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PubMed2002

An evaluation of the effects of high-dose fexofenadine on the central nervous system: a double-blind, placebo-controlled study in healthy volunteers.

BACKGROUND: As regards central nervous system (CNS) effects there are three types of antihistamines. Those that cross the blood-brain barrier and cause widespread impairment of cognitive and psychomotor function; those that cross into the brain and, although without much impairment at low clinical doses, have a dose-related relationship to impairment; and those that do not cross into the brain and therefore possess no intrinsic potential for impairing CNS function. OBJECTIVE: [corrected] To investigate the acute effects of fexofenadine (360 mg) on various aspects of cognitive and psychomotor function in comparison to placebo and promethazine (positive internal control), an antihistamine known to produce psychomotor and cognitive impairment. METHODS: Fifteen healthy volunteers received fexofenadine 360 mg, promethazine 30 mg and placebo in a 3-way cross-over, double-blind study. For each treatment condition, subjects were required to perform a series of tests of cognitive function and psychomotor performance at baseline and 1, 3, 5 and 7 h post-dose. The test battery consisted of critical flicker fusion (CFF), choice reaction time (CRT), compensatory tracking task (CTT) and a subjective assessment of sedation (LARS). RESULTS: Fexofenadine was not distinguishable from placebo in any of the objective and subjective tests for up to seven hours following drug administration. However, all measures were significantly impaired following the administration of promethazine, which confirms the sensitivity of the test battery for sedation. The effects of fexofenadine and placebo were not significantly different from one another, whereas promethazine caused an overall reduction in CFF thresholds when compared to placebo (P < 0.05). There was an overall significant increase (impairment) in recognition, motor and total reaction time (P < 0.05), and both the tracking accuracy and reaction time aspects of CTT were significantly impaired (P < 0.05) following the administration of promethazine. In contrast, the effects of fexofenadine could not be distinguished from the placebo condition. Subjective ratings of sedation were significantly higher with promethazine when compared to placebo (P < 0.05) and fexofenadine (P< 0.05). CONCLUSIONS: Fexofenadine at a dose of 360mg is demonstrably free from disruptive effects on aspects of psychomotor and cognitive function in a study where the psychometric assessments have been shown to be sensitive to impairment, as evidenced by the effects of the verum control promethazine 30 mg. The identification of an antihistamine (fexofenadine) devoid of central effects even at supraclinical doses separates it from currently available first and second generation drugs with no objective evidence of CNS side-effects on cognition and psychomotor function, and highlights the need for the introduction of a third generation of non-sedative antihistamines.

Adult↗
PubMed2001

Airway protection following simulated gastro-oesophageal reflux in sedated and sleeping neonatal piglets during active sleep.

1. In infants, promethazine has been implicated in the pathogenesis of sleep apnoea, apparent life threatening events (ALTE) and the Sudden Infant Death syndrome (SIDS). The aim of the present study was to investigate, in a neonatal animal, the effects of a commonly used promethazine-containing medication on airway protective mechanisms and cardiorespiratory reflexes following simulated gastro-oesophageal reflux (GER) to different levels in the oesophagus and pharynx. 2. Physiological and radiographic recordings were made in 21 naturally sleeping (controls) and 21 sedated (1.5 mg/kg, p.o., promethazine) piglets. On 3 consecutive days physiological recordings were made in all piglets during active sleep. Gastro-oesophageal reflux was simulated by the injection of boluses of 0.5 mL HCl, pH 2 or 3, or NaCl (0.9%) at 37 degrees C into the pharynx, upper or lower oesophagus. 3. In healthy neonatal piglets, minimal sedation with promethazine, which did not affect behaviour during wakefulness, revealed previously unreported findings during active sleep. 4. The most significant effects were observed following simulated GER to the pharynx, with no effect observed in the lower oesophagus. In sedated piglets, compared with naturally sleeping piglets, there was a significant reduction in swallowing (P < 0.01), delayed radiological clearance of fluid (P < 0.05), a reduction in breathing rate, oxygen saturation and heart rate and an increase in apnoea. 5. These findings are consistent with a low dose of promethazine producing a significant attenuation of airway protective mechanisms and, thus, stimulation of the laryngeal chemoreflex. The results suggest a mechanism for the association observed between promethazine use and the occurrence of ALTE and SIDS. The results support continued caution and suggest the need for greater regulation of promethazine-containing medications in infants.

