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PubMed1997

[Drug or plant substances which antagonize venoms or potentiate antivenins].

Dendroaspis jamesoni (Elapidae) and Echis oceliatus (Viperidae) are responsible for most of severe evenomation in Cameroon. Toxicity of venoms of these two species has been measured using mice according to the method of Spearman & Kàrber. The effect on experimental envenomation of various drugs (atropine, promethazine, neostigmine, hydrocortisone, pentosane sulfuric polyester, heparin, tranexamic acid and aminocaproic acid) and plant extracts (Schumanniophyton magnificum, Bidens pilosa, Securidaca longepedunculata and Garcinia lucida) has been observed associated or not with the antivenom lpser Afrique (SAV). The venom of D. jamesoni contains neurotoxins agonizing and antagonising acetylcholine. The toxicity of the venom did not depend on the route of injection. Atropine, promethazine, neostigmine and hydrocortisone protected animals against a venom dose up to 2 LD50. Moreover, atropine and promethazine potentiated the SAV. Similar results have been obtained with extracts from S. magnificum and B. pilosa. The venom of E. ocellatus induces haemorrhage and necrosis. The toxicity increased by 3-fold when the venom was injected through intravenous or intraperitoneal route, compared to intramuscular route. Pentosane sulfuric polyester and tranexamic acid protected mice against doses up to 3 LD50. Pentosane sulfuric polyester, hydrocortisone, heparin and aminocaproic acid increased the SAV protective titre by 50%. However, tried plant extracts weakly antagonised the venom and did not potentiate the SAV.

Aminocaproates↗
PubMed1996

Self-Association of Phenothiazine Drugs: Influence of the Counterion on the Mode of Association

The association characteristics of the phenothiazine drug trimeprazine tartrate in water and aqueous electrolyte solution have been examined using static and dynamic light scattering techniques and compared with those reported for the structurally related drug promethazine hydrochloride, to identify differences in association pattern arising from differences in the counterions of the two drugs. The association of trimeprazine tartrate was micellar in water and in the presence of added electrolyte. A progressive increase of aggregation number and micellar radius was observed with increase of sodium chloride concentration over the range 0.05 to 0.60 M NaCl. This behavior is in contrast to that of promethazine hydrochloride which exhibits continuous association above the critical concentration in electrolyte of concentrations >/=0.2 M NaCl. Moreover, static light scattering curves for trimeprazine tartrate showed a single discontinuity corresponding to the onset of micellization, whereas the association behavior of promethazine hydrochloride (and other phenothiazine drugs with chloride counterions), in water and dilute electrolyte (0.05-0.1 M NaCl), is complex, with discontinuities in solution properties at several critical concentrations. The results of this study highlight the influence of the counterion on the association characteristics of this class of amphiphile.

Journal Article↗
PubMed1994

Comparison of the effects of eleven histamine H1-receptor antagonists on monoamine turnover in the mouse brain.

To compare in vivo effects of eleven compounds of different classes of histamine H1-receptor antagonists (alcoholamines: diphenhydramine, carbinoxamine, and clemastine; ethylenediamines: mepyramine, tripelennamine, and clemizole; alkylamines: triprolidine and chlorpheniramine; piperazines: meclizine and homochlorcyclizine; phenothiazines: promethazine) on neuronal uptake of dopamine (DA), noradrenaline (NA), and 5-hydroxytryptamine (5-HT), the effects on the turnover of these monoamines were examined in the mouse brain, based on the alpha-methyl-p-tyrosine-induced depletion of DA and NA or probenecid-induced accumulation of 5-hydroxyindoleacetic acid. The DA turnover was reduced remarkably by diphenhydramine, tripelennamine, and promethazine, and also significantly by chlorpheniramine, mepyramine, clemizole, and homochlorcyclizine, at doses used in the ordinary animal experiments. The 5-HT turnover was reduced markedly by mepyramine, tripelennamine, and chlorpheniramine. In contrast, the NA turnover was increased by promethazine and homochlorcyclizine, possibly due to their antagonistic effects on alpha-adrenoceptors. These results suggest that (1) the degree of inhibition of the uptake of DA and 5-HT by histamine H1-receptor antagonists is considerably different, (2) most H1-antagonists have little influence on NA uptake and some compounds enhance NA release, and that (3) carbinoxamine, clemastine, triprolidine, and meclizine have comparatively weak influences on monoamine metabolism. These effects on brain monoamine systems may be related to some central actions of histamine H1-receptor antagonists, such as an addiction to these compounds combined with opioids.

