bluuebunny/crossref_metadata_2025_split huggingface dataset:
On the cardiovascular and antiarrhythmic actions of the cardioselective beta‐adrenoceptor antagonist bevantolol in the pig
Authors: Hartog Johannes M. , van Bremen Robert H. , Verdouw Pieter D. 
Published: January 2005

AbstractThe cardioselective beta‐adrenoceptor antagonist bevantolol (1‐[(3,4‐dimethoxyphenethyl)amino]‐3‐(m‐tolyloxy)‐2‐propanol monohydrochloride) was studied for its effects on cardiac performance and on coronary artery occlusion‐induced ventricular fibrillation in anesthetized open‐chest pigs. In doses of 0.5‐‐3.0 mg·kg−1 the drug caused dose‐dependent decreases in cardiac output (10‐‐35%) that were primarily due to a negative chronotropic action, as heart rate decreased considerably more (10‐‐25%) than stroke volume (0‐‐15%). The decrease in stroke volume appeared to be due to a decrease in maxLVdP/dt (up to 40%) and a mild vasoconstriction (≥20%) of the systemic arterial vascular bed. Myocardial blood flow (25‐‐45%) and O2 extraction both decreased, but cerebral blood flow was well preserved. Decreases in perfusion of some organs (kidneys, liver, and stomach) were similar to those in cardiac output, but that of the small intestine was not significantly affected. After ligation of the left anterior descending coronary artery at its midpoint, bevantolol prevented ventricular fibrillation during the earliest phase of ectopic activity, but was ineffective during the second phase of the early arrhythmias.
Centchroman: In vitro metabolism by rat liver homogenate
Authors: Ratna Sanjeev , Roy S. K. , Ray Suprabhat , Kole P. L. , Salman M. , Madhusudan K. P. , Sircar K. P. , Anand N. 
Published: January 2005

AbstractCentchroman (trans‐2,2‐dimethyl‐3‐phenyl‐4‐(p‐(β‐pyrrolidinoethoxy) phenyl)‐7‐methoxy chroman) (I), a postcoital antifertility agent under clinical development was extensively metabolized by rat liver homogenate in vitro. Employing field desorption mass spectrometry, high performance liquid chromatography, comparison with authentic samples, and studies with 2‐14C‐Centchroman, seven metabolites have so far been characterised, which include trans‐3‐phenyl‐4‐(p‐(β‐pyrrolidinoethoxy) phenyl)‐7‐methoxy chroman (II, 37.5%), trans‐2,2‐dimethyl‐3‐phenyl‐4‐(p‐(β pyrrolidinoethoxy) phenyl)‐7‐hydroxy chroman (III, 2.5%), β pyrrolidino‐ethoxy benzene (IV), 2,2‐dimethyl‐4‐(p‐(hydroxy) phenyl)‐7‐methoxy chromene (V, 39.4%), trans‐2,2‐dimethyl‐3‐phenyl‐4‐(p‐(hydroxy) phenyl)‐7‐methoxy chroman (VI, 5.8%), 2,3‐trans‐3,4‐trans‐2‐methyl‐3‐phenyl‐4‐(p‐(β‐pyrrolidinoethoxy) phenyl)‐7‐methoxy chorman (VII, 2.9%), and 2,2‐dimethyl‐4‐(p‐(β‐pyrrolidinoethoxy) phenyl)‐7‐methoxy chroman (VIII, 8.8%). Formation of metabolites V and VIII are unusual cases of dephenylation during metabolism.
The role of the endothelium in arterial thrombosis and the influence of antithrombotic therapy
Authors: Bush Larry R. , Patrick Darryl 
Published: January 2005

