Anti-asthmatic effects of onions. Alk(en)ylsulfinothioic acid alk(en)yl-esters inhibit histamine release, leukotriene and thromboxane biosynthesis in vitro and counteract PAF and allergen-induced bronchial obstruction in vivo.

Five alk(en)ylsulfinothioic acid alk(en)yl-esters isolated from onions and four synthetic thiosulfinates inhibited 5-lipoxygenase of porcine leucocytes, histamine release and leukotriene B4 and C4 biosynthesis of human polymorphonuclear leucocytes, thromboxane B2 biosynthesis by human platelets and allergen- and PAF-induced bronchial obstruction of guinea-pigs. The anti-asthmatic and anti-inflammatory effects of onions depend in part on the thiosulfinate moiety: (Formula: see text).

In vitro IgE eluation and histamine releasability from peripheral leukocytes of atopics and normals.

The relation between the amount of cell-bound IgE and the histamine 'releasability' of peripheral leukocytes was studied in 28 patients with atopic diseases and 26 non-atopic controls after in vitro stimulation with anti-IgE. Cell-bound IgE was eluted in acid buffer (pH 3.7) and the amount of histamine released (HR) into supernatant at this pH was measured. Incubation with acetate buffer (pH 3.7) induced significantly higher spontaneous HR (32 net percent) in atopics compared to 18% in controls. The amount of IgE eluted was significantly higher in atopics: The calculated number of IgE molecules/basophil was 332,000 in atopics compared to 177,000 in controls. There was a significant positive correlation between plasma IgE and in vitro elutable IgE in atopics (r = 0.73) compared to controls (r = 0.24). After a careful washing procedure attempts were made to 'resensitize' the basophils through incubation with autologous plasma or standard IgE solutions. When resensitization was possible, there was no correlation between histamine releasability after resensitization and original IgE content of basophils. It is concluded that the increased histamine releasability from leukocytes of atopic individuals after stimulation with anti-IgE is only in part due to an increased number of IgE molecules per basophil surface. A non-specific increased releasability was demonstrated by increased spontaneous HR rates in acid buffer (pH 3.7). A resensitization with autologous plasma-IgE was possible only in half of the subjects investigated, most of them being atopic. The data support the concept of an altered releasability both towards IgE-dependent and independent stimuli being one possible factor in the pathogenesis of atopic eczema.

Noninvasive Analysis of Lung Function in Small Animals: Compressed Air, Thoracic Gas Volume, Airway Resistance, Maximal Flow Rates, Tidal Volume, Breathing Frequency, l/E Ratio.

We present a noninvasive and highly sensitive system for measuring lung function in small animals. It is based on a two-chambered body plethysmography. Head and body chambers are separated by a cuff around the head of the animal. Aerosols for pharmacologic investigations are generated. Breathing-dependent changes in pressure and/or volume are registered, the signals are digitized. All data are processed in an IBM compatible PC/AT. A multitasking real time operation system shows the signals on line. A special software offers seven different lung function parameters (compressed air, airway resistance, thoracic gas volume, maximal flow rates, tidal volume, breathing frequency, I/E ratio). The results are presented as graph and text documents. Result files are submitted to calculation by standard soft ware. The computer-aided handling allows the simultaneous performance of up to nine pharmacological tests.

Acetophenones: Highly Active Antiasthmatic Compounds of Plant Origin.

In Ayurvedic medicine, Picrorrhiza kurroa Royle ex Benth. is used for the treatment of liver and lung diseases. We could identify the phenol glycoside, androsin, as an active compound preventing allergen- and PAF-induced bronchial obstruction in guinea pigs in vivo. The inhalation of androsin and its aglycon, apocynin, was more effective than the oral intake. More than 20 different acetophenones, either newly synthesized or purchased from commercial sources, have been tested in several pharmacological systems. 3,5-Dimethoxy-4-hydroxyacetophenone (Acetosyringenin) is by far the most active compound preventing allergen- and PAF-induced bronchial obstruction by more than 80% after one single dose of 0.5 mg (aerosol).

Antiasthmatic effects of onions: inhibition of 5-lipoxygenase and cyclooxygenase in vitro by thiosulfinates and "Cepaenes".