Animals↗
PubMed1990

Influence of certain H1-blockers on the step-through active avoidance response in rats.

The inhibitory effects of some newly developed H1-blockers on the step-through active avoidance response in rats were studied in comparison with those of classical H1-blockers. Single administration of diphenhydramine, pyrilamine, promethazine and chlorpheniramine caused dose-related depressant effects on the active avoidance response. Ketotifen and azelastine caused less potent inhibition than the classical H1-blockers, while the effects of astemizole and oxatomide were almost negligible in suppressing the response. Following chronic administration of pyrilamine and promethazine, the acquisition of active avoidance response was significantly retarded compared with the control group, whereas new H1-blockers caused a somewhat but not significantly slower acquisition than the control group. Chronic administration of astemizole and oxatomide caused only transient suppression of the response. However, classical H1-blockers such as pyrilamine and promethazine caused sustained inhibition for as long as drug administration was continued.

Administration, Oral↗
PubMed1986

The effect of antihistaminic drugs on pentazocine antinociception in the rat.

The antinociception produced by pentazocine, diphenhydramine, promethazine, chlorpheniramine, cyclizine and chlorcyclizine in the rat has been measured with a low-temperature (51.5 degrees C) hot-plate from 15 to 75 min following drug administration. The mean reaction times measured at 15 min and the area under the antinociception curves following administration of pentazocine (5 to 30 mg/kg) were linear. Diphenhydramine, chlorpheniramine, promethazine, cyclizine, and chlorcyclizine showed mild antinociceptive potency. The antinociception produced by SC pentazocine (5 and 10 mg/kg) was potentiated, rather than in a simple additive manner, by simultaneous IP administration of 20 mg/kg of diphenhydramine, promethazine, cyclizine, or chlorpheniramine, but not by chlorcyclizine. After concurrent administration of pentazocine and diphenhydramine, diphenhydramine did not alter pentazocine concentrations in the brain and plasma 15 to 75 min following drug administration, nor did pentazocine change diphenhydramine concentrations. Results of this study demonstrate that pentazocine antinociception can be potentiated by several antihistamines and that the potentiation was not due to a mutual effect on metabolism but rather through an as yet undefined mechanism.

Animals↗
PubMed1996

The pharmacological basis for the use of dried sheep placenta in traditional obstetric practice in Nigeria.

Dried sheep placenta is sometimes used in traditional medicine to facilitate labour. The effects of an extract of powdered dried sheep placenta with normal saline on guinea-pig uterus, ileum, spontaneously beating atrium and Langendorff heart, rat uterus and hindquarters, and cat blood pressure were therefore examined. It was found that 1 g of dried sheep placenta had, on the guinea-pig uterus, an oxytocic activity equipotent with 0.075-0.32 i.u. of oxytocin. The oxytocic activity was unaffected at pHs between 4 and 10 or by boiling for 30 min or autoclaving for 15 min. Neither atropine nor promethazine inhibited the oxytocic action, but promethazine inhibited, to the same degree, contractions induced in the ileum by equipotent doses of the infusion and histamine. Atropine, however, had no effect on infusion-induced contractions in the ileum. The vasoconstriction induced in the rat hindquarters was antagonized by promethazine and phentolamine. Cat blood pressure was reduced, but it had positive inotropic and chronotropic effects on the spontaneously beating guinea-pig atrium and on the guinea-pig Langendorff heart. It was concluded that the dried placenta contains a chorionic oxytocic substance the action of which is independent of stimulation of H1 receptors or of muscarinic receptors.

