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Biomedical subjects

H O Heuer

Publications and source records attributed to H O Heuer.

At least 19 recordsLinked to original sources
PubMed1999

Comparative effects of a glucocorticosteroid, theophylline and the peptido-leukotriene-antagonist CGP 45715A on antigen-induced early and late phase airway response and inflammatory cell influx in sensitised guinea pigs.

A novel model of allergic early and late-phase reaction in the airways of conscious guinea pigs was developed and the effect of established and novel antiasthmatic drugs on peak of immediate response, late phase response and associated inflammatory cell influx investigated. Guinea pigs were sensitised twice in adjuvant (50 mg/kg silica + 0.1 ml/kg Bordetella pertussis). Under cover of 10 mg/kg i.p. mepyramine guinea pigs exhibited still a pronounced immediate reaction. During a screening phase about 75% of guinea pigs demonstrated a late phase reaction of decrease of tidal volume between 4-10 h after ovalbumin inhalation. In a cross over study theophylline at 50 mg/kg p.o. (-1 h before ovalbumin) tended to attenuate not only the peak of the immediate reaction by about 69% (P>0.05, n = 12), but inhibited the airway late phase response significantly (P<0.05, 5-10 h, n = 12). Methylprednisolone (40 mg/kg p.o. 1 h before ovalbumin) did not inhibit the immediate response, but the late phase response. In contrast the cysteinyl-leukotriene antagonist CGP 45715A (Iralukast; 30 mg/kg p.o. 2 h before ovalbumin) neither interfered with the peak of the immediate, nor with the late phase response. When bronchoalveolar lavage by orotracheal route was performed 24 h after ovalbumin inhalation, total cell count, eosinophils, neutrophils, macrophages and lymphocytes were significantly increased in ovalbumin-controls compared to sham (n = 5; P<0.05). Methylprednisolone reduced significantly the antigen-induced increase of total cell count and eosinophil number. Neither theophylline nor the cysteinyl-leukotriene receptor antagonist attenuated the antigen-associated cell influx. The results do not provide evidence for a major role of cysteinyl-leukotrienes in the late phase response and inflammatory cell influx in this model.

Animals↗
PubMed1996

Characterisation of a novel airway late phase model in the sensitized guinea pig which uses silica and Bordetella pertussis as adjuvant for sensitization.

The objective of the present investigation was to validate a novel model of allergic late phase reaction in the airways of conscious guinea pigs by monitoring airway function with CO2-forced respiration. In addition airway inflammation as one possible cause for the development of airway late phase reaction was characterized by a novel technique which consists of bronchoalveolar lavage via the orotracheal route. Guinea pigs were sensitized twice at 2-week intervals with ovalbumin in silica and Bordetella pertussis. Two weeks after the booster sensitization all guinea pigs showed an acute decrease of tidal volume under CO2-forced respiration 5-15 min after antigen challenge. In contrast 42 out of 68 (= 62%) screened guinea pigs exhibited airway late phase response between 4-10 h after aerosol antigen challenge. During a subsequent cross-over study methylprednisolone (twice at 16 and 1 h before ovalbumin) did not significantly interfere with the acute response. In contrast the airway late phase response as well the associated eosinophil influx into the bronchoalveolar lavage were attenuated by the steroid. In conclusion, the sensitization procedure in combination with the novel method for monitoring airway function allowed measurement of a reproducible airway late phase response in about 60% of sensitized guinea pigs. The sensitivity of exclusively the late phase response and eosinophil influx to treatment with a glucocorticoid not only correlates this model with clinical pharmacotherapy but also strengthens the inflammatory nature of this model.

Adjuvants, Immunologic↗
PubMed1996

Pharmacological characterisation of a new model of antigen-induced pulmonary late-phase reaction in the conscious guinea pig which uses additional polymyxin B inhalation.

