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At least 883 records · Page 49Linked to original sources
PubMed1987

Evidence for the involvement of calmodulin in the operation of Ca-activated K channels in mouse fibroblasts.

The oscillation of membrane potential in fibroblastic L cells is known to result from periodic stimulation of Ca2+-activated K+ channels due to the oscillatory increase in the intracellular Ca2+ concentration. These repeated hyperpolarizations were inhibited by putative calmodulin antagonists, trifluoperazine (TFP), N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) and promethazine (PMZ), and the concentrations required for half-maximal inhibition were 25, 30 and 300 microM, respectively. These doses were lower than those for reducing the membrane resistance due to nonspecific cell damages. Another calmodulin antagonist, chlorpromazine (CPZ), was also effective, but CPZ-sulfoxide was not. Intracellular pressure injections of calmodulin-interacting divalent cations, Ca2+, Sr2+, Mn2+ and Ni2+, elicited slow hyperpolarizations, whereas Mg2+ and Ba2+, which are known to be essentially inert for calmodulin, failed to evoke any responses. The injection of purified calmodulin also brought about a similar hyperpolarization. Quinine, an inhibitor of Ca2+-activated K+ channels, abolished both Ca2+- and calmodulin-induced hyperpolarizations. TFP prevented Ca2+-induced hyperpolarizations. The TFP effect was partially reversed by the calmodulin injection. It is concluded that calmodulin is involved in the operation of Ca2+-activated K+ channels in fibroblasts.

Animals↗
PubMed1994

The preservation of some oral liquid preparations. The replacement of chloroform by other preservatives.

Chloroform should be considered as an obsolete preservative for pharmaceutical preparations, because of its toxicological implications and its physical instability. The effectiveness of possible alternatives for chloroform in three oral liquid pharmaceutical preparations was investigated, using a microbiological challenge test. Magnesium trisilicate mixture (British Pharmacopoeia) can be adequately preserved with methylparaben (2 g/l). Only insignificant amounts of methylparaben were absorbed by the solids present in the magnesium trisilicate mixture. Ferrous sulfate mixture (British Pharmacopoeia) can be preserved with a mixture of methylparaben (1.8 g/l) and propylparaben (0.2 g/l). Sorbic acid (1 g/l) is a suitable preservative for promethazine hydrochloride syrup.

Administration, Oral↗
PubMed1982

Metabolism and excretion of the quaternary ammonium compound thiazinamium methylsulfate (Multergan) in man. I. Parenteral administration.

The quaternary ammonium compound thiazinamium was found to be metabolized by sulfoxidation solely. No ring hydroxylation products, nor demethylation products (e.g. promethazine) could be found. Thiazinamium sulfoxide was found both in urine and bile, but thiazinamium is-after parenteral administration - mainly excreted in the unchanged form. After intravenous injection about 40% of the dose was excreted, unchanged, in the urine. The excretion was very rapid and almost complete within eight hours. About 9% of the dose was excreted in the urine in the form of thiazinamium sulfoxide cations. After intramuscular injection virtually the same figures for urinary excretion were found. No correlation could be observed between urine production or pH and the amount of drug excreted in urine. In a study involving bile-fistula patients it was found that both thiazinamium cations and thiazinamium sulfoxide cations are excreted to a considerable extent in bile. The amount of unchanged drug in bile was almost equal to that in urine, but the amount of sulfoxide was slightly higher.

Bile↗
PubMed1977

H1 - and H2-receptor mediated responses to histamine on contractility and cyclic AMP of atrial and papillary muscles from guinea-pig hearts.

