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At least 433 records · Page 24Linked to original sources
PubMed1992

Drug distribution between blood and brain as a determinant of antipsychotic drug effects.

Concentrations of the neuroleptics haloperidol, bromperidol, fluphenazine, chlorpromazine and its metabolites nor-1- and nor-2-chlorpromazine, thioridazine and its metabolites mesoridazine, sulforidazine, and northioridazine, and promazine were estimated in serum and brain of rats by high performance liquid chromatography (HPLC) with electrochemical detection following 5 days of chronic administration of drug at typical doses (haloperidol, bromperidol, and fluphenazine 1 mg/kg/day; chlorpromazine, promazine, and thioridazine 25 mg/kg/day). The observed ratio of brain-to-serum concentration of drug varied widely (0.18-62.5) among neuroleptics studied. High potency agents had more favorable brain-to-blood distribution than low potency agents, and a strong correlation (r = 0.734, p < 0.05) was observed between the brain-to-serum ratios of the neuroleptics and standard clinical doses of drug. This finding suggests that drug distribution is a significant determinant of clinical potency. For most neuroleptics, including drugs with high (fluphenazine, haloperidol) and low potency (thioridazine) such as dopamine D2 antagonists, concentration of drug in the brain was similar. If the results are applicable to patients, they suggest that the degree of dopamine D2 blockade achieved during treatment may vary by drug. Chlorpromazine and promazine were notable for producing high concentrations of drug in the brain at typical doses, suggesting that optimal doses might be lower than those in common use. These results may be important in designing and interpreting studies of the effects of neuroleptic drugs in animals and patients.

Animals↗
PubMed2005

Substitution and solvent effects on the photophysical properties of several series of 10-alkylated phenothiazine derivatives.

The photophysical properties of several 2-substituted, 10-alkylated phenothiazines were measured in several solvents to investigate the relevance of the molecular structure in their photophysics and consequent photochemistry. Because the interaction modes of each drug and its corresponding species strongly depend on the variety of microenvironments in the cells, the properties of each one of these species must also be determined separately to understand fully the mechanism of action of the drug and the mechanism of its side effects. Information on the chemical interactions of the different species at the cellular level can be inferred from the corresponding electronic properties. In this work, we present absorption, steady-state, and time-resolved emission, laser flash photolysis, and quantum theoretical results for the ground state, the first excited singlet and triplet states, and the cation radical of promazine hydrochloride (PZ), 2-chlorpromazine hydrochloride (CPZ), 2-trifluoromethylpromazine hydrochloride (TFMPZ), 2-trifluoromethylperazine dihydrochloride (TFMP), 2-thiomethylpromazine (TMPZ), and thioridazine hydrochloride (TR). The corresponding nonalkylated phenothiazines are included as references. The photophysical properties of this drug family depend more on the solvent and the 2-substituents than on the dialkylaminopropyl chain. The largest effect was found for the triplet state of the 2-halogenated derivatives in phosphate buffer (PBS). Both the quantum yield and the lifetime of this intermediate drop to less than 5% of the corresponding value in organic solvents. The triplet state of halogenated promazines is efficiently quenched by a proton-transfer mechanism, and the rate of this quenching correlates very well with the phototoxicity of the promazine drugs. Therefore, we postulate that this species is directly related to the phototoxic side effect of neuroleptic drugs.

Alkylation↗
PubMed1975

Evaluation of xylazine as a sedative and preanesthetic agent in horses.

Xylazine administered intramuscularly (IM) to horses at the dose level of 2 mg/kg was an effective sedative and preanesthetic for thiamylal sodium narcosis or thiamylal sodium and halothane anesthesia. Evaluation of response of cardiovascular, respiratory, and hepatic function did not indicate serious untoward effects, although cardiac and respiratory rate decreased, calculated vigor of left ventricular contraction decreased, calculated peripheral vascular resistance increased, and transient innocuous cardiac arrhythmias occurred. Effects of the anesthetics used on respiratory function (blood gases and pH), using xylazine as a preanesthetic, were comparable with those observed when promazine was used. The onset of action of xylazine given IM was at least as rapid as that occurring when promazine was given intravenously; e.g., 5 minutes for first observable effects, and 15 to 20 minutes for maximal effect. Recovery, times from anesthesia when using xylazine administered IM as a preanesthetic agent were comparable with those reported after promazine was given intravenously; moreover, horses given xylazine were more calm during recovery and seldom tried to stand before they were able.

