ABSTRACT
In order to better understand the variability of pharmacodynamic and pharmacokinetic profiles of terfenadine between the previous studies as well as to qualitatively and quantitatively examine the proarrhythmic potential of its major active metabolite fexofenadine in comparison with that of terfenadine, we directly compared their electropharmacological effects with halothane-anesthetized dogs (n = 3). For this purpose, we adopted a cross-over design, which can directly compare the effects of terfenadine and fexofenadine under the identical metabolic condition. Terfenadine in doses of 0.03 and 0.3 mg/kg increased the mean blood pressure, but that of 3 mg/kg decreased it. Terfenadine also increased the heart rate and ventricular contractility in a dose-related manner; but delayed the atrioventricular nodal and intraventricular conductions as well as repolarization suggesting its proarrhythmic potential. Meanwhile, fexofenadine in the same dose increased the mean blood pressure in a dose-related manner without affecting any of the electrophysiological variables in the same animals that proarrhythmic risk of terfenadine was confirmed, indicating its lack of proarrhythmic risk. Peak plasma concentrations for fexofenadine were 3.7, 8.1 and 11.2 times greater than for terfenadine at each matching dose, indicating terfenadine may be metabolized much faster than fexofenadine. Taken together, after the low and middle doses of terfenadine, vasopressor effect of a metabolite fexofenadine could be greater than the depressor effect of parent compound terfenadine, but its reverse would be correct after the high dose. Thus, the cross-over analysis can be an effective way to better understand drug-induced cardiovascular responses.
Subject(s)
Anesthesia , Arrhythmias, Cardiac/chemically induced , Electrocardiography , Halothane , Terfenadine/analogs & derivatives , Terfenadine/pharmacology , Terfenadine/pharmacokinetics , Animals , Arrhythmias, Cardiac/physiopathology , Blood Pressure/drug effects , Cross-Over Studies , Dogs , Dose-Response Relationship, Drug , Heart Rate/drug effects , Myocardial Contraction/drug effects , Risk , Terfenadine/adverse effectsABSTRACT
Whereas nausea and emesis are burdensome side effects that lead to poor treatment compliance especially in chemotherapy, it is difficult to predict the emetic potential of agents in rats and mice because rodents do not vomit. We examined the effect of emetics on gastric retention and role of serotonin (5-hydroxytryptamine, 5-HT)
Subject(s)
Emetics/pharmacology , Gastric Emptying/drug effects , Receptors, Serotonin, 5-HT3/metabolism , Stomach/drug effects , Anesthesia/methods , Animals , Antiemetics/pharmacology , Antineoplastic Combined Chemotherapy Protocols , Carbon Dioxide/metabolism , Cisplatin/pharmacology , Copper Sulfate/pharmacology , Doxorubicin/pharmacology , Gastric Mucosa/metabolism , Male , Microspheres , Nausea/chemically induced , Ondansetron/pharmacology , Rats , Rats, Sprague-Dawley , Serotonin 5-HT3 Receptor Antagonists/pharmacology , Vomiting/chemically inducedABSTRACT
Nausea and emesis are often observed as side effects with many medicines and may lead to poor treatment compliance. In the present study, we aimed to establish simple methods for predicting nausea and/or emesis in mice, which do not vomit, using drugs and chemicals known to evoke nausea and/or emesis. The gastrointestinal transit test, the liquid gastric emptying by phenol red solution (Phenol red method) and the solid gastric emptying by resin beads (Beads method) were used and the effects of antispasmogenics (atropine, 0.1-3 mg/kg i.p.; salmon calcitonin, 1-30 units/kg i.m.), nauseants (copper sulfate, 1-30 mg/kg p.o.; apomorphine, 0.01-0.3 mg/kg s.c.) and chemotherapeutics (cisplatin, 0.3-10 mg/kg i.v.; doxorubicin, 0.3-10 mg/kg i.v.) were evaluated. In addition, the effects of ondansetron, a serotonin (5-HT)(3) receptor antagonist, on the inhibition of solid gastric emptying induced by salmon calcitonin, copper sulfate, cisplatin and doxorubicin were also assessed. Only the solid gastric emptying method could detect changes of gastric emptying by all drugs and chemicals. We also found that the inhibition of solid gastric emptying induced by cisplatin and doxorubicin was dose-dependently antagonized by ondansetron. However, ondansetron failed to antagonize the salmon calcitonin-induced delay, but exerted only very weak effects with copper sulfate. Solid gastric emptying may be more suitable than gastrointestinal intestinal transit or liquid gastric emptying in mice to predict nausea and/or emesis. Our results also suggest that chemotherapeutic-induced delay of solid gastric emptying mediated via 5-HT(3) receptors in mice could also be useful for prediction purposes.
