the assay of methotrimeprazine and its sulfoxide in plasma. For a 6-ml aliquot, the sensitivity was 2-3 ng/ml for the unchanged drug and 4-5 ng/ml for the sulfoxide. The coefficient of variation, calculated from duplicate analyses of plasma samples, was 8-15% for concentrations between 10 and 100 ng/ml. Patients treated with orally administered methotrimeprazine had higher plasma levels of the sulfoxide than of unmetabolized drug. The method also was applied to the analysis of promazine and chlorpromazine in patient plasma.

Administration, Oral↗
PubMed1976

GLC determination of methotrimeprazine and its sulfoxide in plasma.

A GLC method, based on flame-ionization detection, was developed for the assay of methotrimeprazine and its sulfoxide in plasma. For a 6-ml aliquot, the sensitivity was 2-3 ng/ml for the unchanged drug and 4-5 ng/ml for the sulfoxide. The coefficient of variation, calculated from duplicate analyses of plasma samples, was 8-15% for concentrations between 10 and 100 ng/ml. Patients treated with orally administered methotrimeprazine had higher plasma levels of the sulfoxide than of unmetabolized drug. The method also was applied to the analysis of promazine and chlorpromazine in patient plasma.

Chromatography, Gas↗
PubMed1979

Kinetics of dopamine oxidation by dialkylaminoalkylphenothiazine cation radicals.

The kinetics of dopamine oxidatinon dialkylaminoalkylphenothiazine cation radicals (with two- or three-carbon side chains) were investigated. The two-carbon side-chain derivatives have reaction rates higher than the three-carbon ones. For chlorpromazine and promazine, extrapolation of pH 1-6 data shows that reaction rates become very fast at physiological pH.

Chemical Phenomena↗
PubMed1983

Thermal and photolytic degradation studies of promethazine hydrochloride: a stability-indicating assay.

A stability-indicating GLC method for the analysis of promethazine hydrochloride in polyethylene glycol delivery systems is reported. This method is capable of distinguishing the intact drug from its thermal and photodegradation products. A linear relationship between peak height ratio (promethazine-promazine) and promethazine concentration is found up to a concentration of 600 micrograms/ml. Kinetic studies were performed to determine the photolytic and thermal degradation rates of promethazine hydrochloride as a function of pH. The activation energies at pH 2.98, 3.94, and 5.12 were obtained from linear Arrhenius plots and were found to be 6601, 5888, 5570 cal/mole, respectively. The first-order rate constant increased with increasing pH. The photolytic degradation of promethazine hydrochloride does not follow simple first-order kinetics.

Chromatography, Gas↗
PubMed1984

Behavior of ATP toward phenothiazine drugs.

The tricyclic amines promazine, promethazine, chlorpromazine, triflupromazine, and trifluperazine form solid ion pairs with ATP in a 1:2 molar ratio. There is a good correlation between the measured Ksp and the apparent diffusion constants of the ion pairs with the critical micelle concentration (CMC) of the corresponding phenothiazines. Solid ion pairs are solubilized by phenothiazine micelles; the binding constants of ATP to drug micelles are calculated from solubility data at 25 degrees C and can be related to the CMC of the phenothiazines.

Adenosine Triphosphate↗
PubMed1984

Comparative effects of selected phenothiazine tranquilizers and antihistaminics on bacterial cells 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 micrograms/mL] than antihistaminics (MIC greater than 1.6 micrograms/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.

Adsorption↗
PubMed1989

Pre-clinical studies on boron neutron capture therapy.

The present report provides an overview of the multidisciplinary research effort on BNCT that currently is in progress at The Ohio State University. Areas under investigation include the preparation of boron containing monoclonal antibodies, the synthesis of boron containing derivatives of promazines and phathalocyanines, the development of a rat model for the treatment of glioblastoma by means of BNCT, the design of an accelerator-based neutron irradiation facility, and 10B concentration measurements using alpha track autoradiographic methods. Progress in each of these areas is described and the direction of future research is indicated.

Animals↗
PubMed1987

Relative cytotoxicity of psychotropic drugs in cultured rat hepatocytes.

