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PubMed1984

Reversible effects of phenothiazines on frog gastric stimulation.

The calmodulin inhibitors trifluoperazine (TFP), chlorpromazine (CPZ), and promethazine (PZ) were tested for effects on stimulus-secretion coupling in in vitro bullfrog gastric mucosa. When added to histamine-stimulated tissues, the drugs caused H+ secretion to decrease and transepithelial resistance to increase over a 2-h time course. The potency sequence was TFP (IC50 = 40 microM) greater than CPZ (IC50 = 72 microM) congruent to PZ (IC50 = 72 microM). Anesthetics and other phenothiazines with weak anticalmodulin activity had no effect on secretory parameters. In the presence of histamine, further addition of isobutylmethylxanthine (IBMX, a phosphodiesterase inhibitor) plus dibutyryl cAMP (DBcAMP), IBMX alone, or forskolin (a specific activator of adenylate cyclase) to phenothiazine-inhibited tissues caused full resumption of secretory activity. If TFP (50 microM) was added before stimulation with histamine, the normal increases in tissue cAMP content (which occurs primarily in oxyntic cells), oxyntic cell apical membrane elaboration (morphometric analysis of electron micrographs), and H+ secretion were all blocked. Subsequent addition of IBMX or IBMX plus DBcAMP completely reversed the TFP effect. These results indicate that the histamine-sensitive adenylate cyclase may be the site of TFP inhibition and Ca2+-calmodulin regulation; since these drugs inhibited stimulation by DBcAMP plus IBMX, they may also be exerting additional effects distal to cAMP generation.

Anesthetics, Local↗
PubMed1988

Ca2+ - and cAMP-induced protein phosphorylation in lacrimal gland basolateral membranes.

Basolateral plasma membranes play an integral role in coupling of stimulus to secretion of fluid and protein from the lacrimal gland. To determine if basolateral plasma membranes contain Ca2+- or adenosine 3', 5'-cyclic monophosphate (cAMP)-dependent protein kinases, which could phosphorylate specific proteins important for secretion, a purified preparation of basolateral plasma membranes was prepared from rat exorbital lacrimal glands by differential and density gradient centrifugation. Phosphorylation of basolateral plasma membrane proteins was studied in the presence of [gamma-32P]ATP and was analyzed by sodium dodecyl sulfate-poly-acrylamide gel electrophoresis. Increasing the Ca2+ concentration in the presence of calmodulin stimulated phosphorylation of a 52,000-Mr peptide with a maximal increase in phosphorylation obtained at 3 and 66 microM free Ca2+. The phenothiazines trifluoperazine and promethazine inhibited phosphorylation of this 52,000-Mr peptide; 50% inhibition was obtained at 15 and 95 microM, respectively. Increasing the cAMP level from 0 to 10 microM stimulated phosphorylation of another peptide of 91,000 Mr. This effect could be reproduced by guanosine 3', 5'-cyclic monophosphate, but only at 100 microM. The cAMP concentration causing 50% of maximal phosphorylation was 0.3 microM. We conclude that lacrimal gland basolateral plasma membranes contain Ca2+/calmodulin- and cAMP-dependent protein kinases and protein substrates.

Adenosine Triphosphate↗
PubMed1983

Phenothiazine protection in calcium overload-induced heart failure: a possible role for calmodulin.

The effect of several phenothiazines on the extent of cellular damage resulting from the calcium paradox was examined. Hearts treated with trifluoperazine, a potent calmodulin inhibitor, exhibited less cellular damage than untreated myocardium as reflected by light microscopy, high-energy phosphate content and the loss of protein and creatine phosphokinase into the perfusate. A dose response of this effect revealed a maximal response at about 1 microM trifluoperazine, a concentration which lies well within the range generally attributed to calmodulin inhibition. Several other lines of evidence were also obtained suggesting a possible role for calmodulin in calcium-overload induced necrosis. First, the phenothiazines had little influence on membrane changes believed responsible for altered calcium permeability. Second, trifluoperazine was without major effect unless included in the reperfusion buffer, indicating that the drug is only effective during the phase associated with calcium overload. Finally, less protection was afforded hearts exposed to phenothiazines such as chlorpromazine and promethazine, which are weaker inhibitors of calmodulin, than those treated with the potent inhibitor trifluoperazine. While other interpretations are possible, these studies are consistent with a role for calmodulin in calcium overload-induced heart failure.

