RESUMO
Ularitide (CAS 118812-69-4, urodilatin) is a member of the family of the atrial natriuretic peptides. In the present study, the relaxant effects of ularitide acetate, isoproterenol (isoprenaline) hemisulfate, aminophylline, zaprinast, and different combinations between these drugs were investigated on methacholine chloride-precontracted guinea-pig tracheal smooth muscle. Ularitide acetate was a weaker bronchorelaxant than isoproterenol hemisulfate and aminophylline. Moreover the relaxation induced by ularitide acetate was reversible, while the relaxation induced by isoproterenol hemisulfate, aminophylline, and zaprinast was irreversible. Combinations between in each case two of these substances were overadditive, if the phosphodiesterase-inhibiting component was applicated before the combination partner. Their effects were only additive, if the combination partners were applicated simultaneously. All combinations between ularitide acetate and isoproterenol hemisulfate, aminophylline, or zaprinast respectively relaxed the tracheas irreversibly. These results suggest that ularitide acetate might be a novel partner for classical bronchorelaxants in potent bronchorelaxing combinations in the therapy of asthma bronchiale.
Assuntos
Fator Natriurético Atrial/farmacologia , Broncodilatadores/farmacologia , Músculo Liso/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Traqueia/efeitos dos fármacos , Aminofilina/farmacologia , Animais , Broncoconstritores/farmacologia , Sinergismo Farmacológico , Cobaias , Técnicas In Vitro , Isoproterenol/farmacologia , Masculino , Cloreto de Metacolina/farmacologia , Inibidores de Fosfodiesterase/farmacologia , Purinonas/farmacologiaRESUMO
Endothelial cell contraction plays a pivotal role in vascular leakage. It increases the extravasation of fluid and macromolecules from the lumen into the interstitium. This is also true for bronchial edema. Previous studies have indicated that an elevation of intracellular adenosine-3',5'-cyclic monophosphate (cAMP) or guanosine-3',5'-cyclic monophosphate (cGMP), respectively, can counteract this vascular leakage by improving the endothelial barrier function in analogy to the relaxation of smooth muscle cells. To investigate the potential antiedemateous effects of ularitide acetate (CAS 115966-23-9), isoproterenol hemisulfate (CAS 6078-56-4), sodium nitroprusside (CAS 13755-38-9, SNP), aminophylline (CAS 317-34-0), and combinations of these compounds, their effects on thrombin-induced macromolecular permeability raise in relation to cGMP- or cAMP-levels, respectively, in a model of human umbilical vein endothelial cells (HUVECs) were examined. Ularitide acetate, isoproterenol hemisulfate, and SNP all increased the amount of cyclic nucleotides and decreased the raise in permeability in the following order of potency: isoproterenol hemisulfate > ularitide acetate > SNP. Aminophylline raised both cGMP- and cAMP-levels in a weaker amount and was not able to decrease the thrombin-induced permeability raise on its own. By way of contrast, preincubation of HUVECs with aminophylline resulted in a more than additive potentiation of the cGMP-levels and the permeability lowering induced by ularitide-acetate. These in vitro-data indicate that ularitide-acetate, especially in combination with phosphodiesterase (PDE) inhibitors, could probably have beneficial effects in bronchial permeability edema.
Assuntos
Fator Natriurético Atrial/farmacologia , Broncodilatadores/farmacologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Endotélio Vascular/citologia , Fragmentos de Peptídeos/farmacologia , Trombina/farmacologia , Albuminas/metabolismo , Células Cultivadas , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Endotélio Vascular/efeitos dos fármacos , Feminino , Humanos , Gravidez , Azul TripanoRESUMO
In the isolated perfused rat lung, perfusion with platelet-activating factor causes bronchoconstriction, vasoconstriction and edema formation. The bronchoconstriction and vasoconstriction are largely mediated by thromboxane, whereas the edema formation is due to enhanced vascular permeability unrelated to eicosanoids. Since natriuretic peptides are known to relax smooth muscle and were suggested to attenuate enhanced vascular permeability, we investigated the effect of urodilatin on the PAF-induced alterations in lung function. Pretreatment with urodilatin (0.25 microM or 0.75 microM) reduced the PAF-induced increase in airway and vascular resistance by approximately 50%. Urodilatin pretreatment, however, was completely ineffective against the PAF-induced increase in weight gain and in vascular permeability, as assessed by the vascular filtration coefficient. Furthermore, urodilatin failed to affect the release of thromboxane into the perfusate in PAF-exposed lungs. Thus, urodilatin relaxes airway and vascular smooth muscle, but fails to reduce edema formation in PAF-perfused rat lungs.
