RESUMEN
1. Salmeterol, a novel, long-acting beta-adrenoceptor agonist, has been compared with isoprenaline and salbutamol for activity in vitro on a range of beta-adrenoceptor containing preparations from laboratory animals and man, and in vivo for bronchodilator activity in the conscious guinea-pig. 2. Salmeterol, like isoprenaline and salbutamol, relaxed preparations of both guinea-pig trachea (contracted by prostaglandin (PG)F2alpha or electrical stimulation) and human bronchus (contracted by PGF 2 alpha) in a concentration-related fashion. Salmeterol was of similar potency to isoprenaline and more potent than salbutamol on both airway preparations. 3. Relaxant responses of superfused guinea-pig trachea and human bronchus to isoprenaline and salbutamol declined rapidly when the agonists were washed from the tissues, with complete recovery within 10 min, whereas responses to salmeterol were more persistent. In electrically-stimulated guinea-pig trachea preparations, inhibition by salmeterol persisted for periods of up to 12h, despite continuous superfusion with agonist-free medium. However, these persistent responses were rapidly and fully reversed by the beta-adrenoceptor blocking drug, propranolol (0.1 microM). In further studies on guinea-pig trachea, propranolol caused concentration-related parallel, rightward shifts of salmeterol concentration-effect curves, yielding a pA2 of 9.0. The slope of the Schild plot was 1.02. 4. Another beta-adrenoceptor blocking drug, sotalol (10 microM), also fully and rapidly reversed established submaximal responses to salmeterol in superfused guinea-pig trachea. However, after administration of sotalol was stopped, the antagonism waned, and salmeterol responses were reasserted without the addition of further agonist. 5. In the beta 1-adrenoceptor containing preparation, rat left atria, isoprenaline exhibited potent, concentration-related, positive inotropic activity, whereas salbutamol and salmeterol were at least 2000-5000 fold less potent, and appeared to be partial agonists. At a concentration of 72 microM, salmeterol exhibited weak antagonism of isoprenaline-induced increases in atrial force of contraction. This antagonism was less marked than that caused by salbutamol (42 microM).6. On the guinea-pig isolated gastric fundus strip, a putative beta3-adrenoceptor containing preparation, salbutamol and salmeterol had only modest agonist activity, being 20-30 fold less potent than isoprenaline and the selective ,beta3-adrenoceptor agonist, BRL 35135.7. In conscious guinea-pigs, inhaled salmeterol and salbutamol were approximately equipotent in causing dose-related bronchodilatation. Whereas the duration of action of salbutamol at its threshold-effective dose was less than 90min, the responses to a similarly effective dose of salmeterol were well-maintained for at least 6 h.8. Salmeterol is therefore a potent and selective beta2-adrenoceptor agonist with a remarkably long duration of action in isolated superfused airways smooth muscle. It also causes persistent bronchodilatation in vivo, in the guinea-pig, when administered by the inhaled route.
Asunto(s)
Agonistas Adrenérgicos beta/farmacología , Albuterol/análogos & derivados , Albuterol/antagonistas & inhibidores , Albuterol/farmacología , Animales , Broncodilatadores/farmacología , Dinoprost/farmacología , Estimulación Eléctrica , Cobayas , Humanos , Técnicas In Vitro , Isoproterenol/farmacología , Masculino , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Propranolol/farmacología , Ratas , Xinafoato de Salmeterol , Estómago/efectos de los fármacos , Estómago/fisiología , Tráquea/efectos de los fármacos , Tráquea/fisiologíaRESUMEN
Selected beta 2-stimulants were sought that would stick more firmly than salbutamol at their sites of action on the beta 2-adrenoceptor protein in the cell membrane. Of the substance synthesized and tested it was concluded that salmeterol represented a new class of beta 2-stimulants that because of their exceptionally long duration of action have potential clinical advantages over current available beta 2-stimulants in the treatment of asthma.
Asunto(s)
Agonistas Adrenérgicos beta , Resistencia de las Vías Respiratorias/efectos de los fármacos , Albuterol/análogos & derivados , Asma/tratamiento farmacológico , Albuterol/administración & dosificación , Animales , Preparaciones de Acción Retardada , Cobayas , Humanos , Receptores Adrenérgicos beta/efectos de los fármacos , Xinafoato de SalmeterolRESUMEN
Despite numerous suggestions in the literature that thromboxane A2 is involved in a variety of occlusive vascular diseases, no definitive evidence is available. Arguments have been presented to support the view that such evidence can only come from clinical studies with a highly specific thromboxane receptor-blocking drug. We have now identified such a drug, AH23848, in our laboratories. Preliminary experiments with AH23848, ([1 alpha (Z), 2 beta,5 alpha]-(+/-)-7-[5-[[(1,1'-biphenyl)-4-yl]methoxy]-2-(4-morpholin yl)-3-oxocyclopentyl]-4-heptenoic acid), show that it is a potent, specific thromboxane receptor-blocking drug that is orally active and has a long duration of action. It should be a valuable tool in elucidating any physiologic or pathologic role of thromboxane A2.