Nine thiosulfinates (TS) and four "Cepaenes" (CS) isolated from onions and/or synthetized by us showed dose dependent (0.25 to 100 microM) marked inhibitory effects on both cyclooxygenase (CA, tested on sheep seminal vesicle microsomes) and 5-lipoxygenase activity (LO, tested on porcine leukocytes). The following rank order of activity was observed: saturated aliphatic TS less than aromatic TS approximately alpha, beta-unsaturated TS less than CS. CS inhibited both CA and LO by more than 75% at 10 and 1 microM concentrations respectively. Most likely, these in vitro effects are responsible for antiinflammatory and antiasthmatic properties of onion extracts observed in vivo, at least in part.

Antiasthmatic effects of onion extracts--detection of benzyl- and other isothiocyanates (mustard oils) as antiasthmatic compounds of plant origin.

Previous studies showed the inhibitory effects of crude ethanolic onion extracts (COE) on allergic skin reactions in man as well as on allergen-induced bronchial asthma in man and guinea-pigs. Work is in progress in order to identify both the mode of action of COE and the active substance(s). The present study describes asthma-protective effects of isothiocyanates. Groups of at least 5 guinea-pigs sensitized to ovalbumin were challenged twice (time 0 and 10 min) by the inhalation of ovalbumin 30 min after oral treatment with increasing doses of the agent tested or control solutions. Bronchial obstruction (BO) was measured by whole body plethysmography. Chloroform extracts of onions showed similar protective effects on BO as COE. The water-soluble fraction of COE was inactive. Benzyl-isothiocyanate (BITC) was identified as one component of onion lipids by combined gas chromatography/mass spectrometry. BITC inhibited BO in a dose-dependent fashion: 150 mg/kg: 89%; 75 mg/kg: 76%; 30 mg/kg: 66%; 15 mg/kg: 49%. Ethyl-isothiocyanate and allyl-isothiocyanate showed similar effects; p-hydroxy-benzyl-isothiocyanate, a very unstable mustard oil, was ineffective. Additional experiments showed no antagonistic effects of COE on histamine- or acetylcholine-induced BO. The antiasthmatic effects of onions and - perhaps - other plants may be mediated at least in part by isothiocyanates.

Pancreatic and gastric responses to gastric versus jejunal beer in humans.

To investigate the influence of beer on gastric and pancreatic secretion, 14 fasted volunteers were studied on two different days. A multilumen intestinal tube allowed measurement of intraluminal pressures and collection of gastric and duodenal juices. Seven subjects received in random order 250 ml of either beer or glucose (5.6%, w/v) intragastrically; seven other subjects received these intrajejunally. After 15 min, 48 +/- 8% of beer and 47 +/- 6% of glucose were emptied into the duodenum. Intragastric beer induced a nearly sevenfold increase in gastric acid output as compared with glucose (16.3 +/- 2.9 mmol/h versus 2.5 +/- 0.6 mmol/h; p less than 0.05), intrajejunal beer induced a nearly threefold increase (5.1 +/- 0.8 mmol/h versus 1.7 +/- 0.3 mmol/h). The stimulated gastric acid output was threefold higher after intragastric than after intrajejunal beer. Trypsin output was slightly but significantly (p less than 0.05) stimulated by intragastric beer as compared with glucose (4,639 +/- 460 U/h versus 3,628 +/- 399 U/h) and nearly threefold by intrajejunal beer (2,579 +/- 455 U/h versus 849 +/- 181 U/h) (p less than 0.05). Trypsin response to intragastric beer was 1.8 times higher than after intrajejunal beer (p less than 0.05). Intragastric beer induced a nearly ninefold increase of the 1 h integrated plasma gastrin response as compared with glucose (998 +/- 347 pM min vs 115 +/- 70 pM min) (p less than 0.05). Intrajejunal beer and glucose did not release gastrin. We conclude that both intragastric and intrajejunal beer stimulate gastric acid and pancreatic enzyme secretion; intragastric beer being a more potent stimulant. Gastrin might partially mediate the responses to intragastric but not to intrajejunal beer.

Allergen tachyphylaxis of guinea pigs in vivo; a prostaglandin E mediated phenomenon?