Animals↗
PubMed1988

Respiratory effects of cigarette smoke, dust, and histamine in newborn rabbits.

We studied the respiratory effects of cigarette smoke, 5% histamine aerosol, and dust in unanesthetized 1- to 7-day-old rabbits in a body plethysmograph. Cigarette smoke immediately provoked the animal's arousal and irregular breathing. Histamine and dust had no effect in some of the youngest animals. In others, 5-15 s from the onset of the exposure to either of the two stimuli, respiratory rate increased and the depth of breathing decreased. These changes were more pronounced with age. The fact that effects of dust and aerosol lessened with time of exposure showed adaptation to the stimuli. The age dependence of the reflex response was also observed after injection of 50 micrograms of histamine per kilogram into the external jugular vein in anesthetized (50 mg ketamine + 3 mg acepromazine per kg) and tracheostomized rabbits during the 1st wk of life. In 1-day-old animals, a short-lasting excitation was followed by apnea or a prolongation of expiratory phase. Peak amplitude of the diaphragmatic EMG (EMGdi) increased in all animals, but only in the youngest was the EMGdi increase paralleled by an increase in tidal volume. In vagotomized animals or animals pretreated with H1-blocker, histamine never affected timing parameters in animals greater than 1 day old. In the youngest animals, respiratory depression due to histamine was not abolished after vagotomy or promethazine. The results imply that inputs from the upper airways and the rapidly adapting pulmonary mechanoreceptors exert their effects on the pattern of breathing immediately after birth in rabbits. The importance of those inputs increases with maturation.

Aerosols↗
PubMed1989

Cyclooxygenase blockers inhibit ethanol-induced pulmonary vasoconstriction in lambs.

We investigated the mechanism of ethanol-induced pulmonary vasoconstriction in lambs, by a pharmacological approach. We chronically instrumented 28 lambs to determine whether phentolamine (alpha-block), propranolol (beta-block), promethazine and cimetidine (H1- and H2-block), high-dose indomethacin, or low- and high-dose meclofenamate (cyclooxygenase block) altered the vasoconstriction. Ethanol alone increased pulmonary vascular resistance from 0.14 to 0.49 Torr.ml-1.kg-1.min (U). Only indomethacin (7-8 mg/kg po) and high-dose meclofenamate (7-8 mg/kg iv) abolished the pulmonary vascular response to ethanol infusion. Pulmonary vascular resistance was 0.14 U after ethanol plus indomethacin and was 0.2 U after ethanol plus high-dose meclofenamate (P = NS vs. base line). Low-dose meclofenamate (2 mg/kg) attenuated the vasoconstrictor response. Systemic vascular resistance increased moderately after ethanol and had a similar pattern of inhibition by cyclooxygenase blockade. Cardiac output and heart rate decreased nearly significantly after ethanol (P less than 0.06), a tendency that was also ablated by cyclooxygenase inhibition. Thus the acute cardiocirculatory response to ethanol involves an intact prostaglandin synthase system in lambs. To our knowledge, these data are the first documentation that cyclooxygenase enzyme blockade can eliminate the acute cardiac and vascular effects of ethanol in a whole-animal system.

Adrenergic alpha-Antagonists↗
PubMed1996

Histamine depolarizes cholinergic septal neurons.