Assuntos
Fator Natriurético Atrial/farmacologia , Broncodilatadores/farmacologia , Pulmão/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Análise de Variância , Animais , Broncoconstrição/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Edema/etiologia , Feminino , Pulmão/fisiologia , Tamanho do Órgão/efeitos dos fármacos , Perfusão , Fator de Ativação de Plaquetas , Ratos , Ratos Wistar , Tromboxanos/metabolismo , Resistência Vascular/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacosRESUMO
24 hours after an i.v. injection of 2 mg Sephadex G 200 particles ovalbumin sensitized Sprague Dawley rats show an antigen specific bronchial hyperreactivity and an unspecific hyperreactivity against serotonin. The aim of this study was to investigate the effects of Sephadex on blood parameters and lung pathology to find the morphological substrate of bronchial hyperreactivity in this animal model. In the blood neutrophilia (p < 0.01) but no eosinophilia was present. We conclude that a blood eosinophilia needs not to be necessarily correlated with hyperreactivity of the airways like claimed by other investigators for this animal model. Histologically we found that Sephadex particles are trapped in smaller-diameter arteries of the lung and lead to a granulomatous arteritis consisting mainly of ED1 positive and widely ED2 negative macrophages interspersed with eosinophils and neutrophils. Larger vessels not occluded by particles showed perivascular oedema with infiltration of eosinophils. We report here for the first time a significant hypertrophy of PAS positive goblet cells (p < 0.01) accompanied by a peribronchial infiltration with eosinophils (p < 0.01) and macrophages positive for ED1, ED2 and Ox-6 (p < 0.01) but not Ox-19 positive T-lymphocytes. The authors suggest that the peribronchial inflammation contributes importantly to the onset of bronchial hyperreactivity in this animal model and that the hypertrophy of goblet cells indicates the pathophysiological importance of peribronchial leukocytes.
Assuntos
Hiper-Reatividade Brônquica/induzido quimicamente , Hiper-Reatividade Brônquica/patologia , Dextranos/toxicidade , Animais , Contagem de Células Sanguíneas , Hiper-Reatividade Brônquica/imunologia , Dextranos/administração & dosagem , Feminino , Histocitoquímica , Imuno-Histoquímica , Injeções Intravenosas , Ovalbumina/toxicidade , Ratos , Ratos Sprague-DawleyRESUMO
Fourteen Brown-Norway rats were pretreated with physiological saline (n = 7) or 500 micrograms Sephadex (n = 7) intratracheally. 24 h later, a bronchial provocation test was performed under pentobarbital anaesthesia using increasing doses of acetylcholine aerosol and the degree of bronchospasm was measured using a modified Konzett-Rössler method. Subsequently, leucocyte counts were determined in the bronchoalveolar lavage fluid (BALF), BALF cells were differentiated, and the chemiluminescence of the BALF leucocytes were measured. Finally, the lungs were removed and histologically examined. The cell count in the BALF was significantly (p less than 0.05) increased in the animals pretreated with Sephadex compared to those in the saline group (mean value +/- SEM: 0.38 +/- 0.07 vs. 0.15 +/- 0.02 x 10(6)/ml). This difference was also reflected in the chemiluminescence measurements (2.51 +/- 0.53 vs. 0.20 +/- 0.03 x 10(6) counts/0.5 ml). In the Sephadex-treated animals there was also a significant increase in the absolute number of neutrophil (0.040 +/- 0.010 vs. 0.011 +/- 0.002 x 10(6)/ml) and, in particular, eosinophil granulocytes (0.188 +/- 0.055 vs. 0.003 +/- 0.001 x 10(6)/ml) in the total leucocytes of the BALF. Lung histology showed massive perialveolar and peribronchial oedema and granulomatous infiltrates, primarily with eosinophils, after intratracheal application of Sephadex; these findings were not observed in the saline group. None of these changes in the rats pretreated with Sephadex manifested themselves in increased bronchial reactivity to acetylcholine aerosol. It is uncertain if the Sephadex-induced increase in the eosinophil count is accompanied by an activation of this cell population, which appears to be of importance for the occurrence of bronchial hyperreactivity.