Animals↗
PubMed2001

An investigation into the effects of cetirizine on cognitive function and psychomotor performance in healthy volunteers.

OBJECTIVE: The cognitive and psychomotor effects of 2.5, 5 and 10 mg cetirizine, a second-generation H1 receptor antagonist, were compared with loratadine 10, 20 and 40 mg, promethazine 25 mg and placebo in 24 healthy volunteers in a double-blind, randomised cross-over study. METHODS: Following each dose, subjects were required to perform a series of tests of cognitive function and psychomotor performance at 1.5, 3 and 6 h post-dose. The test battery consisted of critical flicker fusion (CFF), choice reaction time (CRT), compensatory tracking task (CTT) and assessment of subjective sedation (LARS). RESULTS: Cetirizine and loratadine at all doses tested were not significantly different from placebo in any of the tests used. However, as expected for a verum, all measures with the exception of CTT were significantly disrupted by promethazine (P < 0.05). Promethazine caused a reduction in CFF threshold at all test points; these differences were significant at 3 h and 6 h post-dose (P < 0.05). There was also a significant increase in total reaction time at 3 h post-promethazine administration. Subjective reports of sedation were significantly greater following the administration of promethazine at all time points (P < 0.05). CONCLUSIONS: These results allow the conclusion that cetirizine at its recommended therapeutic dose of 10 mg is demonstrably free from disruptive effects on aspects of psychomotor and cognitive function in a study where the psychometric assessments have been shown to be sensitive to impairment, as evidenced by the effects of the positive control, promethazine 25 mg.

Adult↗
PubMed1976

On the anticataleptic action of cyproheptadine.

The anticataleptic action of cyproheptadine, a tricyclic compound known as antiserotonin, anticholinergic and antihistaminic drug in comparison to that of atropine, promethazine, imipramine, desipramine, chlorimipramine and nomifensine was studied in rats. The catalepsy induced by spiperon, pimozide or fluphenazine was antagonized by cyproheptadine, atropine and promethazine. Imipramine and nomifensine were less active, desipramine and chlorimipramine without effect. The reserpine- and alpha-methyltyrosine-catalepsy was counteracted by cyproheptadine, promethazine and nomifensine, but not by atropine or tricyclic antidepressants. Only cyproheptadine and promethazine antagonized the catalepsy caused by a combined treatment with reserpine and alpha-methyltyrosine. The pilocarpine-catalepsy was abolished by atropine, promethazine and nomifensine and unaffected by tricyclic antidepressants. Atropine and promethazine antagonized also the physostigmine-catalepsy. The catalepsy induced by both cholinomimetic drugs was not changed or increased by cyproheptadine. The results presented indicate that cyproheptadine differs in its anticataleptic activity from all the drugs used for comparison. Possible mechansims of this activity are discussed.

Animals↗
PubMed1968

The inhibitory effects in vitro of phenothiazines and other drugs on lipid-peroxidation systems in rat liver microsomes, and their relationship to the liver necrosis produced by carbon tetrachloride.