1. Bath application of 10 microM histamine (HA) resulted in a depolarization or inward current in 58/59 cholinergic neurons located in the medial septum and nucleus of the diagonal band of Broca (MS/DBB) in a slice preparation of rat brain. 2. In bridge mode, the histamine-induced depolarization consisted of both fast and slow phases; inward currents that followed the comparable time course were observed under voltage-clamp conditions. The fast depolarization was associated with variable changes in input resistance, while the slow depolarization always was associated with an increase in input resistance. 3. Both fast and slow responses persisted in the presence of tetrodotoxin (TTX), but only the fast response persisted when transmitter release was abolished by bathing the slice in either a low-Ca(2+)-, high-Mg(2+)-containing medium or one containing Cd2+. 4. When ramp voltage-clamp commands were applied during the fast depolarization, the resultant current-voltage (I-V) curves did not intersect over the range of membrane potentials from -130 to -30 mV. Ionic substitution experiments suggested that the bulk of the ionic current flowing during the fast depolarization was carried by sodium ions. 5. The I-V characteristics of the slow inward current identified it as a reduction in an inwardly rectifying potassium conductance. 6. The fast depolarization was significantly reduced by the H1 receptor antagonists pyrilamine and promethazine, but not by the H2 receptor antagonist cimetidine. Neither the H2 receptor agonist impromidine nor the H3 receptor agonist R-alpha-methylhistamine mimicked the response to HA. None of the agonists or antagonists had any observable effect upon the slow depolarization. 7. We conclude that HA directly depolarizes cholinergic MS/DBB neurons by acting as an H1 receptor, which primarily couples to an increase in a TTX-insensitive Na+ conductance. Additionally, HA evokes a slow depolarization mediated by a decrease in an inwardly rectifying potassium conductance but is not generated by activation of classically defined HA receptor subtypes.

Acetylcholine↗
PubMed2004

Success of acupuncture and acupressure of the Pc 6 acupoint in the treatment of hyperemesis gravidarum.

OBJECTIVE: The aim of this study was to evaluate the antiemetic effect of acupuncture (AP) and acupressure (APr) of the Pc 6 acupoint in pregnant women with hyperemesis gravidarum (HG). METHODS: A prospective, placebo-controlled trial included 36 pregnant women with HG. Two methods of acupuncture were used: bilateral manual AP of the Pc 6 (Neiguan) acupoint (group 1, n = 10) and bilateral APr of the Pc 6 acupoint (group 2, n = 11); furthermore, superficial intracutaneous placebo AP (group 3, n = 8) and placebo APr (group 4, n = 7) was carried out. RESULTS: Anxiodepressive symptoms occurred in 9 pregnant women with HG from group 1, 8 women from group 2, 7 women from group 3, and 5 women from group 4 (p < 0.001). The average gestation age at the occurrence of HG symptoms and the beginning of treatment was 7 weeks in group 1 and 8 weeks in groups 2, 3, and 4. Four women from group 1 and 7 women from groups 2, 3, an 4 needed intravenous compensation of liquid and electrolytes. The antiemetic metoclopramide was given intravenously to 1 woman from group 1, 2 women from group 2, 6 women from group 3, and 4 women from group 4. Promethazine was given to 1 woman from group 2, 1 woman from group 3, and to 3 women from group 4. The efficiency of the HG treatment with AP of the point Pc 6 was 90%, with APr of the Pc 6 63.6%, with placebo AP 12.5%, and with placebo APr 0%. CONCLUSION: Acupuncture (p < 0.0001) and acupressure (p < 0.1) are effective, nonpharmacologic methods for the treatment of HG.

Acupressure↗
PubMed1994

Systemically administered histamine H1 and H2 receptor antagonists do not block the ACTH response to bacterial lipopolysaccharide and interleukin-1.

The administration of lipopolysaccharide (LPS) results in the activation of the hypothalamic-pituitary-adrenal axis (HPAA). We recently reported that the participation and interaction of LPS-induced proinflammatory cytokines were obligatory for the stimulation of adrenocorticotropic hormone (ACTH) release by LPS. LPS and LPS-derived cytokines also stimulate the release of histamine (HA). HA is a known hypothalamic neurotransmitter and activates the HPAA. Therefore, to elucidate the role of HA in LPS- and cytokine-induced ACTH release, we evaluated the effects of several HA H1 and H2 receptor antagonists on the ACTH response to LPS, recombinant human interleukin-1 alpha (rhIL-1 alpha) and HA in mice. Although all 3 of the H1 receptor antagonists administered (mepyramine (MEP), diphenhydramine (DPH) or promethazine (PMZ) were able to block the 10-min ACTH response to HA, only PMZ (a less selective H1 receptor antagonist than MEP) was able to reduce the LPS- or rhIL-1 alpha-induced ACTH responses. Ranitidine, a powerful and selective H2 receptor antagonist, had little effect on the LPS- and rhIL-1 alpha-induced ACTH responses, while metiamide (MET), a much less potent first-generation H2 receptor antagonist, substantially diminished ACTH release. The greater effectiveness of PMZ, in contrast to MEP or DPH, probably relates to the ability of phenothiazine derivatives to inhibit non-HA-dependent pathways involved in the stimulation of the HPAA by cytokines; the same may be true of MET.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenocorticotropic Hormone↗
PubMed1982

Catalepsy produced by long-acting neuroleptics, fluphenazine enanthate and fluphenazine decanoate, in mice.