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Acetilcolina/farmacologia , Brônquios/efeitos dos fármacos , Dextranos/toxicidade , Eosinofilia/induzido quimicamente , Pneumopatias/induzido quimicamente , Animais , Pulmão/patologia , Masculino , Ratos , Ratos Endogâmicos BN , Hipersensibilidade Respiratória/induzido quimicamenteRESUMO
In the first part of this review the important role played by the bronchial hyperreactivity caused by chronic bronchopulmonary inflammation in asthma is described. Deliberately, more emphasis is placed on the role of pro-inflammatory eosinophils, alveolar macrophages, lymphocytes and platelets rather than on mast cells and neutrophils or the numerous mediators. The reason for this is that, on account of the large number of mediators and their multitude of functions and interactions in asthma, antagonism of a specific mediator will probably not be clinically relevant for optimally effective curative treatment of asthma. Inhibition of the infiltration and activation of pro-inflammatory cells is likely to be a more successful approach. In the second part, various animal models of bronchial hyperreactivity, which could be suitable for testing anti-asthmatic drugs, are discussed. Most animal models pay too little attention to chronic bronchopulmonary inflammation as the cause of bronchial hyperreactivity in asthma. In various models the bronchial hyperreactivity is provoked by a single mediator and this leads to selection of specific antagonists which are unlikely to be of clinical benefit. Rats appear to have certain advantages over guinea-pigs as experimental animals for bronchial hyperreactivity.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Asma/tratamento farmacológico , Hiper-Reatividade Brônquica/tratamento farmacológico , Animais , Asma/fisiopatologia , Hiper-Reatividade Brônquica/fisiopatologia , Modelos Animais de Doenças , HumanosRESUMO
A thrombin-like proteinase (THROLP) was detected colorimetrically as the main proteolytic activity (PROA) in the lavage fluid some minutes after antigen challenge of rats for passive peritoneal anaphylaxis (PPA) reaction. THROLP is equivalent to histamine (H) as parameter for the early phase of PPA: both increased significantly after 6 min, but decreased to prechallenge levels 20 min after challenge. H was released from serosal mast cells, in contrast THROLP originates predominantly from plasma leakage and activation of the clotting reaction in PPA. These findings underline the importance of PROA in the sequence of allergic reactions.
Assuntos
Anafilaxia/metabolismo , Endopeptidases/metabolismo , Extravasamento de Materiais Terapêuticos e Diagnósticos , Liberação de Histamina , Trombina/metabolismo , Animais , Corantes , Endopeptidases/análise , Masculino , Ratos , Ratos Endogâmicos , Trombina/análise , Fatores de TempoRESUMO
Single-cell suspensions of murine and human epidermal cells were studied for the presence of peptidoleukotrienes (LTs), using in vitro guinea pig ileum contraction as bioassay and a commercial radioimmunoassay. The calcium ionophore A23187 at 5 x 10(-6) M alone or in combination with arachidonic acid at 10(-4) M caused release of LTC4/D4 within 10-30 min and for up to 18 h. LTB4, as was measured in the chemotaxis assay, was released at different levels and with different kinetics from the same cells. Epidermal cells may thus regulate cutaneous inflammation by secreting potent vasoactive and muscle-contracting in addition to chemotactic lipid mediators.