Anesthesia, Inhalation↗
PubMed1989

Some clinical, haematological and biochemical effects of four tranquilizers in camels (Camelus dromedarius).

Six healthy camels were treated with the tranquilizers propionyl promazine (Combelen), xylazine (Rompun), acepromazine (Calmivet) or chlorpromazine (Largactil) at single intramuscular doses of 0.5, 0.25, 0.1, or 3 mg/kg, respectively; and the onset, duration and degree of sedation produced by each drug was assessed for six hours. The effect of the treatments on some haematological and biochemical parameters was also studied. The onset and duration of action of the tranquilizers were 10 min and 2.1 +/- 0.5 h for propionyl promazine, 4 min and 3.1 +/- 0.4 h for xylazine, 5 min and 2.3 +/- 0.5 h for acepromazine, 7 min and 2.5 +/- 0.4 h for chlorpromazine, respectively. It was observed that 5-10 min after the administration of the four drugs, camels showed slight irritability, dropping of the lower lips and scratching of the nostrils against objects. During the first hour after medication camels showed frequent urination, defaecation and lacrimation. Xylazine seemed to be superior to the other three drugs in producing sedation. No significant effect on the rectal temperature or the respiratory rates of treated camels was seen after the administration of the four drugs. There were consistent, but statistically insignificant decreases (about 10 p. 100) in the haemoglobin concentration and erythrocyte counts of camels one hour after treatment with the tranquilizers. The four drugs, particularly xylazine and propionyl promazine produced significant hyperglycaemia, but did not alter significantly the plasma concentration of urea or activity of aspartate aminotransferase.

Animals↗
PubMed1986

In vivo toxicity of phenothiazines to cells of a transplantable tumor.

The toxicities of three phenothiazines, promazine, chlorpromazine, and trifluoperazine, towards cells of a mouse fibrosarcoma were quantified by means of an in vitro assay of clonogenic cell survival. For all three drugs cell kill was proportional to the amount of drug injected. Following injection of equimolar (0.2 mM/kg) amounts, cell survival was progressively reduced for a period of at least 48 h. On the basis of cell survival at 48 h after administration the ranking of the drugs for cytotoxicity, in ascending order, was trifluoperazine, chlorpromazine, promazine. A period of acute hypoxia prior to processing of the tumor did not enhance the toxicity of any of the drugs, and no change in the size of the hypoxic fraction of the tumor was seen 24 h after the injection of chlorpromazine. On this basis it was concluded that there was no evidence of enhanced toxicity of drugs for either chronically or acutely hypoxic tumor cells. A reduction in the number of clonogenic tumor cells per gram of tumor was largely the result of a fall in the number of viable cells recovered from the tumor. The plating efficiency of surviving cells remained constant or was only slightly depressed.

Animals↗
PubMed1983

Increased paroxysmal activity of partial seizures in man by apomorphine.

In order to study the role of dopamine (DA) in the regulation of seizure mechanisms in man, a non-emetic dose of apomorphine, a direct stimulant of DA receptors, was administered to eight patients effected by different types of epilepsy. The EEG changes induced by apomorphine administration in comparison to those elicited by promazine or placebo were evaluated in a double blind cross-over study. Similarly to promazine treatment, apomorphine worsened the EEG recordings of some patients. The apomorphine-induced increase in paroxysmal activity was observed in patients affected by partial epilepsy and was not related to the sleep-inducing properties of the drug. This effect is interpreted as being the result of a stimulation of DA autoreceptors, mediating a decrease of dopaminergic activity in the central nervous system. The use of apomorphine as an EEG activating agent is suggested.

Adolescent↗
PubMed1978

Microsomal enzymes inducers and serum minerals in carbon-tetrachloride hepatotoxicity.

The effect of ten repeated doses of carbon tetrachloride, phenobarbitone and propionyl promazine when administered alone or simultaneously with CCl4 on serum minerals was investigated. Carbon tetrachloride resulted in a significant increase in serum iron, copper, zinc, calcium, potassium and sodium. A portion of this rise was due to increased permeability in damaged mitochondrial membrane as a result of the action of CCl4. Propionyl promazine when administered alone or together with CCl4 has no effect on serum minerals. Phenobarbitone when administered alone increased serum minerals except sodium, but to a lesser degree than CCl4, while phenobarbitone when given repeatedly together with small doses of CCl4 led to a normalization of serum iron, calcium and potassium. Also serum zinc and copper were lower than in case of CCl4. This may be due to some protective effect of phenobarbitone on liver mitochondria. Serum magnesium was not affected in all the experimental groups.