The cataleptic state induced by the depot-type preparations of fluphenazine (FZ) was investigated in mice. Intramuscular injections of FZ-enanthate or FZ-decanoate produced a marked and long-lasting catalepsy, which was antagonized by trihexyphenidyl, biperiden and promethazine but not by l-dopa. These anticataleptic effects disappeared after several hours and catalepsy occurred again. The cataleptic effects of FZ-enanthate and FZ-decanoate were increased by (D-Ala2, MePhe4, Met(0)5-ol)-enkephalin, aminooxyacetic acid and haloperidol. The results indicate that the cataleptic effects of FZ-enanthate and FZ-decanoate correspond with their long duration of antipsychotic effects and that the catalepsy may involve enkephalinergic, GABAergic and cholinergic as well as dopaminergic neuron activity.

Aminooxyacetic Acid↗
PubMed1989

Effect of histamine on chemotaxis and phagocytosis of human alveolar macrophages and blood monocytes.

We studied in vitro the effect of histamine on the chemotactic and phagocytic abilities of human blood monocytes and alveolar macrophages. The chemotactic response to activated autologous serum, leukotriene B4 or N-formyl-methionine-L-phenylalanine was similar for macrophages and monocytes. Incubation of monocytes with histamine in picomolar concentrations caused a significant chemotactic inhibition (about 25%). This effect was antagonized by cimetidine but not by promethazine. Histamine did not have an effect on alveolar macrophages chemotaxis or phagocytosis. Thus, histamine, in minute concentrations, exerts, in vitro, a partial inhibitory effect on monocyte chemotaxis through activation of H2-type receptors.

Chemotaxis, Leukocyte↗
PubMed1986

Fetal transfusion.

In the Rh-sensitized pregnancy, direct treatment of the fetus has been practiced for over two decades. Although Rh immune prophylaxis has markedly decreased the incidence of Rh sensitization, there are still fetal deaths due to this disease. Current management of the severe form of Rh disease includes serial transabdominal intrauterine transfusions, preterm delivery and intensive neonatal care. Heart failure in the fetus may be treated by administering medications to the mother. Ascites or pericardial effusion are easy to detect with ultrasound imaging. Digoxin and diuretics have been used to reverse the ultrasound evidence of fetal congestive heart failure. Recently, direct fetal intravascular transfusion by fetoscopy has proven effective. In some instances, hydrops fetalis appears to be reversed by such transfusions. The use of promethazine and plasmapheresis have only limited success in ameliorating the disease in the fetus.

Blood Transfusion, Intrauterine↗
PubMed1983

Screening of 16 common therapeutic drugs. Possible association with the Ah locus.

16 common therapeutic agents were screened for differences in sedation or lethality between C57BL/6N and DBA/2N inbred mouse strains that had been previously treated with beta-naphthoflavone. No differences were observed for meprobamate, valium, promethazine, valproic acid, lincomycin, imipramine, terbutaline, propoxyphene, nitrofurantoin, amphotericin B, or diphenhydramine. C57BL/6N mice appeared to be more resistant than DBA/2N mice to the lethal effects of isoxsuprine, niridazole, pentazocine, isoniazid, and hydralazine. None of these latter five drugs had any capacity to displace [3H-1,6]2,3,7,8-tetrachlorodibenzo-p-dioxin from the liver cytosolic Ah receptor in C57BL/6N mice. With the use of beta-naphthoflavone-pretreated offspring from the (C57BL/6N) (DBA/2N)F1 X DBA/2N backcross, a strict correlation (100% of 24 individuals in each case) was found between the Ahb allele and resistance to the lethal effects of isoxsuprine or niridazole. No correlation between the Ah locus and pentazocine, hydralazine, or isoniazid lethality was apparent. These results indicate that presence of the Ahb allele is associated with increased protection against isoxsuprine and niridazole lethality. This increased protection may reflect enhanced detoxication metabolic pathways (e.g., induced cytochrome P1-450 and/or uridine diphosphate glucuronosyltransferase controlled by the Ah locus). The increased protection is not related to interaction of these drugs with the Ah receptor. It should be kept in mind that gene-environment interactions involving the Ah locus and isoxsuprine or niridazole may be important in certain clinical instances.

