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PubMed1989

Beta-adrenoceptor blocking drugs and calcium transport in isolated rat mast cells.

The beta-adrenoceptor blocking (BAB) drugs exaprolol (EXA), metipranolol (MET) and propranolol (PRO) inhibited histamine liberation and degranulation from isolated rat mast cells stimulated with the calcium ionophore A23187. MET was the most and EXA the least active. Atenolol (ATE) had no effect. Inhibition by BAB drugs of secretion induced with A23187 was not accompanied by any change in 45Ca uptake. On the other hand, EXA, MET and PRO significantly decreased 45Ca uptake by mast cells stimulated with 48/80. The effect of BAB drugs on inhibition of A23187-induced secretion from isolated mast cells was dependent on the lipid solubility of the studied drugs.

Adrenergic beta-Antagonists↗
PubMed1999

Pyrethroids and piperonyl-butoxide affect human T-lymphocytes in vitro.

Synthetic pyrethroids are increasingly used as insecticides and are claimed to have a relatively low human toxicity. The aim of this study was to examine the in vitro effects of the synthetic pyrethroid S-bioallethrin alone and in combination with the common synergist piperonyl-butoxide (PBO) on human blood lymphocytes and basophils in atopic individuals and non-atopic control subjects. S-bioallethrin and PBO also caused inhibition of lymphocyte proliferation (MTT-test) after a 72-h culture period in a concentration dependent manner. In contrast to the MTT-measurements the combined agents are more effective in inhibiting interleukin-4 (IL-4)- and interferon-gamma (IFN-gamma)-production. The regulatory IL-4/IFN-gamma balance showed a significant difference between atopic and non-atopic subjects after a culture period of 24-48 h in the presence of micromolar S-bioallethrin (P < 0.001). Furthermore S-bioallethrin, PBO and the combined agents induced histamine release from human basophils. Although this effect was little compared to histamine liberators like FMLP and anti-IgE, the response to S-bioallethrin and PBO was significantly different in atopic donors compared with non-atopics (P < 0.01). In scratch test experiments 4 of 18 tested atopic volunteers showed positive reaction (wheals and flares) to S-bioallethrin and permethrin, whereas no reaction could be measured in the control group (age-matched). These findings demonstrate the immuno- and allergo-toxicological properties of the synthetic pyrethroid S-bioallethrin combined with the synergistic PBO using this in vitro approach with human lymphocytes and basophils.

Adolescent↗
PubMed2001

[Food allergy in the chronic alcoholic and alcohol in food allergy: apropos of 38 cases].

Exacerbation or appearance of hypersensitivity of food origin in chronic alcoholics appears to be linked to a basis of catabolism of histamine, a facilitation of penetration of allergens under the impetus of the mucosa-irritating power of alcohol and its potential as a histamine-liberator; it results frequently in an elevated total IgE that predisposes to conflictual sub-cutaneous mechanisms, so explaining the easy appearance or exacerbation of food allergies. We have used skin tests of the principal food allergens to evaluate the influence of alcohol in the development of allergies, by determining the allergy profile of each patient and consequently, the titres of total IgE. Our results show the potentiating role in the physiopathology of allergy and food intolerance without which it helps as much by an evident inducing role in the appearance of true food allergy.

Adult↗
PubMedDate not supplied

Place of immunological examinations in extrinsic asthma.

The provocation test is - in spite of its drawbacks, especially the risk for the patient - the most reliable way to identify causative agents in extrinsic asthma. The immunological genesis of the obstruction provoked must be proved with adequate methods however. RAST (Radio-allergo-sorbent-test) and histamine liberation are valuable in vitro techniques for the identification of atopic sensitizations. Their disadvantages - the expensive equipment and the time-consuming procedure respectively - limit their widespread use. A carefully performed and evaluated prick test possesses a comparable specificity with acceptable risk. Less satisfying is the situation in nonimmediate asthma. Precipitations tests are at present most valuable. Main indications for immunological methods in extrinsic asthma are: - the identification of causative allergens and the kind of underlying immune reactions; - the control and - in the future - the individualization of hyposensitization procedure. The future use of allergen extracts containing a minimum of non-specific irritants is extremely important.