The relative cytotoxic effects of ten psychotropic drugs were assessed in rat hepatocyte monolayer cultures. Clear concentration-related toxicity was seen in the narrow range of 10(-5) M to 5 X 10(-5) M. The four cytotoxicity endpoints chosen were: release of the cytosolic enzyme, lactate dehydrogenase, and impairment of biosynthesis and secretion of proteins, bile acids and glycerolipids. LDH leakage and inhibition of protein secretion into the culture medium proved to be the parameters which allowed the best differentiation between the test compounds. The inhibition of glycerolipid secretion was the most sensitive test in relation to concentration and time of exposure. Based on the effects of these endpoints, the following ranking of relative in vitro toxicity, using equimolar drug concentrations, could be established: clomipramine greater than imipramine = thioridazine greater than chlorpromazine greater than amitriptyline = fluperlapine greater than haloperidol greater than promazine greater than clozapine much greater than sulpiride. This ranking order of in vitro cytotoxicity correlated well with the potential of the drugs to impair liver function in man. Only clozapine had to be classified as a false negative. There was, however, no correlation between the cytotoxicity and the intracellular accumulation of the test drugs. Furthermore, the comparison of the data obtained with psychotropics with the data from five other amphiphilic cationic drugs was consistent with the widely accepted concept of a direct toxic interaction of the drugs with cytomembranes. This nonspecific toxicity of the membrane-active drugs was further corroborated by a positive correlation between their potential to induce LDH leakage in hepatocytes and their ability to induce hemolysis in red cells. In conclusion, the results obtained in our study strongly suggest that it is possible to assess the relative cytotoxicity of psychotropic drugs in rat hepatocyte cultures. It is proposed that this in vitro system provides a useful tool to evaluate new drugs at an early stage of their development, and to identify the most promising candidates within a class of structurally related compounds. In addition, it allows information to be obtained on possible mechanisms of cytotoxicity.

Animals↗
PubMed1992

Pharmacokinetic interaction between carbamazepine and neuroleptics after combined prolonged treatment in rats.

This study investigates how neuroleptics of phenothiazine or thioxanthene structure influence the pharmacokinetics of carbamazepine. Experiments were carried out on male Wistar rats. Carbamazepine and the neuroleptics were administered i.p., separately or together, for 2 weeks in the following daily doses (mg/kg): carbamazepine 15 during the 1st week of treatment and 20 during the 2nd week of treatment, promazine 10, chlorpromazine 2, perazine 10, chlorprothixene 2, flupenthixol 0.5. One hour after the last injection of carbamazepine and/or the neuroleptic, samples of blood plasma and brain were taken to determine the concentrations of carbamazepine and two of its metabolites: 10,11-epoxide and trans-10,11-diol. The neuroleptics increased the concentration of carbamazepine in plasma and in brain, but tended to decrease (with the exception of chlorpromazine) the concentration of the epoxide and increased the concentration of trans-10,11-diol. Metabolic in vitro studies did not show any significant differences between rats treated with carbamazepine alone and those treated with carbamazepine plus neuroleptic in the rates of the carbamazepine epoxidation, of 10,11-epoxide hydrolysis or of 1-naphthol glucuronidation.

Animals↗
PubMed1989

Interaction of antiaggregant molecule ajoene with membranes. An ESR and 1H, 2H, 31P-NMR study.

The structure of ajoene, a molecule extracted from garlic, has been studied by 1H-NMR and its interaction with model membranes by 1H-, 2H-, 31-P-NMR and ESR experiments. This study clearly shows that the ajoene molecule is located deep in the layer and is close to the interlayer medium. Moreover while NMR experiments show that the membrane structure is only slightly affected by the presence of ajoene, ESR experiments reveal significant modifications in phospholipid dynamics. This interaction, observed before with the phenothiazine derivative, promazine, results in an increase of the membrane fluidity in its hydrophobic part and could be related to clinical properties of ajoene.

Deuterium↗
PubMed1990

The effects of microsphere injections into the left atrium on the myocardial blood supply measured by thermal conductance probes.

Former experiments with thermal conduction probes showed signs of reductions or increases of myocardial perfusion shortly after injection of microspheres into the left atrium. Because of this, 210 measurements made during experiments on 66 dogs under propionyl-promazine/pentobarbital narcosis were newly analysed to verify a possible influence of microspheres (9 microns phi) injected into the left atrium on microcirculation. Using 20 additional dogs in identically performed experiments, the myocardial perfusion was measured using thermal conductance probes, following injections of isotonic NaCl solution (8 ml each), Ringer's solution, 5% glucose, the subject's blood, and isotonic NaCl solution mixed with the surface-active substance Tween 80. These suspension media were injected both with and without unlabelled microspheres (8.6 microns phi). The results led to the following conclusions: An obligatory decrease in the blood supply as the result of a mechanical blocking of capillaries by microspheres can be ruled out. The particles, the suspension media, and a suspension temperature not sufficiently adjusted to the body temperature induce reactive negative or positive changes in the microcirculation of the myocardium. This was found in approx. 45%-75% of cases. Solutions containing particles cause, in the majority of cases, a decrease. The suspension medium with the smallest effect proved to be isotonic NaCl solution. From the results one can conclude that artefacts may arise from the application of the heat conductance probe method when the temperatures are not perfectly matched. However, the injected solution itself can often lead to various reactions in microcirculation which may last up to 5 min. (ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1981

The functional role of the noradrenergic neurons in the thermoregulatory circuits in mice.