Animals↗
PubMedDate not supplied

Antiemetic use in pediatric gastroenteritis: a national survey of emergency physicians, pediatricians, and pediatric emergency physicians.

The objective of this study was to review the use of antiemetics for pediatric gastroenteritis and to determine prescribing patterns of physicians. A mailed cross-sectional survey instrument was sent to randomly selected board-certified emergency medicine, pediatric, and pediatric emergency medicine specialists. A total of 1665 surveys were mailed, with 593 completed surveys returned (35.6% response rate). A majority of responders (60.9%) reported using antiemetics for pediatric gastroenteritis at least once in the past year, with a greater than 50% usage for all three specialty groups. Promethazine was the most commonly used antiemetic in all specialties, and per rectum the most common route of administration. Adverse reactions following a single dose of antiemetic were most frequently reported with prochlorperazine. The most common reason for antiemetic use was to prevent further dehydration. The most common concern regarding antiemetic use was potential for side effects. Occasional antiemetic use appears to be a common practice in treating pediatric gastroenteritis, regardless of specialty. Given the absence of literature on efficacy or safety, these drugs should be used only with careful consideration to potential side effects.

Antiemetics↗
PubMed1990

Prevention of cisplatin-induced vomiting in patients with cancer. A pilot study with a multiagent protocol.

Forty patients receiving a total of 102 courses of cisplatin (CDDP)-based treatment were observed in the present study. The patients received an antiemetic prophylaxis with metoclopramide (6 mg/kg), dexamethasone (12 mg/m2), lorazepam (2.5 mg), promethazine (50 mg), and diazepam (10 mg). Complete protection from acute vomiting was obtained in 77.5% of patients during the first course, and partial protection (1 to 3 episodes of vomiting) was observed in 10.1% additional cases. Complete protection was achieved in 84.6% of males vs 57.1% of females. Patients at their first course of chemotherapy had 80% complete protection compared to 66.7% in those who received prior chemotherapy. No differences in the response rate between patients treated with high versus patients receiving low doses of CDDP were noted. The same pattern of response was observed in subsequent courses of therapy. Side effects were minimal (mild sedation in almost all the cases and hiccups in a few cases). No major extrapyramidal reaction was observed. The regimen used in the study showed good efficacy in preventing acute CDDP-induced nausea and vomiting. Moreover, the very low incidence of major side effects makes this protocol safe and recommendable in patients undergoing CDDP chemotherapy.

Cisplatin↗
PubMed1978

Intravenous ketamine anaesthesia for major abdominal surgery--an assessment of a technique and the influence of ataractic drugs on the psychomimetic effects of ketamine.

Eighty-two patients presenting for major abdominal surgery were divided into five groups, and received intravenous ketamine, muscle relaxation and controlled ventilation with oxygen-enriched air. For maintenance of anaesthesia patients were given a single intravenous dose of either droperidol 5 mg, diazepam 5 mg, promethazine 25 mg, flunitrazepam 0.5 mg or lorazepam 2 mg, followed by incremental doses of ketamine. Flunitrazepam and lorazepam were the adjuvants associated with the lowest incidence of dreaming and emergence phenomena; postanaesthetic sequelae occurred most frequently with both ketamine/diazepam and ketamine/droperidol anaesthesia. However, the differences between the five groups failed to reach statistical significance.

Abdomen↗
PubMed1993

Poisoning due to insect and scorpion stings/bites.