On guinea-pig heart we investigated whether cyclic AMP serves as a messenger for H1 - and/or H2-mediated responses to histamine. (1) On papillary muscle histamine elicited positive inotropic responses which were antagonized by burimamide but not by promethazine. The stimulation of H2-receptors was not only associated with an increase in contractility but also with an increase in cAMP. As shown by the time course of effects for 10(-5) M histamine, the maximal increase in cAMP preceded the maximum in contractility. The mechanical and biochemical responses to histamine were potentiated by the phosphodiesterase inhibitor papaverine, but antagonized by burimamide. (2) On the left guinea-pig atrium containing H1-receptors the inotropic response to histamine (10(-5) M) was not accompanied by increases in cAMP at stimulation frequencies of 0.5 and 2 Hz, respectively. In addition, in the presence of papaverine (3 X 10 (-5) M) no change in the cyclic AMP level occurred after application of histamine. Papaverine by itself, however, concomitantly increased contractility and cyclic AMP at a stimulation frequency of 0.5 Hz. In contrast, at 2 Hz papaverine increased only cAMP leaving the contractility unchanged. At this frequency the well-known Ca2+-antagonistic effect comes into prominence, thus masking the positive inotropic effect attributable to the inhibition of the phosphodiesterase. (3) On the right guinea-pig atrium the mediation of the positive chronotropic response to histamine by H2-receptors which is partly involved in the inotropic effect via the frequency-force relationship does not lead to a concomitant increase in cAMP. Also, in the presence of papaverine, histamine had no influence on the cAMP. However, papaverine potentiated the cardioacceleration produced by histamine. Although it is very likely that the cAMP in the sinus node rises, we were not able to detect an increase in cAMP in the whole atrial tissue. From the present results the conclusion can be drawn that the mediation of the inotropic effect due to stimulation of H2-receptors by histamine is associated with an increase of cyclic AMP, whereas that of H1-receptors is not. The view that cAMP may be the second messenger in the chronotropic action of histamine needs further elucidation by experiments on sino-atrial cells.

Animals↗
PubMed1986

An antiallergic activity of disodium cromoglycate unrelated to mast cell activation.

The pharmacological effects of disodium cromoglycate (DSCG) were studied in rats during the development of reactions to various allergens or carrageenin. DSCG (10 mg/kg and 100 mg/kg, i.v.) showed pronounced inhibitory effects on type I and type III (passive Arthus) allergic reactions. An immunological degranulation of mast cells and a significant decrease in tissue histamine content were observed in type I allergic reactions but not in type III allergic reactions characterized by an apparent infiltration of neutrophils. An antihistaminic agent, promethazine (1 mg/kg, i.v.) was effective only against type I allergic reactions and totally ineffective against type III allergic reactions. Thus, the results obtained above strongly suggest that DSCG exhibits at least two mechanisms of antiallergic action; one is related to mediator release from mast cells and the other is unrelated to mast cell activation.

Allergens↗
PubMed1984

The effects of antiallergic and bronchodilator drugs on platelet-activating factor (PAF-acether) induced bronchospasm and platelet aggregation.

Platelet activating factor (PAF-acether) is a potential mediator of asthma and inflammation. Recently, the suggestion was made that inhibition of PAF-acether by disodium cromoglycate (DSCG) might be partly responsible for the effectiveness of DSCG in asthma. We have extended these studies and examined the effects of antiallergic and bronchodilator drugs on PAF-acether induced bronchospasm after i.v. administration in guinea pigs and in vitro platelet aggregation in rabbits. Neither DSCG nor Wy-41,195, a potent orally effective antiallergic, altered either of the PAF-acether responses. Furthermore, aerosolized ipratropium, promethazine, ketotifen and FPL 55712 failed to affect the PAF-acether-induced bronchospasm. The same drugs were also ineffective against platelet aggregation induced by PAF-acether. In contrast, aerosolized thiazinamium chloride inhibited the bronchospasm and also inhibited PAF-acether-induced platelet aggregation. Thiazinamium chloride possessed weak antiaggregatory effects against ADP and was without effect against arachidonic acid-induced platelet aggregation. Both lipoxygenase and cyclooxygenase products of arachidonic acid metabolism appear to be involved in PAF-acether bronchospasm since i.v. administered lipoxygenase inhibitors (phenidone, BW755c and NDGA) and indomethacin independently inhibited this in vivo response. However, these drugs failed to alter platelet aggregation to PAF-acether. Thiazinamium chloride may be capable of directly antagonizing the PAF-acether-induced platelet aggregatory response and, in addition, inhibiting the synthesis and/or effects of bronchoconstrictor amines and endogenously generated arachidonic acid metabolites.

Animals↗
PubMed1984

Analgesic effect of histamine induced by intracerebral injection into mice.