1. The effects of several phenothiazine derivatives on lipid-peroxidation systems in rat liver microsomes were studied and the results are considered in relation to the hepatotoxic action of carbon tetrachloride. 2. The lipid-peroxidation system coupled to NADPH(2) oxidation and stimulated by an ADP-Fe(2+) mixture is strongly inhibited in vitro by promethazine (50% inhibition at 29mum). Chlorpromazine and Stelazine also inhibit the peroxidation system but are less effective than promethazine. 3. The effects of promethazine on three other systems involving oxygen uptake (sulphite oxidation, orcinol oxidation and mitochondrial succinate oxidation) were also studied. Promethazine does not inhibit these systems to the same extent as it does the NADPH(2)-ADP-Fe(2+) lipid-peroxidation system. 4. Promethazine also produces an inhibition of the NADPH(2)-ADP-Fe(2+) system in liver microsomes after administration in vivo. It is concluded that the inhibition involves the interaction of the drug (or a metabolite of it) with the microsomal electron-transport chain. 5. Several other compounds known to protect the rat against liver necrosis after the administration of carbon tetrachloride were tested for inhibitory action on the NADPH(2)-ADP-Fe(2+) system. No clear correlation was observed between effectiveness in vivo as a protective agent and inhibitory effects on the NADPH(2)-ADP-Fe(2+) system in vitro. 6. Promethazine was found to inhibit the stimulation of lipid peroxidation produced in rat liver microsomes by low concentrations of carbon tetrachloride. This effect occurs at a concentration similar to that observed in vivo after administration of a normal clinical dose.

Adenine Nucleotides↗
PubMed1991

In vivo effects of some histamine H1-receptor antagonists on monoamine metabolism in the mouse brain.

The in vivo effects of four H1-antagonists, diphenhydramine, chlorpheniramine, mepyramine, and promethazine, on the metabolism of noradrenaline (NA), dopamine (DA), and 5-hydroxytryptamine (5-HT) were investigated in the whole mouse brain. Diphenhydramine and chlorpheniramine had no significant effect on levels of NA, 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), DA, and 5-HT, but they significantly decreased levels of 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA). In particular chlorpheniramine markedly decreased 5-HIAA levels at doses as low as 1 mg/kg, i.p. Mepyramine significantly decreased 5-HIAA levels but not those of other substances. High doses of promethazine significantly decreased NA levels but markedly increased those of MHPG, DOPAC, HVA, 5-HT, and 5-HIAA. The DA reduction induced by alpha-methyl-p-tyrosine (alpha-MT) was significantly inhibited by diphenhydramine, chlorpheniramine, and promethazine, but the alpha-MT-induced NA decrease was significantly enhanced by promethazine. The 5-HIAA accumulations induced by probenecid were significantly inhibited by chlorpheniramine and mepyramine. These results suggest: (1) Diphenhydramine and chlorpheniramine inhibit the turnover of both DA and 5-HT by blocking their neuronal uptake. (2) Promethazine and mepyramine inhibit DA and 5-HT turnover, respectively, as a result of the inhibition of the uptake mechanism. (3) Promethazine increases NA turnover by enhancing NA release. The discriminative effects of these drugs on the monoamine systems may be related to some differences in their CNS actions.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1993

Comparison of treatment strategies for Space Motion Sickness.

Treatment strategies for Space Motion Sickness (SMS) were compared using the results of postflight oral debriefings. Standardized questionnaires were administered to all crewmembers immediately following Space Shuttle flights by NASA flight surgeons. Cases of SMS were graded as mild, moderate, or severe based on published criteria, and medication effectiveness was judged based on subjective reports of symptom relief. Since October 1989, medication effectiveness is reported inflight through Private Medical Conferences with the crew. A symptom matrix was analyzed for 19 crewmembers treated with oral combination of scopolamine and dextroamphetamine (scopdex) and 15 crewmembers treated with promethazine delivered by intramuscular i.m. or suppository routes. Scopdex has been given preflight as prophylaxis for SMS, but analysis showed delayed symptom presentation in 9 crewmembers or failed to prevent symptoms in 7. Only 3 crewmembers who took scopdex had no symptoms inflight. Fourteen out of 15 crewmembers treated with i.m. promethazine and 6 of 8 treated with promethazine suppositories after symptom development had immediate (within 1-2 h) symptom relief and required no additional medication. There were no cases of delayed symptom presentation in the crewmembers treated with promethazine. This response is in contrast to untreated crewmembers who typically have slow symptom resolution over 72-96 h. We conclude that promethazine is an effective treatment of SMS symptoms inflight. NASA policy currently recommends treating crewmembers with SMS after symptom development, and no longer recommends prophylaxis with scopdex due to delayed symptom development and apparent variable absorption of oral medications during early flight days.