Asunto(s)
Compuestos de Bifenilo/farmacología , Receptores de Superficie Celular/efectos de los fármacos , Receptores de Prostaglandina/efectos de los fármacos , Tromboxano A2/fisiología , Angina de Pecho/tratamiento farmacológico , Animales , Compuestos de Bifenilo/uso terapéutico , Colágeno/farmacología , Perros , Relación Dosis-Respuesta a Droga , Cobayas , Humanos , Técnicas In Vitro , Masculino , Músculo Liso Vascular/efectos de los fármacos , Agregación Plaquetaria/efectos de los fármacos , Ratas , Receptores de Tromboxanos , Choque Séptico/tratamiento farmacológico , Tromboxano-A Sintasa/antagonistas & inhibidores , Vasoconstricción/efectos de los fármacosRESUMEN
The very late occurrence of gastric carcinoids in a life-span carcinogenicity study with loxtidine in the rat might have resulted from continuous achlorhydria induced by this long-acting unsurmountable histamine H2-antagonist. The nature of the anti-secretory activity of loxtidine was compared with that of ranitidine on histamine-induced acid secretion in the perfused stomach preparation of the rat and in the rat isolated gastric mucosa preparation. Ranitidine and loxtidine had qualitatively different inhibitory effects on acid secretion, ranitidine being a competitive antagonist of histamine even at high concentrations, whereas the effect of loxtidine on both preparations was unsurmountable at relatively low concentrations. These results support the hypothesis that the late formation of gastric carcinoids in rats receiving loxtidine is a consequence of persistent achlorhydria caused by unsurmountable blockade of parietal cell H2-receptors.
Asunto(s)
Tumor Carcinoide/inducido químicamente , Receptores Histamínicos H2/metabolismo , Receptores Histamínicos/metabolismo , Neoplasias Gástricas/inducido químicamente , Triazoles , Animales , Relación Dosis-Respuesta a Droga , Femenino , Ácido Gástrico/metabolismo , Histamina/farmacología , Ranitidina/farmacología , RatasRESUMEN
In this selective review of histamine H2-antagonists, we emphasize the significance of burimamide, the first specific H2-antagonist, in physiology and pharmacology and describe how its discovery led to the development of cimetidine as a new treatment of acid-aggravated disease of the alimentary tract. Developments since cimetidine, include ranitidine, which is a more potent, selectively acting H2-antagonist. A new series of H2-blockers with prolonged activity is discussed, and exemplified, particularly AH 23844. Its prolonged action and its unusual, apparently insurmountable, blocking action is explained in fundamental physicochemical terms.
Asunto(s)
Antagonistas de los Receptores H2 de la Histamina/farmacología , Animales , Aspirina/efectos adversos , Burimamida/farmacología , Fenómenos Químicos , Química , Cimetidina/farmacología , Perros , Furanos/farmacología , Ácido Gástrico/metabolismo , Guanidinas/farmacología , Cobayas , Semivida , Antagonistas de los Receptores H2 de la Histamina/metabolismo , Humanos , Imidazoles/farmacología , Metilaminas/farmacología , Ranitidina/farmacología , Ratas , Estómago/efectos de los fármacos , Tiazoles/farmacología , Triazoles/farmacologíaRESUMEN
1 The antagonist potencies of labetalol and each of its four stereoisomers have been compared at alpha 1-, beta 1- and beta 2-adrenoceptors in anaesthetized dogs and in isolated tissues. 2 The RR stereoisomer is a potent, non-selective antagonist at beta-adrenoceptors but has only weak alpha 1-adrenoceptor blocking activity. 3 The SR stereoisomer was the most potent antagonist at alpha 1-adrenoceptors, and it also had similar potency as an antagonist at beta-adrenoceptors. 4 The alpha- and beta-adrenoceptor blocking profile of the RS stereoisomer is intermediate between that of the RR and SR, but the SS stereoisomer is a relatively weak antagonist at both alpha- and beta-adrenoceptors. 5 It is concluded that, although most of the alpha 1-adrenoceptor blocking activity of labetalol is attributable to the SR stereoisomer and nearly all of its beta-adrenoceptor blocking activity resides in the RR stereoisomer, each of the stereoisomers contributes to the overall pharmacological profile of labetalol.