Animals↗
PubMed1988

Determination of low levels of phenothiazine sulphoxides in phenothiazine drug substances and formulations by thin-layer chromatography-second-derivative spectrofluorimetry.

A thin-layer chromatographic-second derivative spectrofluorimetric procedure has been developed for low levels of sulphoxide (down to 0.01%, w/w) in phenothiazine drug substances and formulations. The method has been applied to prochlorperazine maleate, chlorpromazine hydrochloride and promethazine hydrochloride. It has also been applied to pharmaceutical formulations of promethazine hydrochloride and comparison of the results with those obtained by a published difference spectrophotometric procedure for promethazine sulphoxide showed that there was good agreement. The method is simple, rapid, accurate and precise and seems to have general application to the determination of low levels of sulphoxide in phenothiazine drug substances or formulations.

Chromatography, Thin Layer↗
PubMed2000

Guanine-cytosine rich regions of plasmid DNA can be the target in anti-plasmid effect of phenothiazines.

The antiplasmid effects of promethazine on E. coli is the consequence of special complex formed with a covalently closed circular (ccc) form of plasmid DNA. The exact target in this macromolecule, however, was not clarified until recently. Caffeine and the chemically similar guanosine-5'- monophosphate (GMP) could compete with the antiplasmid effect of promethazine, showing that promethazine or other phenothiazines preferentially bind to xanthine type molecules. Among the xanthines, GMP was more effective at complex-forming than adenosine-5'-monophosphate (AMP). In addition, the Z-DNA was more susceptible than B-DNA. Therefore, one could suppose that guanine-cytosine (G-C) rich regions have higher affinity than adenine-thymine (A-T) rich region on phenothiazines. Because the G-C rich regions have a special role in the DNA stability via three hydrogen bonds, we suppose that these regions could have a key role in some biological effects such as antiplasmid and anticancer activity.

Binding Sites↗
PubMed2001

Redox reactivity of guanyl radicals in plasmid DNA.

PURPOSE: It has been previously argued that gamma-irradiation of plasmid DNA in the presence of thiocyanate ions produces products recognized by the E. coli base excision-repair endonuclease formamidopyrimidine-DNA N-glycosylase (FPG), and there that derive from an intermediate guanyl radical species. The wish was to characterize the reactivity of this intermediate with reducing agents. MATERIALS AND METHODS: Aqueous solutions of plasmid DNA containing either bromide or thiocyanate (10(-3) to 10(-1) mol dm(-3)) and also one of six other additives (azide, ferrocyanide, iodide, nitrite, promethazine, tryptophan, 10(-7) to 10(-3) mol dm(-3)) were subjected to 137Cs gamma-irradiation (662 keV). After irradiation, the plasmid was incubated with FPG. Strand break yields before and after incubation were determined by agarose gel electrophoresis under neutral conditions. RESULTS: The very high yields of FPG-sensitive sites in the presence of SCN- or Br- decreased significantly with increasing concentrations of all of the six additives, with promethazine and tryptophan being the most efficient additives, and azide and iodide the least. CONCLUSIONS: From the results it is possible to estimate values of the rate constants for the reduction of the DNA guanyl radical (5 x 10(5), 2 x 10(5), 10(7) and 10(7) dm3 mol(-1) s(-1) for ferrocyanide, nitrite, promethazine and tryptophan respectively).

Bromides↗
PubMedDate not supplied

Plasmid elimination and immunomodulation by 3-benzazepines in vitro.

For studying the mechanisms of biological activity on 3-benzazepines, antimicrobial effect, F'lac plasmid elimination activity (a plasmid curing effect on F'lac plasmid) and antibody-dependent cellular cytotoxicity (ADCC) test were performed. A weak antiplasmid effect was found at sub-inhibitory concentrations. A combination of [KF4] with verapamil [2] did not alter the ineffectivity, however, [KF4] could inhibit the antiplasmid effect of promethazine, as compared to the control (promethazine alone) plasmid curing effect. A competition between promethazine and [KF4] might exist in plasmid elimination effect. ADCC activity of human leukocytes was enhanced by KF1, KF2, KF3, DA and NE at 1.0 microgram/mL concentrations. The majority of 3-benzazepines [KS02, KM57, KN50, KE04, KI10, KP80] was ineffective for plasmid curing, however, inhibited the ADCC reaction, but they did not show a real dose-dependent effect.