AbstractThe nonthrombogenicity of vascular endothelium, a single layer of cells separating blood‐borne platelets and thrombogenic components of the underlying subendothelium, results from more than its provision of a physical barrier. These cells synthesize and secrete prostacyclin, plasminogen activator, and inhibitors of the coagulation system. They also catabolize proaggregatory agents such as ADP and serotonin (5‐HT). Damage to or removal of the endothelium is, of course, a potent thrombogenic stimulus. We have employed an acute canine model of coronary arterial thrombosis, which combines vessel narrowing and intimal injury as stimuli for repetitive, regular occlusive thrombus formation. Of all agents tested by us and others in this model, prostacyclin, selective thromboxane (TXA2) synthetase inhibitors, and 5‐HT antagonists consistently inhibit thrombus formation. Available data suggest that the antithrombotic actions of TXA2 synthetase inhibitors result in part from vascular metabolism of platelet‐derived endoperoxides, as well as endogenous PGI2 production. Serotonin, alone, exerts weak proaggregatory effects. However, it uniquely amplifies the proaggregatory effects of many physiologic proaggregatory mediators. Serotonin2 antagonists are more potent and consistently antithrombotic in this canine model than TXA2 synthetase inhibitors.The discordance between the marked antithrombotic effects of 5‐ht antagonists and txa2 synthetase inhibitors in vivo and their weak antiaggregatory and proaggregatory effects in vitro, respectively, underscores the danger of relying exclusively upon in vitro platelet aggregatory behavior to assess either the potential importance of a mediator or antithrombotic efficacy of a new drug. On the basis of results obtained from our laboratory and others that employ similar in vivo models of thrombosis, we conclude that (1) since platelet aggregation in vivo is stimulated by many physiologic agonists, in vivo and in vitro, models of aggregation and thrombosis should reflect this; (2) the most potent or efficacious proaggregatory agent in vitro may not necessarily be the most important mediator in vivo and vice versa. Future development of antithrombotic agents should continue; aspirin can be improved upon in several respects. Perhaps future antithrombotic agents will be targeted to specific platelet membrane (g1yco)proteins involved in platelet‐platelet )aggre‐ gation) and platelet‐vessel wall (adhesion) interactions.
Chemical development of astemizole‐like compounds
Authors: Janssens Frans , Janssen Marcel A. C. , Awouters Frans , Niemegeers Carlos J. E. , Vanden Bussche Gabriel 
Published: January 2005

AbstractNewly synthesized diphenylbutylpiperidine derivatives were devoid of neuroleptic activity but were moderately active histamine antagonists in vitro. Their structural relation to classical antihistamines was not evident, but the requirement of a piperidino‐2‐aminobenzimidazole core was confirmed by the synthesis of R 39848, which was more potent. About 500 new compounds related to R 39848 were synthesized by varying in particular the alkyl and aralkyl groups implanted on the piperidine, benzimidazole, and bridging amine nitrogen. Potency, oral activity, and long duration of action in the compound 48/80 lethality test in rats prompted the selection of R 43512 (astemizole) for detailed pharmacological studies. Antiallergic specificity and lack of central effects were the conclusions of all studies, and the higher clinical effectiveness of astemizole was in agreement with a dosage that is not limited by central or other side effects. More extensive chemical modifications of the astemizole molecule were explored, and it is possible that some recent compounds may either have an increased antiallergic effectiveness (R 57959) or be useful in other indications because of a different profile of peripheral actions.
Excretion and biotransformation of astemizole in rats, guinea‐pigs, dogs, and man
Authors: Meuldermans Willem , Hendrickx Jan , Lauwers William , Hurkmans Robert , Swysen Eric , Heykants Jozef 
Published: January 2005

