Preliminary studies of pharmacological antigonism of anaphylaxis in the horse.
Systemic anaphylaxis was induced in seven groups of ponies. Systemic hypotension, pulmonary hypotension, and apnea were observed in the control group. Suppression of anaphylaxis was achieved most efficiently with sodium meclofenamate followed by acetylsalicylic acid and diethylcarboamazine. Tripelennamine and methysergide reduced anaphylaxis minimally and burimamide not at all. The findings suggest that histamine and serotonin are of relatively low significance in equine anaphylaxis whereas kinins, prostaglandins and slow reacting substance may be more important. (+info)
Inhibition of Na(+) current by diphenhydramine and other diphenyl compounds: molecular determinants of selective binding to the inactivated channels.
Diphenhydramine is an H1 histamine receptor antagonist, yet it also has a clinically useful local anesthetic effect. We found that diphenhydramine inhibits the neuronal Na(+) current, and the inhibition is stronger with more positive holding potentials. The dissociation constant between diphenhydramine and the inactivated Na(+) channel is approximately 10 microM, whereas the dissociation constant between diphenhydramine and the resting channel is more than 300 microM. The local anesthetic effect of diphenhydramine thus is ascribable to inhibition of Na(+) current by selective binding of the drug to the inactivated channels. Most interestingly, many other compounds, such as the anti-inflammatory drug diclofenac, the anticonvulsant drug phenytoin, the antidepressant drug imipramine, and the anticholinergic drug benztropine, have similar effects on neuronal Na(+) current. There is no apparent common motif in the chemical structure of these compounds, except that they all contain two phenyl groups. Molecular modeling further shows that the two benzene rings in all these drugs have very similar spatial orientations (stem bond angle, approximately 110 degrees; center-center distance, approximately 5 A). In contrast, the two phenyl groups in phenylbutazone, a drug that has only a slight effect on Na(+) current, are oriented in quite a different way. These findings strongly suggest that the two phenyl groups are the key ligands interacting with the channel. Because the binding counterpart of a benzene ring usually is also a benzene ring, some aromatic side chain groups of the Na(+) channel presumably are realigned during the gating process to make the very different affinity to the aforementioned drugs between the inactivated and the resting channels. (+info)
H1-receptor antagonist, tripelennamine, does not affect arterial hypoxemia in exercising Thoroughbreds.
It has been suggested that pulmonary injury and inflammation-induced histamine release from airway mast cells may contribute to exercise-induced arterial hypoxemia (EIAH). Because stress failure of pulmonary capillaries and EIAH are routinely observed in exercising horses, we examined whether preexercise administration of an H1-receptor antagonist may mitigate EIAH. Two sets of experiments, placebo (saline) and antihistaminic (tripelennamine HCl at 1.10 mg/kg iv, 15 min preexercise) studies, were carried out on seven healthy, exercise-trained Thoroughbred horses in random order 7 days apart. Arterial and mixed venous blood-gas and pH measurements were made at rest before and after saline or drug administration and during incremental exercise leading to maximal exertion at 14 m/s on 3.5% uphill grade for 120 s. Galloping at this workload elicited maximal heart rate and induced exercise-induced pulmonary hemorrhage in all horses in both treatments, thereby indicating that capillary stress failure-related pulmonary injury had occurred. In both treatments, EIAH, desaturation of hemoglobin, hypercapnia, and acidosis of a similar magnitude developed during maximal exertion, and statistically significant differences between the placebo and antihistaminic studies could not be demonstrated. The failure of the H1-receptor antagonist to modify EIAH significantly suggests that pulmonary injury-induced histamine release may not play a major role in bringing about EIAH in Thoroughbred horses. (+info)
Studies of the "antihistaminic" effect of pyribenzamine administered by various routes.
Utilizing histamine electrophoresis, the degree and duration of "antihistaminic" effect of varying doses of Pyribenzamine(R) administered by different routes were studied. Delayed action Pyribenzamine in 50 mg. and 100 mg. dosage exerted a small but measurable anti-whealing effect five hours after ingestion. The larger dose exerted approximately twice the effect of the smaller. The anti-whealing activity lasted five to six hours. Pyribenzamine given intravenously affected the whealing response one hour after administration. A peak of activity was reached two to two and a half hours after injection, and "antihistaminic" effect continued for a total of five hours. The inunction of 250 mg. and 500 mg. of Pyribenzamine in an ointment base resulted in sufficient absorption of the drug to produce a measurable anti-whealing effect. The "antihistaminic" activity was noted three hours after application and lasted 10 to 12 hours from the time of inunction. (+info)
Medullary pain facilitating neurons mediate allodynia in headache-related pain.
Evidence for both histamine H1 and H2 receptors on human articular chondrocytes.
Using specific histamine H1 and H2 receptor antagonists, evidence is presented for the existence of both H1 and H2 receptors on human articular chondrocytes in vitro. Stimulation of the H1 receptor by histamine (range 0.18 to 17.8 mumol/l) significantly increased prostaglandin E (PGE) production, while activation of the histamine H2 receptor increased intracellular cyclic adenosine-5'-monophosphate (AMP). The histamine H1 antagonists mepyramine and tripelennamine blocked the histamine induced increase in PGE production, and the H2 antagonists cimetidine and ranitidine prevented the increase in intracellular cyclic AMP. These observations suggest that mast cell-chondrocyte interactions mediated via histamine may contribute to some of the pathophysiological changes observed in joint disease. (+info)
Histamine H1 receptors on adherent rheumatoid synovial cells in culture: demonstration by radioligand binding and inhibition of histamine-stimulated prostaglandin E production by histamine H1 antagonists.
Histamine H1 receptors have been demonstrated on adherent rheumatoid synovial cells using biochemical and radioligand binding assays in vitro. The addition of histamine (17.8 mumol/l) to nine primary cultures of adherent rheumatoid synovial cells resulted in a two- to 21-fold increase in the production of prostaglandin E (PGE). This increase was inhibited by three H1 receptor antagonists (mepyramine, tripelennamine, and chlorpheniramine) in a dose related manner at concentrations below 10(-6) mol/l. Competitive binding assays with [3H]mepyramine gave ED50 values of approximately 10(-5) mol/l for the three H1 antagonists. H2 receptor antagonists (cimetidine and ranitidine) did not inhibit the histamine induced increase in PGE and did not compete effectively with the binding of H1 antagonists. (+info)