The aim of the present study was to develop a new model of allergic late-phase reaction in the airways of conscious guinea pigs (GPs) and to characterise it by pharmacological intervention. GPs were pretreated with cyclophosphamide and sensitized with ovalbumin (OA) in Al(OH)3. Weekly inhalations of polymyxin B were performed before and during sensitization and continued throughout the study period. Under cover of 10 mg/kg i.p. mepyramine all GPs still exhibited a pronounced immediate reaction (IR), peaking during the first 15 min after OA. Nine out of 15 GPs demonstrated, during screening, a reproducible (twice) second phase (late phase reaction (LPR)] of decreased airflow and tidal volume (TV), peaking 4-8 h after OA. In a cross over study, methylprednisolone (MP) at 30 mg/kg p.o. (16 h and 1 h before OA) significantly inhibited the LPR at its peak (4-8 h) (peak decrease of TV to % of basal: control 49.4 +/- 3.7; MP 78.9 +/- 7.5; p < 0.01: n = 7). After another booster sensitization with 2 micrograms OA/GP under the same conditions, the Paf-antagonist WEB 2347 at 3 mg/kg p.o. (1 h before OA) inhibited the LPR at its peak again (peak decrease of TV to % of basal: control 57.3 +/- 3.5; WEB 2347 74.8 +/- 7.6: p < 0.01; n = 6). In conclusion more than 50% of repeatedly ovalbumin sensitized (and polymyxin B-treated) unanaesthetized GPs developed a reproducible pulmonary late phase reaction (LPR). The LPR peaked at 4-8 h after antigen-exposure. The inhibitory effect by a glucocorticoid and the Paf-antagonist WEB 2347 suggests the inflammatory nature of the LPR and the involvement of platelet-activating factor (Paf) in this model.

Administration, Inhalation↗
PubMed1994

Dissociation of airway responsiveness and bronchoalveolar lavage (BAL) cell composition in sensitized guinea-pigs after daily inhalation of ovalbumin.

The association between inflammatory cell influx, cell activation status and change of airway responsiveness to acetylcholine (ACh) after daily inhalation of ovalbumin (OA) in sensitized guinea-pigs was investigated. Starting 3 weeks after sensitization (OA at 50 mg/kg s.c.+i.p.) guinea-pigs were exposed daily to 2% OA (10 min; under cover of 0.5 mg/kg mepyramine i.p. 15 min before OA) for 2 weeks. Concentration-response curves (CRCs) for inhaled ACh were performed 24 h after the last OA-challenge and 24 h after another single OA-inhalation 1 week later. CRCs for inhaled ACh were neither affected 24 h after the last OA challenge (daily for two weeks) nor 24 h after another OA-inhalation one week later. In contrast, bronchoalveolar lavage (BAL) from repeatedly OA- sensitized/-challenged guinea-pigs immediately after the last CRC showed a significant increase of total cell count by about tenfold and increases in eosinophils by about 20-fold, neutrophils by 30-fold, macrophages by about fivefold and lymphocytes by about tenfold (P < 0.05, multiple Wilcoxon-test). In contrast, markers of cell activation (EPO, MPO) were significantly decreased (P < 0.05). Methylprednisolone almost completely prevented these changes in increased cell numbers and decreased cell activation (vs OA contr., P < 0.05). The lack of increased airway hyperresponsiveness despite a massive inflammatory cell influx suggests other factors controlling airway responsiveness than inflammation.

Acetylcholine↗
PubMed1992

Platelet-activating factor antagonists in experimental shock.

Platelet-activating factor (PAF) at 10 micrograms/kg i.v. induced profound hyperkalemia, changes of hematological parameters, patterns of ECG, and acid-base balance in rats. In separate experiments infusions of PAF at 30 ng/kg/min or injection of endotoxin from E. coli (15 mg/kg i.v.) induced a marked drop in blood pressure. All these changes were antagonized by pretreatment or post-treatment (in case of hypotension) by the selective hetrazepinoic PAF antagonists apafant (WEB 2086, CAS 105219-56-5; 0.1-5 mg/kg i.v.), bepafant (WEB 2170, CAS 114776-28-2; 0.05-1.0 mg/kg i.v.), or STY 2108 (0.01-0.1 mg/kg), respectively. The results support the view that PAF can mimic features of endotoxin shock and that the hetrazepines (like apafant, bepafant) are useful tools to clarify the role of PAF in such conditions.