AbstractThe excretion and biotransformation of astemizole (AST) were studied after single administration in rats (0.16 or 10 mg/kg), guinea‐pigs (0.16 mg/kg), dogs (1 or 10 mg/kg) and humans (30 mg), using three different radiolabels. Orally administered AST was well absorbed and almost completely metabolized in rats, dogs, and humans, whereas in guinea‐pigs about 17% of dose was excreted as parent AST. In the four species urinary excretion of the radioactivity (5–15%) was much less than their fecal excretion (60–90%). Excretion rate of the radioactivity decreased in the order rat ≥ guinea‐pig ≥ dog ≥ man. In male rats, biliary excretion amounted to 70% at 24 hr after dosing, whereas about 45% of the biliary radioactivity was subjected to enterohepatic circulation. The major metabolites were characterized by high performance liquid chromatography (HPLC) and mass spectrometry. A mass balance of the metabolites was made up by HPLC with on‐line radioactivity detection. The major metabolic pathways of AST in the four species were oxidative O‐demethylation, aromatic hydroxylation at the benzimidazole moiety, and oxidative N‐dealkylation at the piperidine nitrogen. Phenolic metabolites resulting from the two former pathways were excreted as their glucuronides in the bile. Desmethylastemizole (DES‐AST) was the main metabolite in rats, 6‐hydroxy‐desmethylastemizole (6‐OH‐DES‐AST) the main metabolite in dogs. In humans, about equal relative amounts of DES‐AST, 6‐OH‐DES‐AST, and norastemizole were found. Sex differences in rats were only minor. The mass balance of the metabolites after a 6‐week dosing at 1 mg/kg/day in dogs was very similar to that after a single dose.
Monte Carlo method for the estimation of statistical significance in pharmacological testing
Authors: Lewi Paul J. , Keersmaekers Roger C. A. , Awouters Frans 
Published: January 2005

AbstractThe Monte Carlo method, also called computer simulation, has been applied to the estimation of confidence limits of pharmacological results. An application of this nonparametric method to observations from the passive cutaneous anaphylaxis test in the rat is described. Confidence limits for the sum of five observations are shown to be reproducible with repeated simulation and to be sensitive to changing experimental conditions. A difference between two anti‐ovalbumin IgE serum batches has been observed from the empirical distributions produced by the Monte Carlo method.
Correction by ketanserin of the platelet‐mediated inhibition of peripheral collateral circulation in the cat: Measurement of blood flow with radioactive microspheres
Authors: De Clerck Fred , Loots Wim , Jageneau Anton , Nevelsteen André 
Published: January 2005

AbstractPlatelets, activated to release vasoactive mediators on a stasis thrombus in the inferior aorta of the cat proximally from a mechanical ligation, induced a loss of collateral tissue perfusion in the hindlegs. Blood platelet number, platelet‐bound 5‐hydroxytryptamine, and plasma levels of 5‐hydroxy‐indoles, thromboxane B2 and 6K‐PGF1α did not differ significantly when measured in systemic arterial blood and in venous blood sampled distally from the stasis thrombus. The platelet‐mediated defect in the function of the collateral circulation in the periphery was corrected by ketanserin. This correction was evidenced by objective parameters such as blood pressure ratios and blood flow rates determined both by plethysmography and by radioactive microsphere measurements of regional tissue perfusion of skeletal muscles. This study demonstrated a predominant role for 5‐hydroxytrytamine in the platelet‐mediated inhibition of peripheral collateral circulation.
Protective activity of ketanserin against serotonin‐induced embryotoxicity and teratogenicity in rats
Authors: van Cauteren Herman , Vandenberghe John , Marsboom Robert 
Published: January 2005

AbstractSerotonin was evaluated for its embryotoxic and teratogenic effects in pregnant Wistar rats at total doses of 10, 15, and 20 mg/kg divided over five injections at day 9 to 11 of pregnancy. At day 22 of pregnancy, rats were sacrificed and examined for number of live, dead, and resorbed fetuses and mean pup weight. Teratological evaluation was carried out by visual inspection, radiography, and sectioning according to Wilson's technique. When compared to placebo controls, serotonin resulted in dose‐dependent embryotoxicity as evidenced by increased embryonal resorption and decreased pup weight. Furthermore, serotonin dose‐dependently induced malformations, which were mainly acrania, encephalocele, hydrocephalocele, cheiloschisis, coelosomia, and rib abnormalities. Ketanserin, when given orally at a dose level of 5 mg/kg 1 hour before each serotonin injection, completely prevented the serotonin‐induced embryotoxicity and teratogenicity.
Dextran‐induced edema formation in mouse ear: A pharmacological evaluation
Authors: van Wauwe Jean P. , Goossens Jan G. 
Published: January 2005