Assuntos
Epiderme/metabolismo , Leucotrienos/biossíntese , Músculo Liso/efeitos dos fármacos , Animais , Ácido Araquidônico/farmacologia , Calcimicina/farmacologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Células Epidérmicas , Cobaias , Humanos , Íleo/efeitos dos fármacos , Técnicas In Vitro , Leucotrienos/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Contração Muscular/efeitos dos fármacos , Radioimunoensaio , SRS-A/biossínteseRESUMO
Picumast dihydrochloride (PDH), (3,4-dimethyl-7-[4-chlorobenzyl) piperazine-1-yl]propoxycoumarin dihydrochloride) is a prophylactically active anti-allergic compound which combines inhibition of mediator release and action. The activity profile of PDH differs clearly from that of known prophylactic anti-allergic drugs such as DSCG and ketotifen. Other inhibitory actions of PDH in addition to its H1-antagonism (and that of its metabolites M2 and M1) may be the cause of the suppression of immediate and late phase allergic reactions in animals as well as allergic rhinitis and bronchial responsiveness and symptom scores in asthmatic patients.
Assuntos
Cumarínicos/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Hipersensibilidade/tratamento farmacológico , Anafilaxia/tratamento farmacológico , Animais , Espasmo Brônquico/prevenção & controle , Ensaios Clínicos como Assunto , Conjuntivite Alérgica/tratamento farmacológico , Cumarínicos/uso terapêutico , Cromolina Sódica/farmacologia , Eosinofilia/prevenção & controle , Eosinófilos/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos H1/uso terapêutico , Humanos , Hipersensibilidade/metabolismo , Neutrófilos/efeitos dos fármacosRESUMO
A thrombin-like proteinase (THROLP) was detected colorimetrically as the main proteolytic activity (PROA) in bronchoalveolar lavage fluid (BALF) 4 and 24 h after ovalbumin aerosol (OVA) challenge of actively immunized rats. Other proinflammatory parameters increased also significantly in BALF, like chemiluminescence of leukocytes (1 h), protein and cell number (24 h after challenge). In parallel, increased bronchoconstrictions against 5-HT aerosols are detected 24 h post OVA challenge. THROLP is an indicator for plasma leakage, activation of the clotting reaction and the protracted inflammation in the airways, which induced bronchial hyperreactivity.
Assuntos
Líquido da Lavagem Broncoalveolar/química , Endopeptidases/análise , Ovalbumina/imunologia , Proteínas/análise , Trombina/análise , Administração por Inalação , Aerossóis , Animais , Líquido da Lavagem Broncoalveolar/citologia , Imunização , Medições Luminescentes , Ratos , Ratos Endogâmicos , Serotonina/farmacologiaRESUMO
Inflammation is accompanied by leukocyte activation (LA). We describe a simple ex vivo technique for studying LA that might help to find new LA inhibitors for the treatment of pathologic events related to LA. Arterial and venous blood samples obtained from six permanently catheterized beagle dogs -60, 0, +15 min and +23 h after i.v. challenge with C 48/80, and also blood samples from six normal beagles, were minimally diluted 1:2.5 with buffer. Total leukocyte counts (LC), and luminol amplified CL, induced by opsonized zymosan (C3-Z), were estimated. Blood samples from dogs elicited CL responses of almost 1/10 the magnitude of erythrocyte-free human leukocytes, whereas blood samples from rats reacted three orders of magnitude less. Obviously quenching of CL by accompanying erythrocytes in blood samples from dogs is not important, for CL correlated almost linearly with the CL in differently diluted samples. In arterial, but not in venous samples from catheterized dogs, absolute CL and LC, both were significantly depressed (p less than or equal to 0.05) 15 min after C 48/80 challenge. CL/10(6) leukocytes was augmented twofold. All leukocyte deviations returned to pre-values 23 h post-challenge.