Adjuvants, Immunologic↗
PubMed1992

Effects of some tricyclic psychopharmacons and structurally related compounds on motility of Proteus vulgaris.

A simple test for the evaluation of drugs interfering with bacterial motility was established with Proteus vulgaris. With this model, promethazine, 7-hydroxy-chlorpromazine, imipramine, 7,8-dioxochlorpromazine and acridine orange were shown to exert significant motility and swarming inhibitory action on Proteus vulgaris strains at subinhibitory concentrations. Quinidine enhanced the antimotility effect of promethazine. The antimotility effect of promethazine was synergized by proton pump inhibitors omeprazole and abscissic acid, but antagonized by extracellular potassium and sodium ions.

Abscisic Acid↗
PubMed2003

Studies on performance and sleepiness with the H1-antihistamine, desloratadine.

INTRODUCTION: The purpose of this study was to establish whether the H1-antihistamine desloratadine (5 mg), the active metabolite of loratadine, is free of effects on performance and sleepiness. METHOD: Effects of desloratadine (5 mg) on psychomotor performance, daytime sleep latencies, subjective sleepiness, and memory were studied in nine healthy volunteers (four men, five women) between the ages of 20 and 39 yr (mean 28.2). Assessments were made 1.0 h pre-ingestion and from 0.5 to 8.0 h post-ingestion. The study was placebo-controlled and double blind with a crossover design, using promethazine (25 mg) as an active control. RESULTS: Promethazine impaired tracking (3.5-5.5 h), choice reaction time (3.5-5.5 h), digit symbol substitution (3.5-5.5 h), and attention (2.0-5.5 h). There was increased objective and subjective sleepiness (2.0-5.5 h) and subjective fatigue (3.5-8.0 h). There were no changes in any of these measures with desloratadine (5 mg). With promethazine, memory was impaired from 2.0-5.0 h. Analysis failed to establish a consistent effect on memory with desloratadine, as there was a change in only one (digit memory recall reaction time) of the twelve memory test measures at only one time point (5.5 h). The change was significant with respect to placebo, but not with respect to the pre-ingestion value. CONCLUSIONS: Desloratadine (5 mg) appears to be free of adverse effects on psychomotor performance, daytime sleep latencies, and subjective sleepiness, and could prove suitable for those involved in skilled activity and transportation.

Adult↗
PubMedDate not supplied

Inhibition of biological effects of endotoxins by phenothiazines.

The importance of change transfer reaction involving endotoxins of bacteria and interactions between endotoxin-induced tumor necrosis factor (TNF) were investigated both in vitro and in vivo in the presence of several phenothiazines. Complex formation between endotoxins and ring-substituted phenothiazines, benzodiazepines, amantadine and promethazine was measured using spectrophotometric methods. The endotoxin-induced hypotensive effect was prevented by phenothiazine pretreatment of the dogs; however, the endotoxin-phenothiazine complex had the same effect as the endotoxin itself. The tumor necrosis factor-inducing ability of endotoxin in human monocytes was prevented by promethazine. The TNF induction by endotoxin was inhibited by promethazine in vivo.

Amantadine↗
PubMed1990

Histamine stimulates glycogen breakdown and increases 45Ca2+ permeability in rat astrocytes in primary culture.