AbstractIntravenous injection of dextran T500 and pontamine sky‐blue dye into mice results in increased vascular permeability and edema formation, characterized by an intense blueing of the ears. By determining the amount of extravasated dye, we compared a number of S2‐serotonin antagonists, H1‐ and H2‐antihistamines, anticholinergics, and inhibitors of arachidonic acid metabolizing enzymes for their effects on ear edema. All S2‐antagonists tested (cinanserin, cyproheptadine, ketanserin, and ritanserin) dose‐dependently suppressed ear blueing. Some H1‐antihistamines (astemizole and azatadine) were also inhibitory, but other H1‐antagonists (brompheniramine, chlorpheniramine, levocabastine, and pyrilamine) failed to weaken the reaction. The anti‐dextran activity of the H1‐blockers seemed to be related to their ability to abolish serotonin‐induced vascular permeability of the mouse ear. Of the compounds interfering with arachidonic acid metabolizing enzymes, only BW 755C, a lipoxygenase inhibitor, proved active. The cyclo‐oxygenase inhibitors indomethacin and suprofen, the thromboxane synthetase inhibitor dazoxiben, the H2‐antagonists cimetidine and ranitidine, and the antichlinergics isopropamide and hexamethonium were inactive. These data provide evidence that the dextran‐induced edema formation in mouse ear is predominantly mediated by serotonin, but they also suggest a participating role for a lipoxygenase‐derived arachidonic acid metabolite(s).
Synthesis of cisapride, a gastrointestinal stimulant derived from cis‐4‐amino‐3‐methoxypiperidine
Authors: van Daele Georges H. P. , De Bruyn Marcel F. L. , Sommen François M. , Janssen Marcel , van Nueten Jan M. , Schuurkes Jan A. J. , Niemegeers Carlos J. E. , Leysen Josée E. 
Published: January 2005

AbstractA novel synthon, 3‐hydroxy‐4,4‐dimethoxy‐N‐phenylmethylpiperidine, is reported on for the preparation of 3‐oxygenated‐4‐substituted piperidines. Different synthetic approaches are described for the synthesis of cis and trans 3‐hydroxy‐ or 3‐methoxy‐1‐substituted‐4‐piperidinamines. The pharmacological properties of benzamides derived from these piperidinamines were evaluated. Several compounds showed a marked activity in tests indicative of potential gastrokinetic activity and were found to be free of dopamine (DA) antagonism. Compounds 31 (cisapride) and 35 were selected for further detailed pharmacological studies.
Old and new approaches to drug treatment of schizophrenia
Authors: Hollister Leo E. 
Published: January 2005

AbstractMore than 30 years have passed since the introduction of effective antipsychotic drugs. These drugs have revolutionized both the treatment of patients with schizophrenia and the thinking about the nature of this disorder. During this time, technical improvements have widened the scope of usefulness of these agents. However, no newer drug has been more effective overall than was the first, chlorpromazine. In addition, many patients respond poorly or not at all to drug therapy; others find the side effects of present drugs unbearable. Tardive dyskinesia and tardive psychosis are developments following long‐term treatment that may have serious import. Many questions about drug therapy remain unanswered. Which drug? How much? Intermittent or continual maintenance therapy? What new approaches to treatment can be considered? Atypical neuroleptics that may specifically bind to receptors in the mesolimbic system constitute the major thrust of current drug development. Interest in benzodiazepines as adjunctive agents have revived. The role of propranolol remains uncertain; it seems more to be an adjunctive treatment. Lithium and carbamazepine may be suitable adjuncts for patients who are otherwise refractory to treatment. Use of neuropeptides was greeted with initial enthusiasm, which is rapidly waning as more experience develops. New approaches to drug treatment for schizophrenia are desperately needed.
Investigation of the negative chronotropic action of SK&F 86466 in the pithed normotensive rat
Authors: Jim Kam F. , Macia Richard A. , Matthews William D. 
Published: January 2005