Aerospace Medicine↗
PubMed2003

Enhancement of plasmid curing by 9-aminoacridine and two phenothiazines in the presence of proton pump inhibitor 1-(2-benzoxazolyl)-3,3,3-trifluoro-2-propanone.

Plasmid-containing bacteria often cause serious therapeutic failure during the treatment of infectious diseases. The selection of resistant-mutant strains and the transfer of mobile genetic determinants (such as plasmids and transposons) of resistance promote increased antibiotic resistance. In the last 30 years the antiplasmid effect of acridine dyes, ethidium bromide, sodium dodecyl sulphate and phenothiazines was described. The main aim of this study was to test the mechanism of the antiplasmid effect of promethazine and 9-aminoacridine on doxycycline-resistant enteric bacteria. The antiplasmid effects of promethazine and 9-aminoacridine were studied on plasmid elimination of native plasmid DNA and plasmid DNA isolated from drug-treated cells of plasmid-containing Escherichia coli, Citrobacter freundii and Enterobacter cloacae. The effects of some phenothiazines on plasmid profiles of bacterial strains isolated from urinary tract infections were analysed by agarose gel electrophoresis. Various complex of plasmid DNA were identified in the presence of promethazine, trifluoperazine and 9-aminoacridine in the agarose gel electrophoresis. Doxycycline resistance of tested enteric bacteria was the target of "curing" in the presence of promethazine and trifluoperazine. The frequency of elimination of tetracycline resistance was low despite the formation of antiplasmid compounds complex with isolated plasmid DNA. Tetracycline resistance plasmid was isolated and re-transformed. The plasmid curing effects of promethazine, trifluoperazine and 9-aminoacridine were increased in the presence of a trifluoroketone proton pump inhibitor on E. coli K12 LE140 strain in a model experiment. We propose that the inefficient penetration of antiplasmid compounds could be responsible for the weak plasmid-curing effect in some clinical isolates and that membrane active, calmodulin- and proton pump inhibitors may be combined for plasmid curing in antibiotic-resistant bacteria.

Acetone↗
PubMed2002

Nanoparticles in plant extracts: influence of drugs on the formation of nanoparticles and precipitates in black tea infusions.

The influence of the neuroleptics fluphenazine and promethazine on the formation of nanoparticles in aqueous tea infusions was investigated using photon correlation spectroscopy. Formation of nanoparticles and of precipitates was observed in decaffeinated tea and caffeine-containing tea. The amount of drug in the nanoparticle fraction was determined at different starting concentrations using high-performance liquid chromatography. In the case of fluphenazine, between 8 and 30% are assigned to the nanoparticles fraction, in the case of promethazine between 30 and 56%. The concentration of free active principle is reduced by about 99% for fluphenazine or by about 90% for promethazine. A loss of pharmacological activity of the neuroleptics is probable. The addition of promethazine to infusions of caffeine containing tea resulted in the formation of nanoparticles with a small size distribution; their mean size was comparable to the diameter of nanoparticles in pure tea infusions. In the case of fluphenazine the mean particle size grew with increasing concentration. Adding promethazine to infusions of decaffeinated tea resulted in the formation of nanoparticles with a broad size distribution. Two different size classes were formed after addition of fluphenazine. Caffeine and neuroleptics both take part in the formation of nanoparticles in caffeine containing tea. The particles were visualized using scanning electron microscopy. Molecular modelling calculations were performed to investigate probable geometries between neuroleptics and thearubigins.

Caffeine↗
PubMed1985

Effect of tricyclic drugs on mitochondrial membrane.