Asunto(s)
Antagonistas Adrenérgicos alfa , Antagonistas Adrenérgicos beta , Etanolaminas/farmacología , Labetalol/farmacología , Anestesia , Animales , Aorta Torácica/efectos de los fármacos , Perros , Cobayas , Técnicas In Vitro , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Conejos , Periodo Refractario Electrofisiológico/efectos de los fármacos , EstereoisomerismoRESUMEN
The animal pharmacology and metabolism of ranitidine have been reviewed. Experiments using guinea-pig isolated right atrium and ileum preparations have shown that ranitidine is a selective, potent, and competitive histamine H2-receptor antagonist. In the conscious dog gastric acid secretion induced by histamine, pentagastrin, bethanechol and food was inhibited by ranitidine at doses 4 to 12 times lower than equi-effective doses of cimetidine. Ranitidine inhibited the formation of aspirin-induced gastric lesions, both in the presence and absence of gastric acid. Unlike cimetidine, ranitidine neither possessed anti-androgenic activity, nor did it inhibit the mixed function oxygenase metabolizing enzyme system in the liver. Ranitidine has been recommended for clinical trial in the treatment of peptic ulcer disease.
Asunto(s)
Furanos/farmacología , Antagonistas de los Receptores H2 de la Histamina/farmacología , Administración Oral , Animales , Aspirina , Compuestos de Betanecol/farmacología , Cimetidina/farmacología , Perros , Furanos/administración & dosificación , Ácido Gástrico/metabolismo , Mucosa Gástrica/efectos de los fármacos , Cobayas , Atrios Cardíacos/efectos de los fármacos , Histamina/farmacología , Antagonistas de los Receptores H2 de la Histamina/administración & dosificación , Técnicas In Vitro , Inyecciones Intravenosas , Masculino , Contracción Miocárdica/efectos de los fármacos , Próstata/efectos de los fármacos , Ranitidina , Ratas , Úlcera Gástrica/prevención & controlRESUMEN
1,1-Azobis[3-methyl-2-phenylbenzimidazolinium]dimethanesulphonate (AH 10407) has an ultrashort, competitive neuromuscular blocking action in the mouse, cat, dog, Cynamolgus monkey and cotton-eared marmoset. 2 AH 10407 is chemically unstable in bicarbonate-containing solutions and is degraded to inactive products. The half-life of AH 10407 in vitro in dog and human whole blood and in Krebs physiological solution is about 1.0 minute. In distilled water and in HCO-3-deficient Krebs solution AH 10407 is much more stable. Base catalyzed degradation is shown to be the prime determinant of the duration of action of the drug. 3 Some pharmacological properties of AH 11244 and AH 11056, close analogues of AH 10407, are briefly described and the duration of their neuromuscular blocking actions rationalized by reference to their chemical stabilities.
Asunto(s)
Bencimidazoles/farmacología , Bloqueantes Neuromusculares/farmacología , Animales , Compuestos Azo/farmacología , Callitrichinae , Gatos , Pollos , Perros , Estabilidad de Medicamentos , Haplorrinos , Hemodinámica/efectos de los fármacos , Técnicas In Vitro , Macaca fascicularis , Contracción Muscular/efectos de los fármacos , Parálisis/inducido químicamente , Ratas , Serotonina/metabolismo , Transmisión Sináptica/efectos de los fármacos , Temperatura , Factores de TiempoRESUMEN
1 The animal pharmacology of labetalol, a drug that blocks both alpha- and beta-adrenoreceptors, is reviewed. 2 In isolated tissues the blockade by labetalol of both alpha- and beta-adrenoreceptors satisfied accepted critera for competitive antagonism. In contrast phentolamine was a competitive antagonist at alpha-adrenoreceptors only, and propranolol a competitive antagonist at beta-adrenoreceptors only. Labetalol was 6-10 times less potent than phentolamine in blocking alpha-adrenoreceptors and 1.5-3 times less potent than propranolol in blocking beta-adrenoreceptors. Labetalol itself was 4-8 times more potent at beta- than at alpha-adrenoreceptors. 3 In anaesthetized dogs labetalol given intravenously blocked vasopressor responses to phenylephrine positive chronotropic, vasodepressor and bronchodilator response to isoprenaline. Phentolamine blocked the effect of phenylephrine only, and propranolol the effects of isoprenaline only. Labetalol was about 7 times less potent than phentolamine in blocking alpha-adrenoreceptors, about 4 times less potent than propranolol in blocking cardiac beta1-adrenoreceptors, and 11-17 times less potent than propranolol in blocking vascular and bronchial beta2-adrenoceptors. This difference in the relative potency of labetalol arises because propranolol is a slightly more potent antagonist at beta2- than at beta1-adrenoreceptors. Labetaol itself was about 16 times more potent at cardiac beta1- than at vascular alpha-adrenoreceptors. In conscious dogs labetaol given orally blocked vasopressor responses to phenylephrine and positive chonotropic responses to isoprenaline. 4 In anesthetized dogs and pithed rats labetaol blocked alpha- or beta-adrenoreceptor-mediated responses to sympathetic nerve stimulation and intravenously administered phenylephrine or isoprenaline to approximately the same extent. 5 Labetalol does not possess partial agonist (intrinsic sympathomimetic) activity at cardiac beta1-adrenoreceptors. 6 The blocking action of labetalol both in vivo was shown to be specific for alpha- and beta-adrenoreceptors. 7 The haemodynamic effects of labetalol are attributable to its adrenoreceptor-blocking actions. The observed responses vary from one experiment situation to another depending on the balance of autonomic influences. For example, in barbitone-anaesthetized dogs, in which sympathetic tone predominates, both labetalol and propranolol reduced heart rate, contractility, output and work--effects which are attributable to beta-adrenoreceptor blockade. Labetalol differed from propranolol in decreasing rather than increasing total peripheral resistance and in causing larger falls in blood pressure at equipotent beta-adrenoreceptor-blocking doses. These differences are probably attributable to peripheral vasodilatation resulting from the vascular alpha-adrenoreceptor-blocking action of labetalol...