Acid-Base Equilibrium↗
PubMed1991

Inhibition of active anaphylaxis in mice and guinea pigs by the new hetrazepinoic PAF antagonist bepafant (WEB 2170).

The aim of this study was to examine the ability of the novel PAF (platelet-activating factor) antagonist WEB 2170 to inhibit active anaphylaxis in mice and guinea pigs. Previous studies with other PAF antagonists have given equivocal results. This study was designed to define conditions under which a clear and significant effect of the PAF antagonist would be shown. WEB 2170 could be shown active, at concentrations of between 1 and 10 mg/kg p.o. in a model of murine anaphylaxis, in which the mice were actively sensitized and also treated with the beta-adrenoceptor antagonist propranolol to potentiate the anaphylactic response. WEB 2170 was also active in guinea pig models of anaphylaxis (tested dose range: 5 mg/kg i.v. and 0.04-3 mg/kg p.o.), in which the guinea pigs were sensitized according to one of three specified immunization schedules and pretreated with low doses of mepyramine before antigen challenge. These results suggest that PAF has a role in active anaphylaxis in mice and guinea pigs. However, to demonstrate this effect in guinea pigs, models must be used in which the effects of histamine release are minimized.

Anaphylaxis↗
PubMed1991

Action of the racemate and the isomers of the platelet-activating factor antagonist bepafant (WEB 2170) after oral administration to guinea-pigs and rats.

The aim of the present study was to clarify whether there is a difference in terms of potency and pharmacodynamic half time between the isomers and the racemate of the platelet-activating factor antagonist WEB 2170 (bepafant) after oral administration to guinea-pigs or rats. The following experiments were performed in the guinea-pig. Infusion of platelet-activating factor at 30 ng/(kg x min) for 30 min to anaesthetized guinea-pigs induced a decrease of respiratory flow and mean arterial blood pressure. Oral pretreatment with WEB 2170 or isomers, respectively, 60 min before infusion of platelet-activating factor inhibited these changes in a dose-dependent manner. The ED50s for inhibition of respiratory flow were: (-) WEB 2170 = 0.018 (0.009-0.036) mg/kg p.o; (+/-) WEB 2170 = 0.021 (0.015-0.03) mg/kg p.o.; (+) WEB 2170 = 1.55 (1.01-3.05) mg/kg p.o. Similar ED50 values were obtained for inhibition of decrease of MAP. Doses of isomers and racemate of WEB 2170 that provided almost complete protection against platelet-activating factor at 1 h after administration were chosen for determination of the duration of the protective effect after oral administration. Oral (-) WEB 2170 or (+/-) WEB 2170 showed almost identical time-response curves for inhibition (t1/2 = 14-17 h; 0.1 mg/kg p.o.) in the guinea-pig, whereas the duration of action of (+) WEB 2170 (3-6 h; 8 mg/kg) was significantly shorter. The following experiments were conducted in the rat. Oral pretreatment with WEB 2170 racemate and isomers resulted in a dose-dependent reversal of platelet-activating factor-induced hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1991

Involvement of platelet-activating factor (PAF) in septic shock and priming as indicated by the effect of hetrazepinoic PAF antagonists.