In astrocyte-enriched cultures from rat brain hemispheres prelabeled with [3H]glucose, histamine stimulates [3H]glycogen breakdown in a concentration-dependent manner, with an EC50 of 0.6 microM. This effect can be induced by activation of both H1 and H2 receptors independently. Thus, neither 1 microM promethazine, an H1 antagonist, or 100 microM metiamide, an H2 antagonist, inhibited the glycogenolytic response to histamine unless they were present together. In addition, the maximal effect of histamine (55% decrease in [3H]glycogen) was also elicited by 300 microM 2-thiazolylethylamine, an H1 agonist, and by 1 mM dimaprit, an H2 agonist. These agonist effects were inhibited by promethazine and metiamide, respectively, and were not additive, indicating that the same glycogen pool was affected. Histamine was more potent in eliciting glycogenolysis through H1 (EC50 of 0.4 microM in the presence of 100 microM metiamide) than through H2 (EC50 of 3.3 microM in the presence of 1 microM promethazine) receptors, as also shown previously for the H1-mediated phosphoinositide hydrolysis compared with the H2-mediated cAMP formation in the same cells. Both dibutyryl cyclic AMP and the Ca2+ ionophore A23187 could independently mimic the glycogenolytic effect of histamine, whereas the absence of extracellular Ca2+ abolished the H1 component of the response. Histamine also stimulated rapid transmembrane 45Ca2+ influx (maximum, 48% of basal at 15 sec) and efflux (maximum, 25% of basal at 1 min) in astrocytes by activation of H1 receptors. This histamine-increased 45Ca2+ entry was abolished by the nonspecific Ca2+ channel blocker lanthanum but not by the voltage-operated Ca2+ channel inhibitor nifedipine. The enhanced 45Ca2+ release was more a consequence of the histamine-increased Ca2+ permeability than intracellular Ca2+ mobilization, because it was largely diminished when Ca2+ entry was prevented and was little affected by pretreatment of the cells with 12-O-tetradecanoyl-phorbol-13-acetate. Thus, the histamine-induced glycogen breakdown in astrocytes may involve increases in cAMP formation and in intracellular Ca2+ levels, this latter resulting mainly from H1-mediated extracellular Ca2+ uptake.

Animals↗
PubMed1986

Comparative study of various H1-blockers on neuropharmacological and behavioral effects including 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate (KB-2413), a new antiallergic agent.

In a conditioned avoidance response tested in rats, all of the H1-blockers employed caused a dose-related inhibition at doses 5-20 mg/kg (i.v.) except for ketotifen that elicited significant suppression even at a dose of 1 mg/kg. No inhibition was seen after administration of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate (KB-2413). ED50s were ranged from 4.1 to 7.4 mg/kg in diphenhydramine, pyrilamine and promethazine. In laminectomized rats, diphenhydramine, pyrilamine, promethazine and ketotifen suppressed the amplitudes of monosynaptic reflex potentials at doses higher than 2 mg/kg (i.v.). In the case of chlorpheniramine, significant inhibition was observed at a dose of 20 mg/kg. In a polysynaptic reflex, similar but less prominent inhibitions were affected by those drugs. However, KB-2413 did not influence spinal reflexes even at a dose of 20 mg/kg. In the rat phrenic nerve-diaphragm preparation, perfusion of H1-blockers at a concentration of 10(-5) M decreased the amplitudes of end-plate potentials except for chlorpheniramine and KB-2413. At 10(-4) M, all the test drugs caused significant inhibition. When the action potential of superior cervical ganglion was measured by the sucrose gap method, promethazine inhibited the action potential significantly at 10(-6) M, but the rest of the test drugs depressed the potentials at 10(-5) M. In spontaneous EEG, all H1-blockers caused a marked drowsy pattern at lower doses (2-5 mg/kg) except for chlorpheniramine, while in higher doses (10-20 mg/kg) epileptic signs in EEG with or without convulsive behavior were noticed. However, after KB-2413 (5-20 mg/kg) neither drowsy nor seizure pattern was observed, in EEG or behavior.

Action Potentials↗
PubMed1981

Effects of antihistaminic drugs in tests for antidepressant action.