Three methods were used to study the analgesic effect of intracerebral injection of histamine (Hi) on mice: the writhing test (acetic acid and phenylquinone), the electrical stimulation of the tail and the hot plate test. At doses higher than 2 micrograms, Hi inhibited the writhing syndrome significantly, and at doses of 10 micrograms or higher, Hi displayed a marked analgesic effect during both the electrical stimulation and hot plate methods. The saline injection produced only a negligible effect. Simultaneous application of Hi and 10 micrograms of diphenhydramine, pyrilamine or promethazine, apparently causing no analgesic effect from a single administration, caused a parallel shift of the dose-response curve of Hi to the right. ED50 of Hi was increased approximately 2, 2.8 and 3.8 times, respectively. However, cimetidine did not reveal any antagonistic effect on Hi-induced analgesia. Subcutaneously administered, 3 mg/kg of morphine augmented the analgesic effect of Hi. In accordance with this, pretreatment of naloxone (0.005 mg/kg) antagonized the analgesic action of Hi almost completely. When 5 mg/kg of leucine-enkephalin, less than the minimum effective dose, was given prior to Hi injection, the analgesic effect of Hi was enhanced. In addition, 10 and 20 micrograms of Hi increased the morphine analgesia markedly and parallel shifted the dose-response curve of morphine to the left.

Analgesics↗
PubMed1987

The pattern of cardiovascular alterations induced by infusion of platelet-activating factor in rabbit is modified by pretreatment with H1-H2 receptor antagonists but not by cyclooxygenase inhibition.

The intravenous infusion of platelet activating factor (PAF) (0.8 micrograms/kg b.w.) induced ECG and hemodynamic alterations characterized by the following sequential three phases. Phase I (15 sec) consisted of a transient bradycardia with reduction in left ventricular pressure (LVPs), mean arterial pressure (MAP) and cardiac output (CO). Phase II developed within 30 sec and consisted of a rise in cardiac frequency, increase in LVPs, MAP and total peripheral resistances (TPR), which were associated with a decrease in CO. Finally, phase III, that occurred about 90 sec after PAF infusion, was characterized by marked ECG changes (ST segment depression and conduction arrhythmias), a decrease in LVPs and MAP, as well as a rise in TPR and in right atrial pressure (RAP). All these alterations were reversible within 30-60 min. Pretreatment with promethazine and cimetidine, as H1 and H2 histamine receptor antagonists, markedly prevented the development of phase II, namely the rise in cardiac frequency, LVPs, MAP and TPR, but did not significantly modify phase I and III. In contrast, pretreatment with indomethacin, an inhibitor of cyclooxygenase, moderatively attenuated, but did not abolish, the three phases of cardiovascular changes induced by PAF infusion.

Animals↗
PubMed1993

In vivo responses of mouse blood cells to platelet-activating factor (PAF): role of the mediators of anaphylaxis.

Intravenous injection of platelet-activating factor (PAF) (0.36 mumol/kg b.w.) in mice induced severe hemoconcentration, leucopenia, thrombocytopenia and finally the death of 85% of the tested animals. Combined inhibition of histamine and serotonin by promethazine and chlorpromazine, 6.24 and 3.12 mg/kg b.w. subcutaneously, protected the mice from PAF in part, reducing the death rate to 43%. These drugs did not protect the mice against the PAF-induced hemoconcentration, leucopenia and thrombocytopenia. Sulfinpyrazone (100 mg/kg b.w.) intravenously was the most effective both in protecting mice from PAF-induced death, reducing the death rate to 17%, and from thrombocytopenia, although hemoconcentration persisted. These results indicated that an important component of the PAF-induced systemic effects is mediated by reactions which can be inhibited by sulfinpyrazone. Furthermore, PAF-induced thrombocytopenia is not a direct PAF effect since it can be inhibited by sulfinpyrazone.

Anaphylaxis↗
PubMed1989

Rocastine (AHR-11325), a rapid acting, nonsedating antihistamine.

Rocastine [AHR-11325, 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido-[3,2-f]-1,4- oxazepine-5(4H)-thione (E)-2-butenedioate)] is a rapid-acting, potent, nonsedating antihistamine. In guinea pigs challenged with a lethal dose of histamine, rocastine is as effective [based on 1 hr. oral, protective dose (PD50S)] as brompheniramine, chlorpheniramine, pyrilamine, and promethazine and superior to astemizole, diphenhydramine, terfenadine, and oxatomide. Rocastine has a faster onset of action than does terfenadine; rocastine being as effective with a 15 min pretreatment time (PD50 = 0.13 mg/kg) as it is with a 1 hr pretreatment time (PD50 = 0.12 mg/kg), while the 15 min PD50 of terfenadine (PD50 = 44.0 mg/kg) is 22 times greater than the 1 hr PD50 (PD50 = 1.93 mg/kg). Against aerosolized histamine, rocastine was 7.12 x, 2.63 x, and equipotent to pyrilamine in preventing histamine-induced prostration at pretreatment times of 1,3, and 6 hr, respectively. Rocastine protected guinea pigs from collapse induced by aerosolized antigen; rocastine was approximately 36 x more potent (based on 1 hr PD50) than diphenhydramine and as potent as oxatomide and terfenadine. Rocastine did not alter the EEG of cats at doses in vast excess (150x) of its antihistaminic dose nor did it potentiate yohimbine toxicity in mice. Further, rocastine possesses no anticholinergic, antiadrenergic, or antiserotonergic properties in vitro. Rocastine is a selective, nonsedating, H1-antagonist with a rapid onset of action.