Subject(s)
Gastric Emptying/drug effects , Gastric Emptying/physiology , Receptors, Serotonin, 5-HT3/physiology , Vomiting/chemically induced , Animals , Antispermatogenic Agents/adverse effects , Apomorphine/adverse effects , Cisplatin/adverse effects , Cisplatin/antagonists & inhibitors , Copper Sulfate/adverse effects , Copper Sulfate/antagonists & inhibitors , Dose-Response Relationship, Drug , Doxorubicin/adverse effects , Doxorubicin/antagonists & inhibitors , Male , Mice , Mice, Inbred Strains , Ondansetron/pharmacology , Serotonin 5-HT3 Receptor Antagonists/pharmacologyABSTRACT
A series of 2-substituted 2-aminopropane-1,3-diols having a biphenyl moiety and their phosphate esters were synthesized to obtain sphingosine 1-phosphate receptor-1 (S1P(1)) receptor agonists with potent immunomodulatory activity accompanied by little or no effect on heart rate. Many of the synthesized compounds sufficiently decreased the number of peripheral blood lymphocytes. Some of the phosphates had potent agonism at S1P(1) but no agonism at S1P(3), which had been reported to be a receptor responsible for heart rate reduction. Although high S1P(1)/S1P(3) selectivity was considered to be favorable to reduce the effect on heart rate, almost all the phosphates showed a remarkable heart rate lowering effect in vivo. The results suggest that other factors in addition to S1P(3) agonism should be responsible for the heart rate reduction caused by S1P(1) agonists. Only 2-amino-2-[2-[2'-fluoro-4'-(4-methylphenylthio)biphenyl-4-yl]ethyl]propane-1,3-diol (6d) was identified as a desired S1P(1) receptor agonist having both the immunomodulatory activity and an attenuated effect on heart rate by a unique screening flow using in vivo evaluating systems primarily.
Subject(s)
Biphenyl Compounds/chemical synthesis , Heart Rate/drug effects , Immunologic Factors/chemical synthesis , Propanolamines/chemical synthesis , Propylene Glycols/chemical synthesis , Receptors, Lysosphingolipid/agonists , Animals , Biphenyl Compounds/adverse effects , Biphenyl Compounds/pharmacology , Cell Line , Cricetinae , Cricetulus , Immunologic Factors/adverse effects , Immunologic Factors/pharmacology , Lymphocyte Count , Male , Mice , Mice, Inbred BALB C , Propanolamines/adverse effects , Propanolamines/pharmacology , Propylene Glycols/adverse effects , Propylene Glycols/pharmacology , Rats , Rats, Inbred F344 , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Spontaneous salivary gland tumors in rats are rare. The authors report a poorly differentiated carcinoma of a submandibular gland in a ten-week-old rat that was positive for vimentin. Microscopically, the neoplastic cells showed a diffuse growth pattern in most areas of the tumor mass and a nestlike structure in a part of the peripheral area. Immunohistochemically, the cells were positive for keratin and vimentin but not for alpha-smooth muscle actin. Ultrastructurally, desmosome-like structures were observed. Based on these findings, the tumor was diagnosed as a poorly differentiated carcinoma. The origin of the neoplastic cells would be either acinar or ductal cells. This suggests that acinar or ductal cells have the potential to transform into vimentin-expressing cells.