Asthma↗
PubMed1992

Newer neuromuscular blocking drugs. An overview of their clinical pharmacology and therapeutic use.

Four new nondepolarising muscle relaxants, pipecuronium bromide, doxacurium chloride, mivacurium chloride and Org 9426 (rocuronium) offer alternatives to the established agents atracurium besilate and vecuronium bromide. Pipecuronium and Org 9426 are steroidal compounds, the latter being a monoquaternary agent, whereas doxacurium and mivacurium are bisquaternary benzylisoquinolinium compounds. Pipecuronium and doxacurium have a relatively slow onset and a long duration of action. Pipecuronium produces maximum block in 3 to 6 min when given in a dose of 45 to 80 micrograms/kg, and a duration of clinical relaxation of between 40 and 110 min. Doxacurium is more potent, but is the least rapid and the longest acting relaxant currently available. When administered in doses of 37 to 80 micrograms/kg, it produces maximum block within 3.5 to 10 min, with a duration of clinical relaxation of 77 to 164 min. The advantage of both pipecuronium and doxacurium is their cardiovascular stability. Both agents are primarily eliminated via the kidneys and both have now been licensed for use in the US. Mivacurium is a muscle relaxant with a short duration of action. When administered in doses of 0.1 to 0.25 mg/kg it produces maximum block in 2 to 4 min, but the duration of clinical relaxation is less than 20 min. Higher doses which could induce a faster neuromuscular block are unfortunately associated with some histamine liberation. The drug is metabolised by plasma cholinesterase. Mivacurium has also been licensed for use in the US. Org 9426 is an agent with a rapid onset but an intermediate duration of action. A dose of 0.5 to 0.6 mg/kg induces maximum block in about 1.5 min and has a duration of clinical relaxation of about 30 min. The rapid onset of effect could be useful for early intubation as an alternative to suxamethonium chloride. However, much more clinical experience is needed with this agent, particularly with regard to duration of action of larger doses and occurrence of side effects. The drug is mainly eliminated via the liver.

Aging↗
PubMed1980

Differential reactivity of isolated mast cells from the rat and guinea pig.

The effects of various chemical histamine liberators on isolated rat peritoneal, rat mesenteric and guinea-pig mesenteric mast cells were examined. All three cell types responded, but to different degrees, to calcium ionophores and surface active agents. The rat mesenteric cells also reponded, but less effectively than the peritoneal cells, to compound 48/80, peptide 401 from bee venom and ATP. Rat mesenteric cells were essentially refractory to the action of dextran and guinea-pig cells were almost totally unresponsive to the named secretagogues. These results show that there are marked functional differences between the mast cells examined and suggest that isolated tissue cells may usefuly complement rat peritoneal cells in the study of anaphylactic and anaphylactoid reactions.

Adenosine Triphosphate↗
PubMed2000

Peptide leucine arginine, a potent immunomodulatory peptide isolated and structurally characterized from the skin of the Northern Leopard frog, Rana pipiens.

On the basis of histamine release from rat peritoneal mast cells, an octadecapeptide was isolated from the skin extract of the Northern Leopard frog (Rana pipiens). This peptide was purified to homogeneity using reversed-phase high performance liquid chromatography and found to have the following primary structure by Edman degradation and pyridylethylation: LVRGCWTKSYPPKPCFVR, in which Cys(5) and Cys(15) are disulfide bridged. The peptide was named peptide leucine-arginine (pLR), reflecting the N- and C-terminal residues. Molecular modeling predicted that pLR possessed a rigid tertiary loop structure with flexible end regions. pLR was synthesized and elicited rapid, noncytolytic histamine release that had a 2-fold greater potency when compared with one of the most active histamine-liberating peptides, namely melittin. pLR was able to permeabilize negatively charged unilamellar lipid vesicles but not neutral vesicles, a finding that was consistent with its nonhemolytic action. pLR inhibited the early development of granulocyte macrophage colonies from bone marrow stem cells but did not induce apoptosis of the end stage granulocytes, i.e. mature neutrophils. pLR therefore displays biological activity with both granulopoietic progenitor cells and mast cells and thus represents a novel bioactive peptide from frog skin.