AbstractSK&F 86466, 6‐chloro‐3‐methyl‐2,3,4,5‐tetrahydro‐1‐H‐3‐benzazepine, is a potent and selective antagonist of the α2‐adrenoceptor in vitro. This compound produced a small pressor response accompanied by a marked bradycardia when administered i.v. to the pithed normotensive rat. The pressor response was not affected by reserpine treatment, pretreatment with α‐ or β‐adrenoceptor antagonists, atropine, or hexamethonium. The bradycardia was markedly reduced by bilateral vagotomy and pretreatment with atropine and attenuated by hexamethonium. The negative chronotropic action of SK&F 86466 was abolished by a combination of vagotomy and atropine. Mediation of the bradycardia by a baroreceptor reflex was ruled out by the observations that a lack of change in heart rate was associated with the vasopressor response to phenylephrine in the pithed rat pretreated with propranolol. It is concluded that the negative chronotropic action of SK&F 86466 in the pithed rat is mediated indirectly by activation of the cholinergic innervation of the heart.
Comparison of the effects of vinpocetine, vincamine, phenytoin, and cinnarizine in a rat model of cerebral ischemia
Authors: King Gary A. , Narcavage Dolores 
Published: January 2005

AbstractVinpocetine is an eburnamenine derivative reported to protect the brain from ischemia, both in experimental animals and in man. Its effects have been directly compared to those of vincamine, phenytoin, and cinnarizine in the Fisher rat following bilateral carotid artery occlusion (BCAO). Upon acute b.i.d. administration (25–100 mg/kg i.p.), both vinpocetine and vincamine significantly increased latency to ischemic convulsion in a dose‐related manner, but neither drug significatly affected survival time. Neither phenytoin nor cinnarizine (25–100 mg/kg, b.i.d.) significantly altered latency to convulsions or survival time. After daily dosing for 5 days, vinpocetine, but none of the other drugs, caused a dose‐related increase in the latency to ischemic convulsion. Vinpocetine's effects occurred at lower doses (25 and 50 mg/kg/day) after subchronic administration than after acute administration. Vinpocetine (25 mg/kg/day) and cinnarizine (100 mg/kg/day) also increased survival time. These results are consistent with other experimental and clinical studies demonstrating a protective effect of vinpocetine against cerebral ischemia and further show that vinpocetine's activity is maintained during repeated administration.
Pharmacologic profile and insulin secretagogue effect of linogliride (McN‐3935), a new, orally effective hypoglycemic agent
Authors: Tutwiler Gene F. , Tuman Robert W. , Joseph John M. , Mihan Brenda B. , Fawthrop Henry , Brentzel H. James 
Published: January 2005