Asunto(s)
Antagonistas Adrenérgicos alfa , Antagonistas Adrenérgicos beta , Etanolaminas/farmacología , Labetalol/farmacología , Animales , Fibras Autónomas Preganglionares/fisiología , Desoxicorticosterona/farmacología , Perros , Estimulación Eléctrica , Cobayas , Hemodinámica/efectos de los fármacos , Hipertensión/fisiopatología , Hipertensión Renal/fisiopatología , Técnicas In Vitro , Isoproterenol/antagonistas & inhibidores , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Fentolamina/farmacología , Fenilefrina/antagonistas & inhibidores , Propranolol/farmacología , Conejos , RatasAsunto(s)
Broncodilatadores/farmacología , Simpatomiméticos/farmacología , Inhibidores de Adenilato Ciclasa , Agonistas Adrenérgicos beta/metabolismo , Agonistas Adrenérgicos beta/farmacología , Anilidas/farmacología , Animales , Catecolaminas/farmacología , Gatos , Perros , Etanolaminas/farmacología , Cobayas , Corazón/efectos de los fármacos , Hexoprenalina/farmacología , Humanos , Técnicas In Vitro , Isoquinolinas/farmacología , Músculo Liso/efectos de los fármacos , Músculos/efectos de los fármacos , Piperidinas/farmacología , Ratas , Receptores Adrenérgicos/efectos de los fármacos , Resorcinoles/análogos & derivados , Relación Estructura-ActividadAsunto(s)
Analgésicos/uso terapéutico , Benzamidas/uso terapéutico , Animales , Ciclohexanos/uso terapéutico , Pulpa Dental/lesiones , Dimetilaminas/uso terapéutico , Perros , Haplorrinos , Humanos , Macaca , Ratones , Ratas , Síndrome de Abstinencia a Sustancias , Trastornos Relacionados con SustanciasAsunto(s)
Compuestos Azo/farmacología , Fármacos Neuromusculares no Despolarizantes/farmacología , Compuestos de Piridinio/farmacología , Animales , Compuestos Azo/antagonistas & inhibidores , Compuestos Azo/toxicidad , Presión Sanguínea/efectos de los fármacos , Gatos , Pollos , Perros , Estimulación Eléctrica , Electrocardiografía , Trietyoduro de Galamina/farmacología , Haplorrinos , Imidazoles/antagonistas & inhibidores , Imidazoles/farmacología , Imidazoles/toxicidad , Masculino , Ratones , Músculos/efectos de los fármacos , Neostigmina/farmacología , Fármacos Neuromusculares no Despolarizantes/antagonistas & inhibidores , Fármacos Neuromusculares no Despolarizantes/toxicidad , Pancuronio/farmacología , Pulso Arterial/efectos de los fármacos , Compuestos de Piridinio/antagonistas & inhibidores , Compuestos de Piridinio/toxicidad , Succinilcolina/farmacología , Factores de TiempoRESUMEN
1. The pharmacological activities of the optical isomers of salbutamol have been examined. (-)-Salbutamol was much more potent than (+)-salbutamol on beta-adrenoceptors.2. Both (-)- and (+)-salbutamol showed high selectivity for beta-adrenoceptors in bronchial muscle compared to cardiac muscle, in this way resembling racemic salbutamol.3. The use of isomeric activity ratio to detect differences between receptors was examined in the light of the results obtained with the isomers of salbutamol.