Adjuvants, Immunologic↗
PubMed1996

Inflammatory reaction and capillary leak syndrome related to cardiopulmonary bypass in neonates undergoing cardiac operations.

We studied the inflammatory reaction related to cardiopulmonary bypass in 24 neonates (median age 6 days) undergoing the arterial switch operation for simple transposition of the great arteries, with respect to the development of postoperative capillary leak syndrome. Complement proteins, leukocyte count, tumor necrosis factor-alpha, and histamine levels were determined before, during, and after cardiopulmonary bypass. Additionally, protein movement from the intravascular into the extravascular space during cardiopulmonary bypass was assessed by the measurement of plasma concentrations of proteins with molecular weights ranging from 21,200 to 718,000. Capillary leak syndrome developed in 13 of the 24 neonates. Patients with capillary leak syndrome, as compared with those without, had preoperatively higher C5a levels (C5a, 3.0 +/- 0.6 microgram/L vs 0.9 +/- 0.2 microgram/L) (mean +/- standard error of the mean) (p < 0.05) and higher leukocyte counts (leukocytes, 17.9 +/- 2.1 X 10(3) cells/ml versus 11.7 +/- 0.8 X 10(3) cells/ml) (p < 0.05), suggesting in these neonates a preoperative inflammatory state. Preoperative clinical and operative data were identical in both patient groups. Before cardiopulmonary bypass, serum protein concentrations were similar in all patients. Ten minutes after institution of cardiopulmonary bypass, protein concentrations fell to significantly lower values in patients with capillary leak syndrome than in those without: albumin (19% +/- 1.5% vs 30% +/- 6% of the prebypass value, p < 0.05), immunoglobulin G (17% +/- 1.5% vs 29% +/- 5.5%, p < 0.001), and alpha 2-macroglobulin (15% +/- 1.2% vs 25% +/- 4%, p < 0.02). During cardiopulmonary bypass, albumin concentrations remained significantly lower in patients with capillary leak syndrome than in those without, whereas hematocrit values were similar in both groups. During cardiopulmonary bypass, patients with capillary leak syndrome also had lower concentrations of complement proteins C3 and C4 but not C1 inhibitor. C3d/C3 ratio and C5a levels were similar in both patient groups. In contrast, histamine liberation during cardiopulmonary bypass was significantly more pronounced in patients with capillary leak syndrome than in those without (725.2 +/- 396.7 pg/ml vs -54.1 +/- 58.4 pg/ml, p < 0.05). Tumor necrosis factor-alpha levels after protamine administration were also significantly higher in patients with capillary leak syndrome (38.1 +/- 10.0 pg/ml vs 15.3 +/- 3.4 pg/ml, p < 0.05). Leukocyte count during and after cardiopulmonary bypass was similar in both patient groups. This study demonstrates increased protein leakage as early as 10 minutes after initiation of.

Acute-Phase Reaction↗
PubMed1979

[Situation and trends of hyposensitisation treatment (author's transl)].

Since the introduction of the hyposensitization treatment by Noon and Freeman in 1911, an essential change of the hyposensibilisation technique, despite numerous recently published results, has not been able to be demonstrated up to now. In most cases, treatment is still done with and allergen mixture consisting of a variety of unknown compounds with changing composition according to own experiences concerning initial and final dosis of the allergen or the application intervals. The linkage of the allergens to chemical substances, the modification into so-called allergoids as well as the investigation of the hyposensitisation success, such as determination of blocking antibodies, the course of the titre of specific antibodies by the RAST technique, the histamin liberation from leucocytes of allergic persons after antigen contact and the lymphocyte stimulation by allergens are starting points for developing a scientific base to the hyposensitisation treatment and for introducing new results mainly from experiments on animals into the clinical practice. Standardisation of allergens, optimisation of the dosis and the application intervals as well as the further decrease of the allergenicity and the optimal choice of the adjuvants have to be regarded as the problems to be solved in the next future. On the other hand, the use of allergen determinants linked to non-immune carriers or the induction of a tolerance by another way seem to be not yet a subject with clinical relevance during the next years.