Anaphylaxis↗
PubMed1976

Characterization of an adenylate cyclase system sensitive to histamine H2-receptor excitation in cells from dog gastric mucosa.

A method of preparing viable cells from dog gastric mucosa is described. Cyclic AMP in these cells is elevated by histamine and 4-methyl histamine but 2-methyl histamine is only a weak agonist. The effects on cyclic AMP levels are inhibited competitively by metiamide and burimamide which give apparent KBvalues of 3.5x10-7 M and 2.3x10-6 M, respectively. These values are similar to those reported for other histamine H2-receptor systems. The H1-receptor antagonists, mepyramine and chlorpheniramine, have no inhibitory effect on the histamine induced elevation of cyclic AMP: promethazine inhibits the system but not by a competitive mechanism. It is concluded that the histamine stimulated adenylate cyclase system is probably located in the parietal cell component.

Adenylyl Cyclase Inhibitors↗
PubMed1981

Influence of lipid peroxidation on lipoprotein secretion by isolated hepatocytes.

Isolated rat liver cells have been exposed to 3 different lipid peroxidation-inducing agents, CCl4, FeCl3 and cumene hydroperoxide, and the rates of malonaldehyde production and of lipoprotein secretion have been compared. Results indicate that it is possible to induce a high degree of lipid peroxidation without inducing strong changes in lipoprotein secretion. Only in CCl4-poisoned hepatocytes is lipoprotein secretion strongly impaired. In this experimental condition, the effect of free radical scavengers, or inhibitors of lipid peroxidation, as well as the behavior of both lipid peroxidation and lipoprotein secretion, have been evaluated. Promethazine and propyl gallate prevented malonaldehyde production, but neither agent reduced covalent binding nor improved secretion. Menadione, on the contrary, besides inhibiting malonaldehyde production, decreased covalent binding and protected against the impairment of secretion. These data lead to the conclusion that covalent binding of CCl4 metabolites, rather than lipid peroxidation products, accounts for the derangement of lipoprotein secretion in CCl4-poisoned liver cells.

Animals↗
PubMed1993

Nasal ketamine for paediatric premedication.

Ketamine in a dose of 6 mg.kg-1 was nasally administered in 86 healthy children (ASA I and II), aged from two to five years undergoing elective general, urological or plastic surgery, 20 to 40 min before the scheduled surgery time. These children were compared with 62 others, also aged from two to five years, in whom promethazine and meperidine, 1 mg.kg-1 of each, were injected im. Sedation was started as excellent in 48 and as adequate in 19 children in the ketamine group, compared with nine and 12 respectively in Group 2 (P < 0.05), while salivation was similar in both groups. We conclude that nasal ketamine is an alternative to im preanaesthetic sedation administration in children aged from two to five years.

Administration, Intranasal↗
PubMed2004

Postoperative nausea and vomiting in the plastic surgery patient.

Despite great advances in modern medicine, postoperative nausea and vomiting (PONV) continue to be a significant problem without a definitive cure. This article describes a prospective study conducted with 143 plastic surgery patients at a single institution between 1998 and 2000 to identify preoperative risk factors for PONV that may be specific to plastic surgery patients. In addition, a prophylactic regimen was identified that demonstrated a decrease in the incidence of PONV from the published incidence of 22% to 3%. The regimen includes the use of multiple antiemetic agents including ondansetron (Zofran) promethazine (Phenergan), and metoclopramide (Reglan), with the addition of dexamethasone (Decadron) in selected cases

Ambulatory Surgical Procedures↗
PubMed1997

A feasibility study of 1-h paclitaxel infusion in patients with solid tumors.