AbstractLinogliride (McN‐3935) [N‐(1‐methyl‐2‐pyrrolidinylidene)‐N'‐phenyl‐4‐morpholinecarboximidamide] was selected for clinical evaluation as a potential orally effective hypoglycemic agent for treatment of noninsulin‐dependent diabetes mellitus. Linogliride is structurally unrelated to sulfonylureas and biguanides. It produced a dose‐dependent hypoglycemic effect in nondiabetic rats, mice, and dogs. The minimum effective oral doses that lowered fasting blood glucose levels and improved glucose tolerance were 1–5 mg/kg. Comparison of the dose‐response curves from fasting rat studies showed linogliride to be approximately two times more potent than the related compound pirogliride and approximately eight times more potent than tolbutamide. Tolerance to its hypoglycemic effect did not develop in rat and dog 3‐day repeat dose studies. Linogliride did not alter plasma lactic acid levels in normal and streptozotocin‐induced diabetic rats, and it improved glucose tolerance whether the glucose was administered orally or parenterally. In nondiabetic rats and dogs, decreases in fasting blood glucose levels following linogliride administration were associated with elevated (two‐ to fourfold) plasma insulin concentrations. Linogliride was inactive in depancreatized diabetic dogs. In genetically diabetic (db/db) mice and streptozotocin‐induced diabetic rats, linogliride (25–100 mg/kg p.o.) produced variable, nondose‐dependent reductions of blood glucose levels, unlike the sulfonylureas, which were consistently ineffective in these diabetic rodent models. In conclusion, although the observed activity in diabetic rodent models is suggestive of a potential nonpancreatic mechanism, the experimental evidence to date indicates that the acute effectiveness of linogliride as a hypoglycemic agent is due primarily to stimulation of insulin release.
Hydrocortisone inreases β‐adrenergic receptors in rat musculus longissimus and heart
Authors: Boecklen Eberhard , Flad Siegfried , von Faber Hans 
Published: January 2005

AbstractThe effect of hydrocortisone on rat β‐adrenergic receptor density in musculus longissimus and heart was studied using the antogonist (3H)dihydroalprenolol. Five days of treatment with 50 mg/kg hydrocortisone increased the density of β‐adrenergic receptors 2.4 times in musculus longissimus and 1.4 times in heart. The results suggest that an increase in β‐adrenergic receptor density is responsible for some side effects of glucocortocoseroid administration.
Mechanism of acute vasodepressor responses elicited by tiprinast and disodium cromoglycate following intravenous injection in anesthetized dogs
Authors: Gomoll Allen W. , Temple Davis L. 
Published: January 2005

AbstractBolus intravenous injection of tiprinast at a 1 mg/kg but not a subsequent 3‐mg/kg dose produced a transient vasodepressor response and concurrent bradycardia in closed‐chest, anesthetized dogs. This pattern was analogous to that elicited by disodium cromoglycate (cromolyn) in another series of dogs. Prior exposure of dogs to a slow 15‐min infusion of either tiprinast or cromolyn (100)μg/kg/min for 15 min significantly attenuated the hypotensions and bradycardia produced by subsequent bolus injection of either agent. The infusions themselves failed to cause sustained, dose‐related decreases in either blood pressure or heart rate beyond those noted durning the first 3–5 min after initiation. Atropine (1 mg/kg, i.v.) pretreatment, bilateral vagotomy, or a combination of atropine and vagotomy each sifnificantly reduced these acute cardiovascular responses. It is concluded that tiprinast, like cromolyn, appears to elicit a cardiac reflec (Bezold‐Jarisch) in the anesthetized dog. The significance of this response, if any, in humans or in relation to the mechanism of antiallergic action(s) of these compounds is uncertain.
Pharmacological studies on factors influencing the collecting phase of the cystometrogram in urethane‐anesthetized rats
Authors: Maggi Carlo Alberto , Santicioli Paolo , Meli Alberto 
Published: January 2005

AbstractThe effect of various pharmacological interventions on the collecting phase of cystometrogram (CMG) has been investigated by means of a new cystometric procedure in urethane‐anesthetized rats. The method involves the transvesical infusion, through a needle inserted in the bladder dome, of warm (37°C) saline at a rat (2.8 ml/h) simulating a maximal hourly diuresis value for this species. In these conditions bladder voiding is produced through the activation of a supraspinal vesico‐vesical reflex. Either chemical (6‐hydroxydopamine, reserpine) or surgical (section of hypogastric nerves) sympathectomy produced a picture of detrusor hyperreflexia and urine dripping, mimicking cystometric finding of human disease. This new procedure may be useful for screening and development of new drugs for treatment of urinary incontinence.