Assuntos
Anafilaxia/sangue , Leucócitos/metabolismo , Medições Luminescentes , Anafilaxia/induzido quimicamente , Anafilaxia/imunologia , Animais , Cães , Feminino , Técnicas In Vitro , Inflamação/sangue , Inflamação/tratamento farmacológico , Contagem de Leucócitos , Leucócitos/imunologia , Masculino , Oxigênio/sangue , p-Metoxi-N-metilfenetilaminaRESUMO
This study confirms the strong inhibition of therapeutic concentrations of the antiinflammatory agent nimesulide (NI) on the chemiluminescence (CL) of human leucocytes (HL) after stimulation with opsonized zymosan (C3Z), and extends the findings to peritoneal (RPL) and bronchoalveolar leucocytes (RBAL) collected from actively immunized rats 24 h after i.v. injection of Sephadex. Additionally we demonstrate that NI is a strong inhibitor of proteinase release (PR) from HL. The reference drugs tested for comparison were indomethacin (I), BW 755 C (BW), phenidon (PH), mepacrin (M) and nedrocromil (NE). The rank order of potency for suppression of PR and CL was nearly independent of the cell type and stimulus: PH greater than or equal to BW greater than M greater than NI = 4-OH-NI much greater than I greater than NE. NI was the superior inhibitor of HL activation compared with I as measured either by PR or CL (factor 7), and also of CL of RPL and RBAL (factor 2-3). NI inhibited the PR from HL and CL of RPL or RBAL almost equipotently (IC30: 10-20 micrograms/ml), whereas PH, BW, M and I were 6-10 times more effective as CL inhibitors compared with their PR inhibition. In contrast NE showed a preferential inhibition of PR. This unique inhibition profile on leucocyte activation in vitro may be related to the differences of NI and I which are also existing in their antiinflammatory activities in vivo.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Leucócitos/efeitos dos fármacos , 4,5-Di-Hidro-1-(3-(Trifluormetil)Fenil)-1H-Pirazol-3-Amina/farmacologia , Animais , Humanos , Técnicas In Vitro , Indometacina/farmacologia , Inibidores de Lipoxigenase , Medições Luminescentes , Nedocromil , Fosfolipases A/antagonistas & inibidores , Pirazóis/farmacologia , Quinacrina/farmacologia , Quinolonas/farmacologia , Ratos , Sulfonamidas/farmacologiaRESUMO
Activation and generation of inflammatory mediators by different leukocytes may be important in the pathogenesis of airway hyperreactivity. We studied the effect of active sensitization with ovalbumin as antigen and i.v. treatment with Sephadex particles on bronchial reactivity (BR) in rats and its possible relation to leukocyte infiltration (LI) and activation (LA) in bronchoalveolar lavage (BAL). A marked BR to aerosols of serotonin (5-HT) and ovalbumin was found in Sephadex treated animals but not in control animals. In parallel to this a marked increase in BAL cell count from Sephadex-treated animals compared to controls was seen. This increase in BAL cell count corresponded with a clear augmentation of spontaneous, buffer-induced and C3Z-induced, luminol-amplified CL. We deduce that detection of CL of BAL cells from rats might be used for studying inflammatory mechanisms which lead to a hyperreactive bronchus.
Assuntos
Brônquios/fisiopatologia , Líquido da Lavagem Broncoalveolar/citologia , Leucócitos/fisiologia , Medições Luminescentes , Animais , Asma/patologia , Asma/fisiopatologia , Feminino , Leucócitos/citologia , Ratos , Ratos Endogâmicos , ZimosanRESUMO
Picumast dihydrochloride (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarin dihydrochloride) was compared with cromoglycate, ketotifen and mepyramine as an inhibitor of allergic and anaphylactoid reactions. 1. In guinea-pigs, pretreatment with picumast dihydrochloride given intravenously, orally or by inhalation prevented bronchospasm induced by antigen or histamine. The fraction of the bronchospasm remaining after mepyramine pretreatment was further reduced by picumast dihydrochloride. 2. Systemic administration of picumast dihydrochloride inhibited antigen-induced conjunctivitis, whereas mepyramine and ketotifen were inactive. 3. Intravenous and oral pretreatment with picumast dihydrochloride inhibited the antigen-induced mast cell degranulation in rat mesentery. The effective doses of cromoglycate given intravenously were twice as high as those of picumast dihydrochloride. Picumast dihydrochloride did not inhibit antigen-induced bronchoconstriction in rats. 4. The cutaneous reaction induced with Ascaris antigen in atopic monkeys was insensitive to the antihistaminic action of ketotifen, whereas it was inhibited by low doses of picumast dihydrochloride. Both compounds suppressed skin reactions induced by histamine. 5. Picumast dihydrochloride decreased IgE production in atopic high responder mice. It did not prevent autoimmune nephritis in NZB/W mice. 6. In rats, picumast dihydrochloride did not reduce cotton pellet granuloma, nor adjuvant arthritis. The inhibition of carrageenin oedema is presumably due to its anti-oedematous properties rather than to an antiproliferative activity. In conclusion, the inhibition of allergic and anaphylactoid reactions by picumast dihydrochloride can be attributed to a combined inhibition of liberation and action of histamine and other mediators.