The optimal schedule for paclitaxel administration has not yet been determined. This phase I/II study was carried out to evaluate the safety of paclitaxel administration by 1-h infusion in the outpatient setting. A total of 43 patients with advanced pretreated malignancies (18 breast, 18 ovarian, and 7 non-small-cell lung cancers) received at least 2 cycles of paclitaxel given at 175 mg/ m2 in a single dose by 1-h i.v. infusion. This protocol was repeated every 21 days. All patients were premedicated as follows: promethazine given i.m. at 50 mg, dexamethasone given at 16 mg in 250 ml normal saline by i.v. infusion for 20 min and ranitidine given i.v. at 50 mg in 250 ml normal saline over 15 min, all premedication being carried out 1 h before the paclitaxel infusion. In a total of 156 cycles, only 1 patient presented with a hypersensitivity reaction (grade 2 urticaria in 1 cycle) and another patient developed transient facial flushing (in 1 cycle: this was resolved by slowing of the infusion rate) on this schedule of paclitaxel administration. Other adverse side effects were usually mild and well tolerated. Alopecia was universal; myelosuppression was uncommon because our patients were supported with granulocyte colony-stimulating factor (G-CSF, lenograstim) given at 34 IU/day in the presence of a neutrophil count of < 500 microliters; neutropenia was seen in 50/156 (32%) cycles and was mild. Neurotoxicity was the most serious adverse effect, and all patients experienced mild to severe neuro-muscular toxicity, mainly in the form of peripheral sensorimotor neuropathy and myalgias. In conclusion, 1-h paclitaxel administration is safe and reduces the duration of treatment, making its use more convenient and easy in the outpatient setting. A prospective comparison of 1-h versus 3-h paclitaxel infusion in terms of efficacy and toxicity is the subject of our current randomized study.

Aged↗
PubMed1980

Prevention of postoperative tubal adhesions. Comparative study of commonly used agents.

Tubal abrasions were surgically induced in 25 rhesus monkeys following demonstration of tubal patency. Five monkeys received dexamethasone, promethazine, and ampicillin perioperatively, five received intraperitoneal 10% dextran 40, five received intraperitoneal 32% dextran 70, and 10 received no additional therapy. Fimbrial biopsies were obtained from two additional monkeys treated with 32% dextran 70 before and postoperatively on days 2, 5, and 7. Only those treated with 32% dextran 70 retained tubal patency and avoided development of adhesions, involving fimbria, omentum, ovary, uterus, and bladder. Histologic examination of fimbrial biopsies demonstrated sufficient epithelial repair to have occurred during the 5 days 32% dextran 70 remained in the pelvin cavity to prevent adhesion formation.

Ampicillin↗
PubMed1983

Carbon tetrachloride and bromotrichloromethane toxicity. Dual role of covalent binding of metabolic cleavage products and lipid peroxidation in depression of microsomal calcium sequestration.

We have investigated the importance of covalent binding and lipid peroxidation on the depression of microsomal calcium sequestration associated with in vitro metabolism of 14CCl4. Studies with CBrCl3 are also reported. In aerobic systems, promethazine was used to block lipid peroxidation, measured as malondialdehyde (MDA) generation. Effects of low levels of lipid peroxidation were tested in Fe2+-supplemented systems free of halogenated hydrocarbons. The results indicate that microsomal calcium sequestration can be depressed significantly by metabolism of either CCl4 or CBrCl3 in the absence of MDA generation, or by lipid peroxidation occurring in the absence of halogenated hydrocarbons.

Animals↗
PubMed1987

Effects of thiazinamium chloride and other antihistamines on phosphatidylcholine secretion in rat type II pneumocyte cultures.

Thiazinamium chloride (TCl) stimulated phosphatidylcholine secretion in cultures of adult rat type II pneumocytes in a concentration-dependent manner in the range 10(-9)-10(-6) M. At the optimal concentration, secretion was stimulated by 46% which is approximately half the stimulatory effect of the beta-agonists terbutaline and isoproterenol. TCl did not increase the rate of choline incorporation into cellular phosphatidylcholine or of lactate dehydrogenase release so its effect on secretion was not secondary to phosphatidylcholine synthesis or cell injury. Since TCl has antihistaminic properties, we examined the effects of other antihistamines. The H-1 antagonists promethazine, which is structurally similar to thiazinamium, and pyrilamine, which has a different structure, also stimulated secretion but the H-2 antagonist, cimetidine, did not. The effects of TCl and pyrilamine were additive to those of terbutaline, suggesting that the mechanisms of action of the antihistamines and the beta-agonist were different. Although we were unable to demonstrate an inhibitory effect of histamine itself on either basal or terbutaline-stimulated phosphatidylcholine secretion, it is possible that histamine plays a regulatory role in lung surfactant secretion.

Animals↗