The effects of tricyclic drugs (clomipramine, imipramine, chlorpromazine and promethazine) on isolated liver mitochondria of rats were examined. All the drugs tested accelerated state 4 respiration. Their stimulative potency at concentrations below 100 microM was in the order of chlorpromazine greater than clomipramine greater than imipramine, promethazine. On state 3 respiration, the chlorine containing drugs had an inhibitive effect at high concentrations, while the other drugs seemed to have a slightly stimulative effect. These drugs stimulated latent ATPase activity of mitochondria. Clomipramine and chlorpromazine inhibited 2, 4-dinitrophenol-stimulated ATPase activity in a dose-dependent fashion. Imipramine also inhibited 2, 4-dinitrophenol-stimulated ATPase activity at high concentrations. Promethazine, however, had almost no effect. All the drugs induced potassium release from mitochondrial vesicles, and their potency was in the order of clomipramine greater than chlorpromazine greater than imipramine greater than promethazine. These results suggest that clomipramine, imipramine, chlorpromazine and promethazine cause impediments in both mitochondrial respiration and ion compartmentation, and that the chlorine containing drugs are more toxic than others on the functions of the mitochondrial membrane.

Adenosine Triphosphatases↗
PubMed1992

Comparison of treatment strategies for Space Motion Sickness.

Treatment strategies for Space Motion Sickness were compared using the results of postflight oral debriefings. Standardized questionnaires were administered to all crewmembers immediately following Space Shuttle flights by NASA flight surgeons. Cases of Space Motion Sickness were graded as mild, moderate or severe based on published criteria, and medication effectiveness was judged based on subjective reports of symptom relief. Since October 1989, medication effectiveness is reported inflight through Private Medical Conferences with the crew. A symptom matrix was analyzed for 19 crewmembers treated with an oral combination of scopolamine and dextroamphetamine (scopdex) and 15 crewmembers treated with promethazine delivered by intramuscular (IM) or suppository routes. Scopdex has been given preflight as prophaxis for Space Motion Sickness but analysis showed delayed symptom presentation in 9 crewmembers or failed to prevent symptoms in 7. Only three crewmembers who took scopdex had no symptoms inflight. Fourteen out of 15 crewmembers treated with IM promethazine and 6 of 8 treated with promethazine suppositories after symptom development had immediate (within 12 h) symptom relief and required no additional medication. There were no cases of delayed symptom presentation in the crewmembers treated with promethazine. This response is in contrast to untreated crewmembers who typically have slow symptom resolution over 72-96 h. We conclude that promethazine is an effective treatment of Space Motion Sickness symptoms inflight. NASA policy currently recommends treating crewmembers with Space Motion Sickness after symptom development, and no longer recommends prophylaxis with scopdex due to delayed symptom development and apparent variable absorption of oral medications during early flight days.

Aerospace Medicine↗
PubMed1988

On the interaction between H1- and H2-histaminergic receptors in the histamine release and the realization of its vascular effects in rat skin.

The influence of the H1- and H2-histaminergic blockers promethazine and cimetidine, respectively, as well as of a combination of both drugs on the histamine release from rat ear skin, induced by compound 48/80, was studied. Cimetidine did not interfere with the effects of comp. 48/80, while promethazine increased almost three times the histamine-releasing effects of comp. 48/80. This effect of promethazine was reduced when the latter was combined with cimetidine. Cimetidine and promethazine did not produce any per se effect on the histamine content of the ear skin tissue. The two histaminergic blockers antagonized the vasodilation induced by exogenous histamine injected intradermally, the combination of the drugs in the higher dose used being most efficient. The effect of the combination was more pronounced as compared to that of promethazine when applied alone in the corresponding dose (25 mg/kg) and was almost equal to the effect of cimetidine administered alone in a dose of 200 mg/kg. The results suggest an important role for H2-histaminergic receptors in the skin vessels of rat as well as in the prevention of the mast cell degranulation at least in cases when it is induced by comp. 48/80.

Animals↗
PubMed1985

Evaluation of antimotion sickness drug side effects on performance.