Pharmacological data obtained with hetrazepinoic platelet-activating factor (PAF) antagonists, such as apafant (WEB 2086) and bepafant (WEB 2170), indicate a role for PAF in septic shock and in the priming process. The effect of PAF antagonists in different models of shock states favors a role for PAF in endotoxin associated lethality, activation of inflammatory blood cells with release of mediators, cardiovascular failure and increased vascular permeability, and in the development of shock organs and organ failure. The priming process (e.g., by endotoxin or tumor necrosis factor) towards an increased susceptibility towards minute amounts of PAF has to be taken into account when considering the pathophysiological significance of PAF under in vivo conditions and in septic shock.

Animals↗
PubMed1991

Effect of the hetrazepinoic platelet-activating factor antagonist Bepafant (WEB 2170) in models of active and passive anaphylaxis in mice and guinea pigs.

The selective hetrazepinoic platelet-activating factor (PAF) antagonist WEB 2170 (Bepafant) was used to study the pathophysiological role of PAF in several models of anaphylaxis in mice and guinea pigs. In actively sensitized mice, the PAF antagonist WEB 2170 (1.0-10 mg/kg p.o.) protected mice from anaphylactic death in a dose-dependent manner when the anaphylactic response was potentiated by the beta-receptor antagonist propranolol. When active anaphylaxis in guinea pigs was induced intravenously by 100 mg/kg ovalbumin (OA) in the presence of small doses of the antihistamine mepyramine, additional treatment with oral or intravenous WEB 2170 protected the guinea pigs from anaphylactic death. Also, the remaining anaphylactic bronchoconstriction and blood pressure changes (including anaphylactic hypotension) were attenuated. When guinea pigs were passively sensitized with a heterologous antibody via the tracheal route and then challenged by ovalbumin (100 mg/kg i.v.) 24 hr after sensitization in the presence of 0.003 mg/kg i.v. mepyramine, additional treatment with tracheal WEB 2170 at 0.1-1 mg/kg protected the guinea pigs dose-dependently not only from anaphylactic death but also from a further decrease of respiratory flow and changes of blood pressure. Increased levels of PAF-like activity (20-50 ng PAF/whole lung) were detected in lungs removed from antigen-challenged animals. The results suggest a causative role for PAF in active and passive anaphylaxis.

Anaphylaxis↗
PubMed1991

Platelet-activating factor type activity in plasma from patients with septicemia and other diseases.

The purpose of the present study was to determine whether increased levels of platelet-activating factor (PAF) type activity can be detected in plasma from patients with septicemia and other diseases. A level of PAF below 0.5 ng/mL of plasma was considered normal. We found that plasma from a patient with adverse anaphylactoidic reaction to intravenous analgetics contained 2.1 ng PAF/mL. In seven patients with septicemia, including urosepsis, endocarditis and peritonitis, and with positive blood culture, increased plasma PAF levels (1-20 ng PAF/mL) were observed. Other patients with clinical indications of septicemia had negative blood cultures and/or increased levels of C-reactive protein (CRP). Yet, in the plasma from these patients, no increased PAF levels were detected under the assay conditions used. Two patients with allergic asthma, requiring treatment with steroids, had no measurable plasma PAF. In the plasma from a patient with idiopathic thrombocytopenic purpura (ITP) only an "endogenous" inhibitor of PAF induced platelet aggregation was initially observed. In spite of this, the patient responded to treatment with the PAF antagonist WEB 2086 with a dramatic increase in platelet count (Lohmann et al., Lancet ii, 1147, 1988). Thereafter, also increased PAF levels (3.3 ng PAF/mL) were detected in plasma, although some "endogenous" inhibitor of PAF was still present. In conclusion, increased PAF levels in plasma from patients support a role of PAF in certain human disease states, such as in anaphylactoid reaction, sepsis and septic shock. The type, relevance and specificity of endogenous inhibitors of PAF deserve further study.

Adult↗
PubMed1991

Pharmacodynamics, pharmacokinetics and safety profile of the new platelet-activating factor antagonist apafant in man.