Intracerebroventricular (i.c.v.) treatment of mice with 6-hydroxydopamine (6-OHDA; 20--50 micrograms per mouse), which depletes brain noradrenaline (NA) and DA, completely prevents or significantly diminishes the hypothermic effect of various classes of drugs: dopaminomimetics--apomorphine (0.5--10 mg/kg), piribedil (40--100 mg/kg), bromocriptine (3 to 10 mg/kg), CM 29-712 (2--10 mg/kg), d, l-amphetamine (1--2 mg/kg), and L-DOPA (10--100 mg/kg) in combination with Ro 4-4602 (5--40 mg/kg); cholinomimetics--oxotremorine (0.04--0.05 mg/kg), arecoline (5--10 mg/kg) and pilocarpine (2--3 mg/kg); neuroleptics--chlorpromazine, promazine, perphenazine, chlorprothixene, haloperidol, fluanisone (5--10 mg/kg); central alpha-adrenoblocker aceperone (20--40 mg/kg); inhibitor of tyrosine-hydroxylase alpha-methyltyrosine (200--300 mg/kg); inhibitor of dopamine-beta-hydroxylase--disulfiram (150--250 mg/kg) and FLA-63 (15--25 mg/kg). This antihypothermic effect was demonstrated up to 3 months after administration of 6-OHDA for DA-mimetics and neuroleptics and up to 3 weeks for cholinomimetics. The hypothermic effect of presumable GABA-mimetics Phenybut (100--150 mg/kg) and Lioresal (10--25 mg/kg) was enhanced by a prior 6-OHDA treatment. Pretreatment of mice with desipramine (25 to 30 mg/kg i.p.), protriptyline (20 mg/kg) or AW 15(1)1129 (15--20 mg/kg) 20--45 min before 6-OHDA administration protects the central NA-ergic neurons from a destructive effect of 6-OHDA and partially or completely counteracts the antihypothermic as well as prohypothermic (in the case of GABA-mimetics) effect of 6-OHDA. In rats desipramine counteracted antihypothermic effect of 6-OHDA in the case of piribedil, but not of apomorphine. Intracerebroventricular treatment of mice with a low (15 microgram) dose of 5, 6-dihydroxytryptamine (5, 6-DHT) enhanced the hypothermic effects of DA-mimetics; higher doses of 5, 6-DHT (26 and 30 micrograms) and 5, 7-DHT (40 and 46 micrograms) diminished the hypothermic effects; the antihypothermic effect of 6-OHDA was stronger than that of equimolar doses of 5, 6- or 5,7-DHT; desipramine pretreatment counteracted antihypothermic effects of 5, 6-DHT and 5, 7-DHT as well as depletion of brain NA they produce. The data presented reveal the key position for NA-ergic neurons in a temperature regulation and, particularly, in effects of various drugs on body temperature in mice. The tentative fragment of the neuronal thermoregulatory circuit is proposed in attempt to account for the presented an other known data concerning drug action (and interactions) on core temperature in mice.

Animals↗
PubMed1990

Tricyclic drugs reduce proton motive force in Leishmania donovani promastigotes.

Tricyclic compounds have been suggested as potential anti-leishmanial drugs. We have studied the effect of tricyclic drugs on several cellular functions in L. donovani promastigotes. Imipramine inhibits proline transport and reduces delta pH and cellular ATP at relatively high concentrations (IC50 = 50-80 microM). High concentrations of imipramine are also required to kill L. donovani promastigotes (LD50 greater than 50 microM). The presence of a chlorine atom in the side ring of either imipramine or promazine results in a three-fold increase in both IC50 and LD50 values. Tricyclic compounds in which the nitrogen in the middle ring was substituted with a carbon atom (amitryptyline and chlorprothixene) are most effective in causing cell death and in decreasing proline transport and delta pH (IC50 congruent to 5 microM), whereas depletion of cellular ATP requires a higher drug concentration (IC50 = 12 microM). Transchlorprothixene has IC50 values for proline transport, delta pH and cellular ATP that are similar to those of amitriptyline, whereas the cis isomer is less active. Imipramine, chlomipramine and chlorpromazine decrease the membrane potential in promastigotes. There is a direct correlation between inhibition of membrane transport of proline and the size of the membrane potential at various concentrations of the drugs. Taken together, the multiple effects of the tricyclic drugs on cellular functions in Leishmania suggest that the drugs cause cellular death by non-specific mechanisms, probably involving a general increase in membrane permeability.

Adenosine Triphosphate↗