Assuntos
Cumarínicos/farmacologia , Antagonistas dos Receptores Histamínicos H1/farmacologia , Hipersensibilidade/tratamento farmacológico , Resistência das Vias Respiratórias/efeitos dos fármacos , Animais , Artrite Experimental/prevenção & controle , Espasmo Brônquico/induzido quimicamente , Espasmo Brônquico/prevenção & controle , Conjuntivite/prevenção & controle , Cães , Edema/induzido quimicamente , Edema/prevenção & controle , Feminino , Granuloma/prevenção & controle , Cobaias , Imunização Passiva , Imunoglobulina E/biossíntese , Complacência Pulmonar/efeitos dos fármacos , Macaca , Masculino , Camundongos , Anafilaxia Cutânea Passiva/efeitos dos fármacos , Ratos , Ratos EndogâmicosRESUMO
The present experiments were carried out to elucidate the chemical structure and the pharmacological activity of the main metabolites of picumast (3,4-dimethyl-7-[4-(4-chlorobenzyl)piperazine-1-yl]propoxycoumarin ). The metabolic pathways were identical in animals and man, but there were major quantitative differences. The fraction of the radioactivity in the plasma attributable to the parent compound 0.5 to 3 h after oral administration of picumast dihydrochloride was less than 15% in animals but 95% to 57% in man. Inhibition of the C3-zymosan-induced chemilumiescence of human leucocytes was taken as an indicator of the diminished liberation of mediators and inhibition of the histamine-induced contraction of isolated guinea-pig lung strips as an example for the antagonism of picumast dihydrochloride to mediators of allergic reactions. Stepwise oxidation of the 3-methyl substituent of the coumarin ring to the alcohol and the carbonic acid increased the histaminolytic potency, but decreased the inhibition of chemiluminescence. Another metabolite formed by cleavage of the piperazine-containing side chain was inactive in both tests.
Assuntos
Cumarínicos/metabolismo , Antagonistas dos Receptores Histamínicos H1/metabolismo , Animais , Biotransformação , Cromatografia Líquida de Alta Pressão , Cromatografia em Camada Fina , Cumarínicos/farmacologia , Cumarínicos/urina , Cães , Cobaias , Antagonistas dos Receptores Histamínicos H1/farmacologia , Antagonistas dos Receptores Histamínicos H1/urina , Técnicas In Vitro , Leucócitos/efeitos dos fármacos , Medições Luminescentes , Pulmão/efeitos dos fármacos , Especificidade da Espécie , Zimosan/farmacologiaRESUMO
The antagonism of the antiallergic compounds picumast (PIC; Boehringer Mannheim) and ketotifen (K; Sandoz) against pro-allergic mediators like histamine (H), acetylcholine (ACh), SRS-A and LTC4 as well as against the unspecific spasmogen BaCl2 was compared in the bioassay of superfused guinea pig ileum. For the evaluation of an SRS-A antagonism crude SRS-A from antigen-stimulated guinea pig lung fragments in Krebs buffer was used with the addition of atropine and mepyramine. PIC (approximately 10(-6)-10(-5) mol/l) antagonized clearly all tested spasmogens in a concentration-dependent manner. Its predominant antagonism (IC30: 2-3 X 10(-6) mol/l) was against H, LTC4 and SRS-A, which are presumably important mediators of allergic reactions. ACh- or BaCl2-induced spasms were inhibited to the same extent with a 4 or 6 times higher concentration of PIC. K was approximately 20 times more potent as antagonist against H and approximately 8 times more potent against ACh, whereas the antagonism against LTC4- or BaCl2-induced spasms reached only 1/3 of that of PIC. An antagonism of PIC against SRS-A, LTC4 and H may contribute to its antiallergic activity in vivo. K showed little activity against LTC4 but could antagonize more selectively H- and ACh-mediated effects.