Platelet-activating factor (PAF) is a unique phospholipid mediator with multifunctional properties. Evidence generated in experimental studies suggests that PAF plays a pathogenetic role in anaphylactic, inflammatory and immunogenic reactions. Apafant (WEB 2086, CAS 105219-56-5), a novel synthetic PAF receptor antagonist, was administered to a total of 101 healthy volunteers within 5 studies to investigate its pharmacologic activity, pharmacokinetic behaviour and safety profile. Pharmacologic activity was monitored by inhibition of 5 x 10(-8) mol/l PAF-induced platelet aggregation ex vivo. The following treatment schedules were studied: oral single dose 1.25 to 400 mg; oral multiple dose 100 mg t.i.d. over 7 days; i.v. infusion 0.5 to 50 mg (over 30 min); inhalative administration up to 1.0 mg. PAF induced platelet aggregation was virtually completely inhibited by single oral doses of 20 mg upwards, throughout during the multiple oral dose study, at all dose levels tested in the i.v. study and (significantly but not completely) at 0.5 and 1.0 mg in the inhalative study. Following oral administrations (capsules) apafant is absorbed rapidly (tmax 1 to 2 h), there is linear pharmacokinetics for the mean plasma concentrations of apafant measured by RIA as well as for the areas under the curve (AUCs). Approximately 60% of apafant is bound to plasma protein, the mean volume of distribution is 28 l, about 44% of an oral dose is excreted in the urine, the mean renal clearance is 192 ml/min. No accumulation of the drug occurred in volunteers with normal kidney function. No clinically relevant drug related adverse events or changes in laboratory or vital parameters such as blood pressure, heart rate, respiratory rate and ECG were observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

PAF receptor antagonists influence asphyxia-induced changes of the inner ear.

The influence of a transient asphyxia on cochlear potentials, i.e. endolymphatic potential (EP), summating potential (SP) and cochlear microphonics (CM) was investigated in guinea pigs which were injected with two different PAF receptor antagonists before. It could be shown that apafant (WEB 2086) and bepafant (WEB 2170) significantly reduced the asphyxia-induced potential changes compared to controls. The results suggest a mediating role of PAF in the asphyxia model. The impact of the findings for therapeutics is discussed.

Animals↗
PubMed1991

The effects of hetrazepine PAF antagonists in preclinical models of asthma.

In different disease related animal models of asthma selective and potent hetrazepine paf-antagonists (like the hetrazepines WEB 2086 and WEB 2170) inhibit (i) allergen-induced bronchoconstriction, (ii) antigen-induced infiltrations of eosinophils, (iii) lung-edema formation by antigen, (iv) late phase response and (v) bronchial hyperreactivity to antigen. In addition the formation and release of other mediators (like leukotrienes, thromboxanes, histamine) are inhibited in vivo, although a direct interaction of hetrazepinoic paf-antagonists with these mediators has been excluded. The participation of paf in a chain of pathophysiological events involving other mediators, and the possibility of synergistic interactions, open up the possibility that antagonists of paf may have apparent effects extending beyond those anticipated for a single mediator.

Anaphylaxis↗
PubMed1990

Inhibitory effects of the new PAF acether antagonist WEB-2086 on pharmacologic changes induced by PAF inhalation in human beings.

Recent research on asthma mediators has concentrated more and more on platelet-activating factor (PAF), which is one of the most potent bronchoconstrictors known thus far. Inhalant PAF challenge in healthy volunteers may provide a mean of testing PAF antagonists. The usefulness of the PAF provocation test in measuring the pharmacologic activity of a new PAF antagonist, WEB-2086, has been examined in 12 healthy volunteers in a double-blind, placebo-controlled, within-subject crossover study. PAF-induced immediate bronchoconstriction, slight hemodynamic changes, and PAF-related subjective side effects. Premedication with WEB-2086 (40 mg) completely prevented any increase in airway resistance after PAF inhalation, as well as development of most of the cardiovascular and side effects induced by PAF. The clear protection against PAF-induced pharmacologic effects can be explained by the specific PAF-antagonistic activity of WEB-2086. The method described in this article may be applied as a useful tool for looking at PAF-antagonistic activity in healthy volunteers.