This project has employed a computerized pursuit meter which has a high correlation with operational performance (2) to test the principal antimotion sickness drugs. Proficiency scores on the pursuit meter task were improved over placebo scores in subjects with d-amphetamine 10 mg and 5 mg, the combination of promethazine 25 mg plus scopolamine 0.4 mg with d-amphetamine 10 mg, and the combination of scopolamine 1 mg with d-amphetamine 10 mg. Scores were not significantly different from placebo scores in tests with scopolamine 0.25 mg, 0.5 mg, or 0.6 mg; marezine 50 mg; meclizine 50 mg; or dimenhydrinate 50 mg. This was also true for the combination of scopolamine 1 mg with d-amphetamine 5 mg, and that of promethazine 25 mg with d-amphetamine 10 mg. A statistically significant decrement of performance scores was seen with scopolamine 1 mg or 0.8 mg, and with promethazine 25 mg oral or 25 mg I.M. The combination of promethazine 25 mg with scopolamein 0.4 mg, and that of promethazine 25 mg oral plus 25 mg I.M. with d-amphetamine 10 mg, also gave significant decrements from placebo scores. These results indicate that selected doses and combinations of antimotion sickness drugs can be used without loss of operational proficiency.

Adolescent↗
PubMed1995

Interaction between tricyclic psychopharmacons and some antibiotics.

The tricyclic psychopharmacons, e.g. clozapine, promethazine and imipramine cure plasmids and inhibit plasmid transfer among bacteria due to the inhibition of supercoiling activity on DNA gyrase. In addition an interaction was found between clozapine, imipramine, promethazine and some antibiotics, e.g. penicillins and tetracycline in vitro. The nature of interaction is based on a charge transfer complex, which is formed between clozapine, imipramine, promethazine and penicillins. Differential spectrophotometry showed that ampicillin reduced the highest energy peaks of clozapine, promethazine and imipramine. Streptomycin did not alter the spectrum of clozapine; however, tetracycline somewhat reduced all the peaks of clozapine. Clozapine and promethazine exhibited a synergistic effect with ampicillin, tetracycline and gentamicin on Escherichia coli cells in in vitro. This kind of interaction was missing in the case of imipramine.

Anti-Bacterial Agents↗
PubMed1997

Chloroquine-induced pruritus in malaria fever: contribution of malaria parasitaemia and the effects of prednisolone, niacin, and their combination, compared with antihistamine.

AIMS: Chloroquine treatment of malaria fever, results in a generalized pruritus of unknown mechanism in up to 60% of adult Africans, by contrast pruritus is unusual in Caucasians following chloroquine use. METHODS: We conducted a double-blind, randomized, parallel group study to examine and compare the antipruritic effects of promethazine, niacin, prednisolone and their combination on pruritus induced by chloroquine, in 28 historical itching patients with parasitologically proven malaria fever. We also evaluated the role of the antecedent malaria parasite density in the severity of chloroquine pruritus intensity. RESULTS: The concurrent administration of chloroquine (2.1 g base total dose) with prednisolone caused a statistically significant reduction in the pruritus AUC (0, 72 h) (P < 0.001 ANOVA) compared with the antihistamine promethazine alone. The areas under the pruritus intensity-time curve were promethazine 105 +/- 28 (units h), niacin 76 +/- 22, prednisolone 28 +/- 24, and prednisolone and niacin 34 +/- 17 (P < 0.001 ANOVA). The 95% confidence interval for the difference in the pruritus AUC between prednisolone and promethazine was 8.4 to 145.6 units h. There was a statistically significant and positive correlation between the pruritus intensity (AUC 0, 72 h) and the malaria parasite load in the itching subjects, not receiving prednisolone (n = 9) (r = 0.73, P = 0.026 ANOVA). CONCLUSION: A single oral dose of prednisolone (10 mg) may be preferable to the antihistamine promethazine (25 mg) as an antipruritic agent for concurrent prescription with chloroquine in individuals predisposed to severe itching. Malaria parasite clearance and clinical amelioration were unaffected by any of the treatments.

Adult↗
PubMed1998

Antitussive action of antihistamines is independent of sedative and ventilation activity in the guinea pig.