Ovalbumin (OA) sensitized guinea pigs were repeatedly challenged with 1% OA in saline nebulized ultrasonically at the 0, 10, 20, 60 and 70th min. The intensity of bronchial obstruction was measured by body plethysmography. The first three challenges (0. 10, 20 min) caused strong asthmatic reactions in all animals, the last two (60, 70 min) only mild one in 10 out of 15 animals. The development of this "tachyphylaxis" was markedly reduced by pretreatment of the animals with cyclooxygenase inhibitors (indomethacin 10 mg/kg intraperitoneally resp, acetylsalicylic acid 10 mg/kg orally 2 h before tests). The effect of both inhibitors (i.e. inhibition of tachyphylaxis) was abolished by supplementing prostaglandin E2 as aerosol simultaneously to the allergen (100-200 ng per inhalation). The results suggest that allergen tachyphylaxis we have observed in vivo might be due to synthesis of cyclooxygenase products, e.g. prostaglandin E.

In vivo allergen tachyphylaxis in guinea pig lung is mediated by endogenous prostaglandin E biosynthesis.

The term "allergen tachyphylaxis" (AT) describes a progressively decreased bronchial reactivity to allergen exposition after repeated allergen challenge [in our test system measured by sequential inhalative antigen challenge of sensitized guinea pigs (GP)]. The hypothesis that AT is mediated by endogenous prostaglandin E (PGE) biosynthesis was tested in vivo on GP sensitized to ovalbumin (OA). Different groups of animals were challenged with simultaneous inhalation of OA (repeatedly at time 0, 10, 20, 60 and 70 min) together with inhibitors of PGE-biosynthesis ( parachloromercurobenzoic acid = PCMB, copper sulfate = Cu, copper dithiotreitol complex = CuDTT , dithiotreitol = DTT and dimercaptopropanol = DMP) or agents increasing PGE production (aurothioglucose = Au, zinc dithiotreitol complex = ZnDTT and reduced glutathion = GSH). Bronchial obstruction was measured by whole body plethysmography . PCMB, Cu, CuDTT , DTT and DMP inhibited AT, whereas Au and ZnDTT enhanced AT. Acetylsalicylic acid (ASA) treatment prevented AT. Aerosols of PGE2, but not of prostacyclin or prostaglandin D2 restored AT in ASA treated animals. In addition to these in vivo experiments in vitro investigations showed that PCMB, Cu and DTT decreased while ZnDTT increased PGE biosynthesis of allergen challenged GP lungs. It is concluded that AT, an important self-protecting mechanism of GP bronchial asthma, is mediated at least in part via endogenous PGE.

Sequential histamine inhalations cause increased bronchial histamine reactivity in guinea pigs: role of platelets, thromboxanes and prostacyclin.

Groups of 6-15 guinea pigs sensitized to ovalbumin were challenged by repeated inhalations of a constant histamine dose at time 0, 10, 20, 60 and 70 min. Bronchial obstruction was measured by whole body plethysmography. The degree of bronchial obstruction increased from one challenge to the other reaching maximal values after 70 min. This increase of bronchial responsiveness to histamine after repeated histamine challenges was reduced by pretreatment with clemastine (histamine H1-receptor antagonist, 0.12 mg/kg i.p., n = 7, P less than 0.05) and more effectively by combined clemastine/cimetidine pretreatment (combined H1-H2-receptor antagonists, 0.12 resp. 10 mg/kg, n = 7, P less than 0.001); pretreatment with acetylsalicylic acid (10 mg/kg orally) accelerated the increase of bronchial responsiveness to histamine (n = 9, P less than 0.01 at the second challenge), inhalation of prostacyclin (1 microgram) prior to each histamine inhalation prevented the increase of bronchial histamine sensitivity totally (n = 10, P less than 0.001), whereas inhibition of thromboxane biosynthesis (imidazol, 10 mg/kg i.p., n = 6; 4-[2-(1H-imidazol-1-yl)ethoxy]benzoic acid, 10 mg/kg i.p., n = 9; imidazo(1,5-a)pyridine-5-hexanoic acid, 1 mg/kg i.p., n = 8) as well as immunologic platelet depletion were ineffective in our test system. We conclude that prostacyclin inhibits the increase of bronchial responsiveness to histamine after sequential histamine inhalation challenges by a platelet independent mechanism. 1-(3-phenyl-2-propenyl)-1H-imidazol, the fourth type of thromboxane synthetase inhibitor tested (10 mg/kg i.p., n = 15) showed specific effects which may be attributed to antihistamine functions.