Assuntos
Acetilcolina/antagonistas & inibidores , Compostos de Bário , Bário/antagonistas & inibidores , Cloretos , Cumarínicos/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Cetotifeno/farmacologia , SRS-A/antagonistas & inibidores , Animais , Avaliação Pré-Clínica de Medicamentos , Cobaias , Íleo/efeitos dos fármacos , Contração Muscular/efeitos dos fármacosRESUMO
The inhibitory potency of the antiallergic compounds picumast (PIC; Boehringer Mannheim) and ketotifen (K; Sandoz) on the release of 3 preformed and 3 newly generated inflammatory mediators was estimated as an indicator for their antiallergic activity. Peripheral human leukocytes (HL) or rat alveolar macrophages (RAM) were stimulated by opsonized zymosan (C3-Z) and/or anti-IgE antibody, following preincubation times with PIC and K. SRS-A was measured with the help of a guinea pig ileum bioassay, PGE2 and TxB2 by RIA (NEN), histamine (H) by an automated fluorimetric procedure, tryptic proteinase (P) by a colorimetric test employing Tos-Gly-Pro-Arg-pNA (Chromozym TH; Boehringer Mannheim) as chromogenic substrate and beta-glucuronidase (beta-G) by a colorimetric test (Sigma). PIC (IC30: 2 X 10(-5) mol/l) was 100 times more potent than K as inhibitor of the anti-IgE-induced release of H and P and also 5 times more potent as inhibitor of SRS-A-formation/release in/from HL. In contrast, on RAM, K (IC30: 7 X 10(-6) mol/l) had a 3 times greater potency as inhibitor of the C3-Z-induced SRS-A formation and suppressed PGE2 release (4 X 10(-5)-2 X 10(-4) mol/l), whereas PIC (2 X 10(-5) mol/l) potentiated PGE2 release remarkably. TxB2 release from RAM was inhibited nearly equipotently by PIC and K. beta-G release was strongly potentiated by K (greater than or equal to 8 X 10(-6) mol/l), but weakly inhibited by PIC (2 X 10(-5) mol/l). PIC (greater than or equal to 4 X 10(-5) mol/l) also increased the beta-G release and in the same manner the anti-IgE- or C3-Z-induced release of other 'preformed' mediators like H and P from HL.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Cumarínicos/farmacologia , Liberação de Histamina/efeitos dos fármacos , Cetotifeno/farmacologia , Leucócitos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Prostaglandinas/metabolismo , SRS-A/metabolismo , Animais , Anticorpos Anti-Idiotípicos/imunologia , Complemento C3/antagonistas & inibidores , Avaliação Pré-Clínica de Medicamentos , Humanos , Imunoglobulina E/imunologia , Leucócitos/metabolismo , Macrófagos/metabolismo , Alvéolos Pulmonares/citologia , Ratos , Zimosan/antagonistas & inibidoresRESUMO
To determine whether anaphylactoid reactions during dialysis are the result of allergy to ethylene oxide (EtO) used for sterilisation of dialysis equipment, EtO-specific cytophilic antibodies on basophils were detected by means of a sensitive protease-release assay. Antibodies were found in 2 of 44 healthy controls, 2 of 16 staff members, 4 of 17 patients with preterminal uraemia, and 35 of 83 dialysis patients. 22 of the dialysis patients with antibodies, but only 9 of those without had anaphylactoid reactions during dialysis. Symptoms were more common in patients with antibodies. Symptoms and antibodies were less in a unit where dialysers were rinsed more thoroughly, and were increased in patients with a history of atopy. EtO antibodies decreased or became undetectable in patients who were dialysed with non-EtO-sterilised equipment for eight weeks, and symptoms improved strikingly. On re-exposure to EtO-sterilised material, symptoms returned and EtO-induced protease release increased. EtO sterilisation of dialysis equipment should be discontinued.