We studied the oral actions of antihistamines from six chemical classes, namely: the ethanolamines (ENA, diphenhydramine and clemastine); ethylenediamines (EDA, pyrilamine and tripelennamine); piperidines (PPD, terfenadine and astemizole); piperazines (PPZ, hydroxyzine and cetirizine); phenothiazines (PTZ, promethazine), and the alkylamines (ALA, chlorpheniramine and bromopheniramine) on cough reflexes, pentobarbital-induced sedation and minute ventilation in the conscious guinea pig. Antihistamines of the ENA class had minimal effects on capsaicin-induced cough although both diphenhydramine (30 and 100 mg/kg p.o.) and clemastine (30 and 100 mg/kg p.o.) increased sedation time (ST). The PPZ class demonstrated both antitussive and sedating activity. The minimum effective oral antitussive dose (MED) of cetirizine and hydroxyzine was 30 and 10 mg/kg, respectively. The EDA did not exhibit antitussive activity. Tripelennamine (10, 30 and 100 mg/kg p.o.) but not pyrilamine enhanced ST. The MED for the PTZ, promethazine, was 10 mg/kg, and at 100 mg/kg promethazine increased ST. The ALA group displayed antitussive activity but only chlorpheniramine (10 mg/kg p. o.) had any effects on ST. The MED for chlorpheniramine and bromopheniramine was 3 and 10 mg/kg p.o., respectively. The PPD antihistamines, namely terfenadine and astemizole, inhibited cough (MED 30 and 10 mg/kg p.o.) without sedative effects. Of the antihistamines tested only promethazine (100 mg/kg p.o.) depressed ventilation responses; however, this dose of promethazine was associated with adverse behavioral effects. The present findings indicate that the antitussive actions of antihistamines are not directly related to histamine H1-receptor blockade because several antihistamines did not antagonize capsaicin-induced cough. In addition, the antitussive actions of antihistamines are independent of their sedative or ventilation effects.

Administration, Oral↗
PubMed1963

On the nature of the chemical mediators involved in anaphylactic reactions in mice.

The effects of mepyramine, promethazine, chlorpromazine and lysergic acid diethylamide have been compared on the capillary permeability changes of the skin, produced by histamine, by 5-hydroxytryptamine and by passive cutaneous anaphylaxis in mice. Promethazine, mepyramine and chlorpromazine can inhibit, in decreasing order of activity, the effect of histamine, whilst lysergic acid diethylamide is inactive. Lysergic acid diethylamide and chlorpromazine are equally potent inhibitors of the action of 5-hydroxytryptamine on the peripheral vascular bed, whilst mepyramine is inactive. Promethazine has intermediate activity. Passive cutaneous anaphylaxis is strongly inhibited by chlorpromazine and by promethazine. Mepyramine and lysergic acid diethylamide, each injected alone, affect only weakly the anaphylactic reaction. However, passive cutaneous anaphylaxis is almost completely abolished by the simultaneous injection of the two last antagonists. It is suggested that the anaphylactic reaction in mice is the result of simultaneous release of both mediators, histamine and 5-hydroxytryptamine, each of them strengthening the effect of the other.

Anaphylaxis↗
PubMed1997

Inhibition of lung surfactant secretion from alveolar type II cells and annexin II tetramer-mediated membrane fusion by phenothiazines.

We investigated the effects of phenothiazines on lung surfactant secretion from rat alveolar epithelial type II cells and on annexin II tetramer (Anx IIt)-mediated membrane fusion. Trifluoperazine and promethazine inhibited ATP-stimulated phosphatidylcholine (PC) secretion from type II cells in a dose-dependent manner. Concentrations that cause 50% inhibition (IC50) were approximately 3 and 25 microM for trifluoperazine and promethazine, respectively. Promethazine also inhibited PC secretion of type II cells stimulated by other secretagogues, including calcium ionophore A23187, phorbol 12-myristate 13-acetate, and terbutaline that are known to stimulate PC secretion via different signal transduction pathways. Since we have recently determined that Anx IIt is involved in PC secretion of type II cells, we examined whether phenothiazines influence Anx IIt's activity. Trifluoperazine and promethazine inhibited Anx IIt's ability to aggregate phosphatidylserine (PS) liposomes, to fuse PS/phosphatidylethanolamine (PE) liposomes, and to fuse PS/PE liposomes with lamellar bodies. These results suggest a relationship between lung surfactant secretion and Anx IIt-mediated membrane fusion.

Adenosine Triphosphate↗