Administration, Inhalation↗
PubMed1990

Tumor necrosis factor (TNF) and endotoxin prime effects of PAF in vivo.

The purpose of the present study in NMRI mice was to investigate the action of platelet-activating factor (PAF) on mortality and intestinal transit velocity, the interaction of endotoxin or tumor necrosis factor (TNF) with the effect of PAF on these parameters and the effect of the PAF antagonist WEB 2086 on the endotoxin/TNF- and PAF-induced changes. PAF at a high dose (200 micrograms/kg i.v.) increased mortality and reduced transit velocity. This effect was inhibited by WEB 2086 (0.01-0.5 mg/kg i.p.) in a dose-dependent manner. Pretreatment with endotoxin (S. typhosa; 10 micrograms/kg i.v.) or TNF (40 micrograms/kg i.v.) enhanced the activity of PAF resulting in increased mortality and reduced transit velocity. This enhanced activity of PAF in the case of pretreatment with endotoxin or TNF occurred at doses at which PAF, endotoxin or TNF given alone did not significantly affect these parameters. The ability of endotoxin or TNF to enhance the effect of PAF was maximal, if the time delay between endotoxin and subsequent PAF administration was about 1-2 h. WEB 2086 (0.01-1 mg/kg i.p.) inhibited this priming in a dose-dependent fashion. These findings support suggestions of a role for PAF in endotoxin shock and TNF-associated shock-like syndrome.

Animals↗
PubMed1990

Pharmacologic activity of bepafant (WEB 2170), a new and selective hetrazepinoic antagonist of platelet activating factor.

The hetrazepine WEB 2170 (international nonproprietary name: bepafant), a thieno-triazolodiazepine that is structurally related to the recently described platelet activating factor (PAF) antagonist WEB 2086, is a potent and selective PAF antagonist both in vitro and in vivo. WEB 2170 inhibited PAF-induced human platelet and neutrophil aggregation in vitro (IC50 values: 0.3 and 0.83 microM, respectively) but had little or no inhibitory action against aggregation induced by other agonists. The potency in vitro was comparable to that described recently for WEB 2086 (Casals-Stenzel, J., Muacevic, G. and Weber, K.H.: J. Pharmacol. Exp. Ther. 241: 974-981, 1987). When guinea pigs were given i.v. infusions of PAF at 30 ng x kg-1 x min-1, oral (0.005-0.5 mg/kg) as well as intravenous (0.005-0.05 mg/kg) treatment with WEB 2170 abrogated the intrathoracic accumulation of 111In-labeled platelets, the bronchoconstriction and the hypotension as well as the finally occurring death in a dose-dependent fashion. Oral (0.01-1 mg/kg) and intravenous (0.005-0.1 mg/kg) WEB 2170 shared with the beta 2 agonist fenoterol and the steroid dexamethasone the property of protecting elderly NMRI mice from the lethal effect of PAF. In anesthetized rats, intravenous (0.001-0.1 mg/kg) and oral (0.05-1 mg/kg) WEB 2170 inhibited PAF-induced hypotension in a dose-related manner. Coadministration of WEB 2170 inhibited PAF-induced increase of vascular permeability in rat skin very effectively. The half-time of duration of action in the rat was estimated to be about 5 to 6 h after oral administration and about 1.1 to 2.3 h after intravenous application. In conclusion, the hetrazepine WEB 2170 is a strong and selective PAF antagonist, which is in vitro more or less equipotent to WEB 2086. In contrast, in vivo oral WEB 2170 is--depending on the species and considered parameter--about 5 to 40 times more potent against exogenous PAF-induced alterations than the recently described hetrazepine WEB 2086. Particularly in mice and rats, oral WEB 2170 is by far superior to WEB 2086.

Administration, Oral↗