Animals↗
PubMed1990

Differential effects of psychotropic drugs on feeding in rats: is histamine blockade involved?

The present animal studies tested the hypothesis that drug-induced blockade of histamine-1 receptors leads to appetite stimulation. Test agents included the antipsychotic promazine which has very potent antihistaminic effects, as well as the antipsychotic haloperidol and the antidepressant desipramine which both have negligible antihistaminic effects. In support of the hypothesis, significant appetite stimulation occurred only with promazine, while the other two test agents did not increase feeding, and even produced some suppression in food intake.

Animals↗
PubMed1989

Metabolism and pharmacokinetic studies of propionylpromazine in horses.

The propionylpromazine concentrations in plasma after intramuscular administration to horses were determined using gas chromatography with nitrogen-phosphorus detection. After hydrolysis by beta-glucuronidase/arylsulphatase, the parent drug and three metabolites were detected in urine. The metabolites were identified as 2-(1-hydroxypropyl)promazine, 2-(1-propenyl)promazine and 7-hydroxypropionylpromazine by gas chromatography-mass spectrometry. No N-demethylated or sulphoxidated metabolites of propionylpromazine were observed in the horse urine.

Animals↗
PubMed1999

A previously unidentified acepromazine metabolite in humans: implications for the measurement of acepromazine in blood.

High-performance liquid chromatography-diode-array detection results obtained during the investigation of two cases involving acepromazine prompted us to study the stability of the drug in blood. It was found that acepromazine can undergo in vitro conversion by human red blood cells to 2-(1-hydroxyethyl)promazine, a product that has been reported as a minor urinary metabolite in horse urine but not previously identified in humans. Further, our analytical findings in the two cases examined suggest that 2-(1-hydroxyethyl)promazine may be the major unconjugated metabolite of acepromazine in humans. These findings have important implications for the analytical toxicology of acepromazine.

Acepromazine↗
PubMed1983

Liquid chromatographic separation of antidepressant drugs: I. Tricyclics.

A simple normal-phase (silica), high-performance liquid chromatographic (HPLC) assay of amitriptyline (AMI), doxepin (DOX), imipramine (IMI), nortriptyline (NORT), desmethyldoxepin (DESDOX), desipramine (DESIP), and protriptyline (PRO) in serum with no coelution is described here. Trimipramine and promazine were used as internal standards. Extraction of the 1.0-ml serum samples (collected in plastic) was done with Bond-Elut C18 columns. The compounds of interest were eluted with 10 mM methanolic ammonium acetate. The eluates were evaporated at 56-58 degrees C and reconstituted with 200 microliters of the mobile phase. The mobile phase was absolute ethanol-acetonitrile-tert-butylamine (98:2:0.05, vol/vol/vol). Detection of eluted drugs was at 254 nm at 0.01 absorbance units full scale (AUFS), except for PRO, which was detected at 229 nm at 0.02 AUFS. Absolute recoveries were 87-97%. A 5-micron silica (4.6 X 250 mm) HPLC column was used; results with a 10-micron silica column (3.9 X 300 mm) are also presented. Peak height ratios with trimipramine were linear for each analyte between 25 and 1200 ng/ml. Peak height ratios with promazine as the internal standard were linear for each analyte between 25 and 600 ng/ml. Detection limits under the conditions described were 2 ng/ml for AMI, DOX, and IMI, 4 ng/ml for NORT, DESDOX, and DESIP, and 10 ng/ml for PRO. Coefficients of within-day and day-to-day variation at three concentration levels were less than 9.8% and less than 11.2%, respectively. The hydroxylated metabolites of IMI, DES, NORT, and the cis isomer of DOX are discussed. Steady-state daily dosages and corresponding serum levels are presented for 69 patients. The total assay time was less than 10 min for DESIP and 12 min for PRO. This assay can be used in correlating serum levels with clinical effects, compliancy, and pharmacokinetic studies.

Amitriptyline↗
PubMed1989

Clinical effects of azaperone-metomidate, as compared to propionylpromazine-xylazine-metomidate or xylazine-ketamine combinations in anaesthesia of dogs.