Adjuvants, Immunologic↗
PubMed2003

Involvement of arachidonic acid in nonimmunologic production of superoxide in mast cells.

BACKGROUND: A number of different molecules are known to be involved in the signal pathway to release histamine from mast cells, among which arachidonic acid (AA) is one of the key mediators. On the other hand, we found that the application of compound 48/80, a typical histamine liberator, generated superoxide in mast cells. In the present study, we investigated the mechanism of superoxide production in mast cells with respect to AA signaling in conjunction with a fine structural analysis. METHODS: Superoxide production was monitored by chemiluminescence in rat peritoneal mast cells and their subfractions after various treatments. For scanning electron micrography, the conditions for fixation and freeze-fracture were optimized to get natural fine images. RESULTS: Compound 48/80 induced superoxide production in the isolated mast cells and some of their subfractions possibly through intracellular increase in Ca(2+) concentration, activation of cytosolic phospholipase A(2), and release of AA. DISCUSSION: The present results indicate the critical role of AA in the signal pathway to generate superoxide from mast cells in response to compound 48/80.

Animals↗
PubMedDate not supplied

Comparative oral and topical decongestant effects of phenylpropanolamine and d-pseudoephedrine.

Nonselective adrenergic alpha-agonists such as phenylpropanolamine and d-pseudoephedrine are widely used as decongestants to treat nasal congestion associated with a variety of nasal diseases. Although the activity of these drugs is well established in clinical studies, a direct comparison of their nasal decongestant effect as determined by changes in nasal cavity dimensions and nasal architecture has not been studied. Using acoustic rhinometry, we evaluated the effects of these drugs on nasal cavity volume, minimum cross-sectional area (Amin), and the distance from the nosepiece to the Amin (Dmin) in a feline, pharmacological model of nasal congestion. Administration of topical compound 48/80 (1%), a mast cell histamine liberator, into the left nasal passageway decreased nasal volume by 66%, reduced Amin by 51%, and increased Dmin by 116%. The congestive responses to compound 48/80 (1%) were reproducible through six weeks. In a subset of cats, the nasal cavity volume effect of repetitive exposure to compound 48/80, given once every two weeks for six weeks, was not different from the nasal responses after the initial exposure to compound 48/80. Pretreatment with oral phenylpropanolamine (10 mg/kg) or oral d-pseudoephedrine (10 mg/kg) attenuated the nasal effects of compound 48/80, but were associated with a pronounced increase in systolic blood pressure of +51 and +82 mmHg, respectively. A similar decongestant profile was observed with phenylpropanolamine (1%) and d-pseudoephedrine (1%) when given topically. Topical phenylpropanolamine (1%) and d-pseudoephedrine (1%) 45 minutes after dosing increased blood pressure +44 and +17 mmHg, respectively, over control animals. We conclude that oral and topical phenylpropanolamine and d-pseudoephedrine display equieffective nasal decongestant activity and produce similar cardiovascular profiles characterized by significant increases in blood pressure.

Administration, Oral↗
PubMedDate not supplied

[Value of the basophil stimulation test in the diagnosis of juvenile bronchial asthma].

The diagnostic value of histamine liberation from basophil granulocytes (BST) was investigated in asthmatic children with house dust, house dust mite or moulds allergy. BST corresponded at about 80% to skin prick test (PRICK) and radio-allergo-sorbens test (RAST) in 178 patients. The relevance of the results of BST, PRICK and RAST for the asthmatic symptoms was proved by bronchial provocation in 77 children. BST corresponded clearly better to the inhalation test than PRICK and RAST. Correspondence of BST in house dust mite allergy amounted to 94%, in house dust allergy to 100%, and in moulds allergy to 77%. Overall correspondence of BST was 92%. Even when RAST and PRICK showed different results correspondence of BST attained 91%. In cases with identical results of BST, PRICK and RAST the bronchial provocation test corresponded in 98%. It is concluded, that if history fits to BST, RAST and PRICK bronchial provocation is no longer essential for the diagnosis of relevant allergens in perennial childhood asthma. This seems to hold also in cases of house dust or house dust mite allergy, where the result of PRICK or RAST is different. Especially in childhood the use of BST in the diagnostic procedure provides the following advantages: risks of bronchial provocation and the necessary hospitalisation can be avoided, cooperation of the patient is not needed, and costs can be reduced.