Antihistaminics of various chemical structures: chlorcyclizine, chloropyramine, chlorpheniramine, clemastine, diphenhydramine, mepyramine, promethazine, and thenalidine were investigated for the action in tests for antidepressant drugs. The antihistaminics did not affect significantly the spontaneous locomotor activity of rats. Most of them (chloropyramine, chlorpheniramine, diphenhydramine, promethazine and thenalidine) increased amphetamine hypermotility but chlorcyclizine significantly inhibited, and clemastine and mepyramine did not affect it. In mice, chlorcyclizine, mepyramine and promethazine inhibited amphetamine hypermotility, while others antihistaminics were without effect. L-DOPA-induced hypermotility in mice was inhibited by all compounds tested. With the exception of chlorpheniramine and mepyramine, all tested antihistaminics produced hypothermia in mice, although fife of them (chlorpheniramine, diphenhydramine, chlorcyclizine, chloropyramine and thenalidine) antagonized the reserpine-induced hypothermia. With the exception of mepyramine and clemastine, the compounds tested shortened the period of immobility of rats in the behavioral despair test. The results indicate that only few antihistaminics have pharmacological profile resembling tricyclic or atypical antidepressant drugs.

Amphetamine↗
PubMed1982

Drug-receptor interaction on plasmid elimination by phenothiazines and imipramine in Escherichia coli.

Plasmid elimination in Escherichia coli by a quaternary amine of chlorpromazine was demonstrated on different incompatibility groups of plasmid. The biological effect of the drug depends partly on the host bacteria and partly on the plasmid itself. Various receptor substrates such as adenosine, dopamine, histamine and norepinephrine do not alter the plasmid elimination by promethazine and imipramine. None of the known drug-receptors studied are involved in drug binding of the bacteria. The direct membrane action of imipramine and promethazine was demonstrated in electron microscopic studies and alterations in the bacterial membrane such as discontinuities, phase separation or rarely extensive lytic alterations were observed. Magnesium ions prevent the ultrastructural membrane alterations caused by imipramine and promethazine. There is some evidence that the drugs bind to two different receptor sites simultaneously on the plasmid replication site. The first and strongest binding has to be ionic through the side chain amino group, displacing the bivalent cations. In turn, the two aromatic rings of the fixed (ionically bound) drug molecules bind weakly through pi-electrons, hydrophobically or by a charge transfer complex. This weaker binding together with the ionic one are essential for biologic action and lead to the inhibition of plasmid replication. A schematic model of the effect of tricyclic psychotropic drugs on the bacterial membrane is proposed.

Binding Sites↗
PubMed1992

Investigation of anti-motion sickness drugs in the squirrel monkey.

Early attempts to develop an animal model for anti-motion sickness drugs, using dogs and cats; were unsuccessful. Dogs did not show a beneficial effect of scopolamine (probably the best single anti-motion sickness drug for humans thus far) and the findings in cats were not definitive. The authors have developed an animal model using the squirrel monkey (Saimiri sciureus) of the Bolivian phenotype. Unrestrained monkeys in a small lucite cage were tested in an apparatus that induces motion sickness by combining vertical oscillation and horizontal rotation in a visually unrestricted laboratory environment. Signs of motion sickness were scored using a rating scale. Ten susceptible monkeys (weighing 800-1000 g) were given a total of five tests each, to establish the baseline susceptibility level. Based on the anticholinergic activity of scopolamine, the sensitivity of squirrel monkey to scopolamine was investigated, and the appropriate dose of scopolamine for this species was determined. Then various anti-motion sickness preparations were administered in subsequent tests: 100 ug scopolamine per monkey; 140 ug dexedrine; 50 ug scopolamine plus 70 ug dexedrine; 100 ug scopolamine plus 140 ug dexedrine; 3 mg promethazine; 3 mg promethazine plus 3 mg ephedrine. All these preparations were significantly effective in preventing motion sickness in the monkeys. Ephedrine, by itself, which is marginally effective in humans, was ineffective in the monkeys at the doses tried (0.3-6.0 mg). The squirrel monkey appears to be a good animal model for antimotion sickness drugs. Peripherally acting antihistamines such as astemizole and terfenadine were found to be ineffective, whereas flunarizine, and an arginine vasopressin V1 antagonist, showed significant activity in preventing motion sickness.

Animals↗