Eighteen dogs of Tanzanian breeds divided into three groups of 6 were anaesthetized using either azaperone-metomidate (2 mg/kg, i.m. and 10 mg/kg i.p., respectively), propionyl promazine-xylazine-metomidate (2 mg/kg i.m., 1 mg/kg i.m. and 10 mg/kg i.p., respectively), or xylazine-ketamine (1 mg/kg i.m. and 11 mg/kg i.m., respectively). The clinical effects on respiration rate, heart rate and body temperature were studied until recovery. Hypersensitivity to noise was associated with azaperone metomidate anaesthesia. The other combination produced a smooth and uneventful induction and recovery from anaesthesia. Muscle relaxation and analgesia were adequate in all groups. Duration of xylazine-ketamine anaesthesia was shortest (30 +/- 5 minutes) followed by azaperone metomidate (50 +/- 15 minutes) and the longest duration was with propionyl promazine-xylazine-ketamine (120 minutes). Azaperone and metomidate was associated with marked increases in cardiac and respiration rates and marked hypothermia, which persisted throughout. Minimal changes were observed in the other combinations. Azaperone-metomidate seems to be preferable due to the moderate period of anaesthesia adequate for most operations. However, all the three combinations offer a practical application because of the convenient route of administration.

Anesthesia↗
PubMed1989

In vivo photodegradation of chlorpromazine.

The in vivo photodegradation of chlorpromazine (CPZ) in the skin was investigated after systemic administration of 3H-CPZ to shaven Wistar rats and exposure to UV-A. Promazine (PZ) and 2-hydroxy-promazine (2-OH-PZ) appeared to be formed in irradiated rats, but not in the skin of rats kept in the dark. This indicates that upon irradiation with UV-A the PZ-radical is formed which can be held responsible for the photobinding to eye and skin constituents as observed earlier [Schoonderwoerd and Beijersbergen von Henegouwen (1987) Photochem. Photobiol. 46, 501-505]. Chlorpromazine-sulfoxide (CPZSO) is a major metabolite of CPZ. Less CPZSO was found in the skin of irradiated rats compared to those kept in the dark. As this appeared not to be caused by photobinding or photodegradation of CPZSO it can be concluded that CPZSO is not a photoproduct of CPZ under these experimental conditions. This study shows that the in vivo photodegradation of CPZ proceeds via the promazinyl radical rather than via the radical cation.

Animals↗
PubMed1997

Phototoxic properties of neuroleptic drugs.

BACKGROUND: Photo-induced eruptions are well-known adverse effects of some neuroleptic drugs, particularly chlorpromazine. OBJECTIVE: By a photohemolysis test we assessed in vitro the phototoxic properties of 12 phenothiazines (chlorpromazine, dixyrazine, fluphenazine, levomepromazine, perazine, perphenazine, promazine, promethazine, prothipendyl, thioridazine, trifluoperazine, triflupromazine) and 5 thioxanthenes (chlorprothixene, clopenthixol, flupenthixol, thiothixene, zuclopenthixol). METHODS: Human erythrocytes from 3 donors were incubated with the compounds and irradiated with light sources rich in UVA or UVB, respectively. Doses were up to 100 J/cm2 UVA or up to 1,600 mJ/cm2 UVB. Photo-induced hemolysis was calculated as percentage of complete hemolysis. RESULTS: Photo-induced hemolysis >10% due to radiation rich in UVA was found with chlorpromazine (maximal median: 98%), dixyrazine (100%), fluphenazine (84%), perazine (100%), perphenazine (100%), promazine (16%), promethazine (25%), prothipendyl (96%), trifluoperazine (100%), triflupromazine (76%), chlorprothixene (100%) and thiothixene (31%). UVB-rich radiation induced hemolysis only with chlorpromazine (73%), dixyrazine (45%) and perazine (60%). CONCLUSION: Most neuroleptics are strongly phototoxic in vitro indicating a potential risk for photo-induced reactions also to occur in patients treated with these drugs.

Antipsychotic Agents↗
PubMed1980

Use of dissociative anesthetics for the immobilization of captive bears: blood gas, hematology and biochemistry values.