Allergens↗
PubMed1965

Mediators of inflammation in leukocyte lysosomes. II. Mechanism of action of lysosomal cationic protein upon vascular permeability in the rat.

The vascular permeability-increasing action of rabbit PMNL lysosomes has been studied in skin and cremaster muscle of the rat. Both an extract of frozen-thawed granules and a cathepsin-free cationic protein fraction of the granules (which had previously been demonstrated to cause leukocyte adhesion and emigration in vivo) induce increased vascular permeability in skin and muscle which resembles that produced by histamine or histamine-liberators with respect to the timing of the response and the predominant type of microvessel affected. Extracts of frozen-thawed lysosomes and the inflammatory lysosomal cationic protein both cause disruption of rat mesenteric mast cells in vitro, whereas a granule-free cytoplasmic fraction of PMN leukocytes and a non-inflammatory cationic protein fraction of the granules do not do so under identical test conditions. The mastocytolytic action of lysosomal materials in vitro is not inhibited in the presence of 10 kallikrein-inhibiting units of trasylol per ml. The mast cell rupturing fraction of PMNL granules (cationic protein) possesses no detectable peroxidase activity or acid-mucopolysaccharase activity. When compared with compound 48/80 on the basis of estimated molecular weight, the lysosomal cationic protein appears to be at least as active as the latter compound with respect to in vitro mastocytolytic potency. Chronic pretreatment of rats with an agent known to reduce tissue mast cell numbers causes marked suppression of the vascular permeability change normally induced in skin and muscle by lysosomal extracts and cationic protein. Similar results are obtained if lysosomal materials are tested in rats pretreated with an antihistaminic. These observations are discussed with respect to the mode of action of PMNL lysosomes in the early and late phases of local tissue-injury reactions.

Animals↗
PubMed1994

Hypersensitivity reactions to carboplatin. Report of two patients, review of the literature, and discussion of diagnostic procedures and management.

BACKGROUND: Hypersensitivity reactions are rare but sometimes life-threatening complications of cytostatic combinations containing platinum compounds. Only approximately 40 instances of such hypersensitivity have been reported in association with carboplatin treatment. However, the symptoms probably often are misinterpreted. METHOD: Signs and symptoms of two patients with severe hypersensitivity reactions to carboplatin are presented. Intracutaneous tests with carboplatin were performed in these two patients and in five control patients receiving carboplatin therapy without unexpected side effects. RESULTS: Both patients had received several cycles of a carboplatin-containing combination chemotherapy. In both patients, hypersensitivity reactions became manifest for the first time after cumulative doses of 3900 and 5400 mg, respectively. Symptoms included dyspnea, tachycardia, angina pectoris, hypotension, diarrhea, edema, and rash. In both patients, a positive urticarial reaction to intracutaneous carboplatin (diluted 1:10 with normal saline) was observed, whereas five control patients undergoing carboplatin therapy without adverse reaction had negative test results. There were no signs of delayed hypersensitivity. Serum immunoglobulin E levels were normal. Symptoms were ameliorated but not suppressed when one patient was reexposed after premedication with corticosteroids and histamine antagonists. Both patients tolerated high doses of cisplatin without allergic reactions. CONCLUSIONS: Although they are rare, hypersensitivity reactions can be serious complications of carboplatin therapy. Simple intracutaneous tests might help to establish the diagnosis to avoid dangerous reexposures. Although the pathogenetic mechanisms are not fully understood, the clinical and experimental findings suggest an anaphylactic type of hypersensitivity, perhaps aggravated to some extent by nonspecific histamine liberation. There seems to be no general cross-reactivity to cisplatin.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Chronic myelogenous leukemia-derived basophilic granulocytes express a functional active receptor for the anaphylatoxin C3a.