Comparison of histamine release and prostaglandin E2 production of human basophils in atopic and normal individuals.

The influence of arachidonic acid (AA) metabolism upon histamine release (HR) from human basophils after stimulation with anti-IgE was studied in 23 atopic and 11 normal individuals. HR occurred significantly faster in atopics than in normals; the total amount of HR after a 40 min incubation period was not significantly different between the two groups. Indomethacin and acetylsalicylic acid (ASA) increased the quantity of HR significantly both in atopics and normals without influencing the time course. Addition of exogenous PGE2 decreased HR; here atopics were more affected than normals 5 and 10 min after challenge with anti-IgE. Production of PGE2 after stimulation with anti-IgE was very low in both groups (in the range of 30-50 pg/10(6) cells) and often below detection limit (10-20 pg/ml). Addition of glutathione (GSH), a coenzyme of PGE2-isomerase, increased PGE2 production 2 to 5-fold during stimulation with anti-IgE. These data support the idea that arachidonic acid metabolites play an important role in modulating the "releasability" of human basophils. It is suggested that the basophils of atopic individuals may release their histamine faster than normals - perhaps on the basis of a more slowly acting endogenous feedback mechanism by PGE2. Both phenomena support the idea of an altered "releasability" of basophils from atopics compared to normals.

Altered releasability of vasoactive mediator secreting cells in atopic eczema.

A summarizing survey of different studies in atopic eczema involving three types of cells (platelets, neutrophils, basophils) and their mediators is given. Platelets were found to release normal amounts of serotonin upon stimulation with epinephrine, thrombin and slightly reduced amounts after aggregated IgG stimulation. Serotonin uptake by washed platelets was found to be slower in atopics than in normals. Neutrophils showed a decreased release of beta-glucuronidase to stimuli like zymosan or aggregated IgG in atopics compared to controls. This might be regarded as a contributory factor to the well-known decreased resistance to infections observed in atopic eczema. Basophils in most studies released increased amounts of histamine in the atopic population compared to controls, especially after stimulation with anti-IgE. Concomitantly to the histamine release there was a slight increase in prostaglandin E2 production both in atopics and normals, which was increased by preincubation with reduced glutathion-a coenzyme of PGE2 isomerase. Histamine release tended to occur faster in atopics. Two possible factors influencing releasability characteristics were studied, namely the cyclic nucleotide system and arachidonic acid (AA) dependent mechanisms. Leucocytes of atopics showed a decreased response of cAMP to beta-adrenergic and an increased response of cGMP to cholinergic stimulation. Significant augmentation of anti-IgE-induced histamine release was observed after cholinergic stimulation. AA metabolites obviously play a regulating role in mediator release. PGE2 inhibited histamine release to various stimuli both in atopics and in normals. Indomethacin enhanced histamine release, especially after anti-IgE stimulation in atopics, while it inhibited complement-dependent release reactions both in atopics and in normals. The exogenous inhibitors of lipoxygenase eicosatetraynoic acid (ETYA) and nordihydroguaretic acid (NDGA) inhibited histamine release equally in atopics and normals. The endogenous lipoxygenase inhibitor 15-HETE showed no inhibitory but rather a slight enhancing effect upon histamine release. It is concluded that patients with atopic eczema often exhibit altered releasability patterns to a variety of stimuli. On the basis of our findings we describe "altered releasability" as one factor of a vicious cycle between increased IgE-production, mediator secretion and T cell regulatory disturbances in the pathogenesis of atopic eczema.

[Clinical application of extracts of Echinacea purpurea or Echinacea pallida. Critical evaluation of controlled clinical studies]. / Klinische Anwendung von Extrakten aus Echinacea purpurea oder Echinacea pallida. Kritische Wertung kontrollierter klinischer Studien.

The phytotherapy should be understood as being integrated into the rational pharmacotherapy. The modern phytotherapy tries hard to proof effects with pharmacological and clinical studies. The task force E of the federal bureau of health of Germany has made a statement regarding this problem. This article reviews only controlled clinical trials about the application of extracts of echinacea purpura or echinacea pallida.