Nineteen bears, representing five species (Helarctos malayanus, Ursus americanus, Ursus arctos, Tremarctos ornatus, Melursus ursinus) were immobilized a total of 52 times using either phencyclidine-promazine or tiletamine-zolazepam. Blood gas, hematology, and serum biochemistry values were determined during the immobilizations. Immobilizations conducted with tiletamine-zolazepam were characterized by rapid induction and recovery times, good muscle relaxation, and relative freedom from convulsions. Bears immobilized with phencyclidine-promazine had longer induction and recovery times and showed convulsive activity in 29% of the trials with that combination.

Animals↗
PubMed1975

Studies on the stability of injectable solutions of some phenothiazines. Part 1: Effects of pH and buffer systems.

The stability of phenothiazines is affected by the pH-value of the solution. At the pH-values of maximum stability, triflupromazine hydrochloride and chlorpromazine hydrochloride are more stable than promazine hydrochloride. The stability of chlorpromazine hydrochloride in the Sörensen's phosphate buffer is slightly higher than that in the McIlvaine's citric acid-phosphate buffer system. On the other hand, the stbility of promazine hydrochloride and triflupromazine hydrochloride in the latter buffer system is slightly higher than that in the former one.

Buffers↗
PubMed1989

The diagnosis of short penis as a cause of impotentia coeundi in bulls.

Short penis condition was diagnosed as the cause of impotentia coeundi in 10 bulls, aged 2.5 to 5 yr. The diagnosis was based on observation of service attempts, measurement of the extended penis, and elimination of other causes of impotence. Measurements of the penis were made under general inhalation anesthesia or pudendal nerve block. These measurements were then compared with those of 10 control bulls, matched for age and breed and having no history of impotence; the latter measurements were likewise obtained under general anesthesia, pudendal nerve block or sedation. with propionyl promazine. Similar measurements were obtained from 10 yearling bulls under propionyl promazine sedation. Measurements obtained under general anesthesia or pudendal nerve block in the same bull were usually similar and repeatable, while phenothiazine tranquillization produced incomplete and variable relaxation of the retractor penis muscles. The dimension best correlated with impotence due to short penis was the distance from the tip of the extended penis to the preputial orifice in its resting position. In 10 bulls in which short penis was diagnosed, this distance was 10 to 22 cm, while in 10 control bulls with no history of impotence it was 25 to 42 cm. The distances from the tip of the extended penis to the preputial reflection (fornix) and to the neck of the scrotum were also shorter in affected than in control bulls. Although observation of service ability remains the cornerstone of diagnosis of short penis, a presumptive diagnosis can be made if penile protrusion of less than 25 cm can be obtained in an adult bull under general anesthesia or pudendal nerve block. Phenothiazine tranquillization is suitable for screening examinations but not for definitive diagnosis.

Journal Article↗
PubMed1998

Phenothiazine inhibitors of trypanothione reductase as potential antitrypanosomal and antileishmanial drugs.

Given the role of trypanothione in the redox defenses of pathogenic trypanosomal and leishmanial parasites, in contrast to glutathione for their mammalian hosts, selective inhibitors of trypanothione reductase are potential drug leads against trypanosomiasis and leishmaniasis. In the present study, the rational drug design approach was used to discover tricyclic neuroleptic molecular frameworks as lead structures for the development of inhibitors, selective for trypanothione reductase over host glutathione reductase. From a homology-modeled structure for trypanothione reductase, replaced in the later stages of the study by the X-ray coordinates for the enzyme from Crithidia fasciculata, a series of inhibitors based on phenothiazine was designed. These were shown to be reversible inhibitors of trypanothione reductase from Trypanosoma cruzi, linearly competitive with trypanothione as substrate and noncompetitive with NADPH, consistent with ping-pong bi bi kinetics. Analogues, synthesized to define structure-activity relationships for the active site, included N-acylpromazines, 2-substituted phenothiazines, and trisubstituted promazines. Analysis of Ki and I50 data, on the basis of calculated log P and molar refractivity values, provided evidence of a specially favored fit of small 2-substituents (especially 2-chloro and 2-trifluoromethyl), with a remote hydrophobic patch on the enzyme accessible for larger, hydrophobic 2-substituents. There was also evidence of an additional hydrophobic enzymic region available to suitable N-substituents of the promazine nucleus. Ki data also indicated that the phenothiazine nucleus can adopt more than one inhibitory orientation in its binding site. Selected compounds were tested for in vitro activity against Trypanosoma brucei, T. cruzi, and Leishmania donovani, with selective activities in the micromolar range being determined for a number of them.

Animals↗