The receptor for the inflammatory peptide C3a has scarcely been examined on human cells. This work demonstrates that human tumor-derived basophilic granulocytes express C3a receptors, and presents parts of the hitherto unknown C3a-signal transduction. When incubated with IL-3, these cells specifically liberated histamine on C3a stimulation. Independent from IL-3, 240,000 +/- 100,000 receptors per cell with a Kd of 5.6 +/- 0.9 nM were determined. [Ca2+]i increased from 120 +/- 35 nM to 300 +/- 80 nM after a C3a challenge, as measured by digital imaging fluorescence microscopy, and rested at its basal level in the presence of C3a-desArg, the immediate catabolic product of C3a in vivo. This [Ca2+]i increase could be completely desensitized homologously by C3a as well as inhibited by up to 75% by pertussis toxin. Thus, tumor-derived basophils are suitable for cloning of the human C3a receptor.

Anaphylatoxins↗
PubMed1997

The mechanisms of compound 48/80-induced superoxide generation mediated by A-kinase in rat peritoneal mast cells.

This investigation was undertaken to clarify the mechanisms of superoxide anion (O2-) generation in rat peritoneal mast cells. Compound 48/80, a typical histamine liberator mediated by calcium influx, elicited O2- generation from the mast cells in a dose-dependent fashion. It was demonstrated by immunohistochemical study and Western blot analysis that the mast cells contained the 47-kDa phagocyte oxidase (p47phox) protein, which was one cytosolic component of the NADPH oxidase system. Arachidonic acid stimulated O2- generation in the mast cells, but other unsaturated fatty acids had no effect. On the other hand, 48/80-induced O2- generation was inhibited by phospholipase A2 inhibitors, such as arachidonyl trifluoromethyl ketone and manoalide. Forskolin, isoprenaline, and dibutyryl cyclic AMP inhibited the O2- generation, and KT-5720, a cyclic AMP-dependent protein kinase (A-kinase) inhibitor, markedly enhanced the O2- generation. These findings suggest that O2- is generated by a NADPH oxidase-like enzyme system in mast cells and that this enzyme system is activated by arachidonic acid released by cytosolic phospholipase A2. Thus, it is regulated by the cyclic AMP-A kinase system.

Animals↗
PubMed1980

Electron microscopic demonstration of metals in rat mast cells. A cytochemical study based on an improved sulphide silver method.

This paper describes a modification of a cytochemical method for the demonstration of heavy metals. The well localized precipitate in the mast cell granules, which is also present in granules that have been separated from the cell, suggest that the metals are localized in the granules. It is demonstrated that "mast cell" grown cultures do not contain precipitate. The chelating and histamine inhibiting agent 8-hydroxyquinoline produced no changes in the histochemical pattern of the mast cell granules before nor after treatment with the histamine liberator 48/80 which provokes a release of granules from the cells. These observations suggest either that the metal (zinc) is bound to the granules in such a manner that the chelating agent cannot chemically, or based on the configuration of the metal-containing molecule, reach the metal and thereby prevent its transformation to a metal suphide.

Animals↗
PubMed1975

A study of the perineurium in peripheral nerve pathology.

The response of the perineurium to the following experimental systems was investigated by light and electron microscopy: nerve crush, cold lesion and microinjection of (a) histamine liberator, (b) potassium cyanide, (c) lysophosphatidyl choline (LPC). Where myelin breakdown occurred, lipid globules were seen within Schwann cells, macrophages and also perineurial cells. Where increased vascular permeability occurred, proteinaceous material leaked from endoneurial vessels into the endoneurial space and later appeared between perineurial laminae. It is suggested that the normal homeostatic function of the perineurium is extended in pathology to the removal of protein and lipid debris. In this way the perineurium contributes to the restoration of the normal microenvironment of peripheral nerve fibres.

Animals↗