1. A retrospective study, 1980 to 1989 inclusive, of hospital admission cases due to insect and scorpion stings or bites was carried out in the six main central hospitals of Zimbabwe's four main cities. 2. A total of 92 cases were recorded and analysed. This constituted 1.5% of all hospital admissions for poisoning which were analysed during that time. 3. Of the 92 cases the highest number of victims were seen in the 2-to-5-year age group (29.3%), followed by the 6-to-10-year age group (23.9%). In other age groups the incidence of poisoning was distributed approximately evenly with the 41 to 50 and the over 60-year age groups having the least number of victims, (2.2%). 4. The main groups of insects associated with poisoning were bees, 44.6%; wasps, 8.7%; and spiders 8.7%. A further 32.6% of the insect stings were not specified. Scorpion stings accounted for 5.4% of incidences. 5. No fatalities occurred. 6. Treatment consisted mainly of the administration of promethazine, as an antihistamine in 35% of the cases, steroids (16.5% of the cases), perhaps for their anti-allergic effects, and paracetamol, a mild analgesic, (14.7% of the cases). Interestingly, 22.6% of the cases were given an antibiotic (14.1% of which were penicillins). Adrenaline was administered in only 1.7% of the cases. 7. The majority of the recorded cases, 49.4%, were hospitalized for at least a day and the average duration of hospitalization was 6.4 days.

Adolescent↗
PubMed1988

Sedation in pediatric patients undergoing diagnostic procedures.

Sedation is routinely used in pediatric patients undergoing diagnostic procedures. Meperidine with promethazine and chlorpromazine; meperidine with pentobarbital; and meperidine, morphine, pentobarbital, thiopental, methohexital, chloral hydrate, and benzodiazepines as single agents have been used at different doses in patients for various procedures including computed tomography, endoscopy, electroencephalography, and bone marrow biopsies. Most available studies, however, have not compared these drugs in a controlled and blind manner, and the data have often been collected retrospectively. In addition, the degree and duration of sedation required may depend on the procedure. Thus, it is difficult to recommend the drug of choice for producing sedation. Serious cardiac and respiratory effects and excessive sedation have been associated with these drugs, even when normal doses were used. Controlled studies and specific guidelines are needed for optimal use and monitoring of these drugs in pediatric patients.

Child↗
PubMed1999

Analysis of Apparent Noncompetitive Responses to Competitive H(1)-Histamine Receptor Antagonists in Fluorescent Imaging Plate Reader-Based Calcium Assays.

We have examined the utility of high throughput fluorescent imaging plate reader (FLIPR)-based calcium assays for pharmacological characterization of G-protein coupled receptors (GPCRs) using recombinant and native human H1-histamine receptors (H(1)-HR), expressed in HEK293 and HeLa S3 cells, respectively, as model systems. For stably transfected HEK293 cell lines, the potency of histamine for elevating intracellular calcium increased (pD(2), 7.13 and 7.86) with increased H(1)-HR density (about 0.8 and 14 pmol/mg protein, respectively), though histamine binding affinities were similar. The classic H(1)-HR competitive antagonists diphenhydramine and chlorpheniramine appeared noncompetitive by causing depressions of the maximal histamine responses along with rightward shifts of histamine concentration-response curves, thus precluding Schild analysis. Applying the generalized Cheng-Prusoff equation to antagonist concentration-response curves for inhibition of fixed histamine concentrations yielded apparent pK(b) values that were consistent among recombinant and native receptors at different expression levels. These pK(b) values for diphenhydramine and chlorpheniramine (e.g., 7.83 and 8.77, respectively) were in good agreement with binding pK(i) values (e.g., 7.98 and 8.52, respectively). Apparent antagonist affinities determined from FLIPR calcium and competition binding assays were also consistent for the competitive antagonists mepyramine, tripelennamine, and promethazine. In phosphoinositide hydrolysis assays, chlorpheniramine exhibited insurmountable inhibition of histamine calcium responses, although to a lesser extent than that observed in calcium assays; pK(b) values were similar. These results demonstrate that competitive antagonist potencies can be attained from FLIPR-derived data by application of the generalized Cheng-Prusoff equation, despite apparent noncompetitive antagonism under these assay conditions. Apparent noncompetitive antagonist effects may in part be attributable to a lack of equilibrium of histamine and antagonists with H(1)-HR within the short duration of rapid transient effects of histamine on intracellular calcium.

Journal Article↗