bluuebunny/crossref_metadata_2025 huggingface dataset:
Studies of the antihypertensive effects of CL 242,817, a new angiotensin‐I converting enzyme inhibitor [S−(R*, s*)]‐1‐[(3‐acetylthio)‐3‐benzoyl‐2‐methyl propionyl‐L‐proline]
Authors: Lai F. M. , Cervoni P. , Chan P. S. , Shepherd C. A. , Ronsberg M. A. , Quirk G. J. , Thibault L. , Scully P. , Tanikella T.
Published: January 2005

The antihypertensive activity of CL 242, 817 and captopril were evaluated in conscious, unrestrained aorta‐coarcted hypertensive rats (AHR); spontaneously hypertensive rats (SHR); and in the two‐kidney, one‐clip, Goldblatt renal hypertensive beagle (RH2 dog). In AHR, equimolar oral doses of CL 242,817 (5 mg/kg) and captopril (3 mg/kg) had rapid onsets of action and relatively long durations of action. CL 242,817 was significantly more potent and longer‐acting than captopril. In the SHR, CL 242,817 was effective in lowering blood pressure by oral, intravenous, or intraperitoneal routes of administration, although less effectively than in AHR. In RH2 dogs, pretreated with the diuretic quinethazone, CL 242,817 (20 mg/kg, p.o.) lowered blood pressure more effectively than an equimolar dose of captopril (12 mg/kg). In RH2 dogs sodium‐depleted by furosemide pretreatment and maintained on a salt‐free diet to raise plasma renin activity (PRA) levels, CL 242,817 (20 mg/kg, p.o) was more effective than an equimolar oral dose of captorpril (12 mg/kg) in lowering blood pressure. In RH2 dogs, repletion of body sodium (and reduction in PRA) by maintenance on a normal sodium diet for 14 days decreased the antihypertensive effect of CL 242,817 and abolished that of captopril. The data suggest that angiotensin converting enzyme inhibitors (ACEI) are more effective in models in which PRA is elevated and the hypertension appears to be renin‐dependent. The RH2 dog that is sodium‐depleted by furosemide and mainted on a sodium‐free diet appears to be a suitable model for evaluating the antihypertensive effects of ACEI.
Ophthalmic drug delivery systems
Authors: Shell John W.
Published: January 2005

New ophthalmic drug delivery systems are curently receiving increased attention, in part because of the expected emergence of new drugs with short biological half‐lives whose usefulness may depend on a more continuous drug supply than eyedrops can provide, but also because of the potential of some delivery systems to reduce the side effects of the more potent drugs recently introduced or presently under investigation. Some ophthalmic delivery systems extend the duration of drug action by enhancement of corneal absorption; these systems include soluble gels and emulsions, hydrophilic ocular inserts, ion‐pair associations, prodrugs, and liposomes. Since these systems enhance the “pulse entry” of the drug, they are limited to use with drugs whose dose‐related side effects are not serious. Other delivery systems provide for a controlled release of drugs and therefore minimize the pulse entry with which side effects are associated. They can be based on any of several different mechanisms and include both erodible and nonerodible matrices. The various delivery systems that have recently been developed and those that are currently known to be under investigation are described in this paper, along with some observations regarding the future outlook of ophthalmic drug delivery systems.
Early experience with CGP 4718 A (Sercloremine), a new selective and reversible MAO‐A and 5‐HT‐uptake inhibitor, in the treatment of depressive patients
Authors: Delini‐Stula A. , Fischbach R. , Gnirss F. , Bures E. , Pöldinger W.
Published: January 2005

Tolerability of CGP 4718 A (sercloremine), a 4‐(5‐chloro‐2‐benzofuranyl)‐1‐methyl‐piperdine, as well as the effects on target symptoms in 22 hospitalized depressed patients, were investigated in an open, multicenter study. In daily doses of 50 to 150 mg, the compound was well tolerated. There were no changes in cardiovascular parameters (blood pressure, ECG) nor were there changes in laboratory values that could be considered of clinical relevance. Of concern, however, were sleep disturbances, which appeared to be aggravated in the majority of treated patients. There were only a few other side‐effects that could be related to the drug treatment, and they were mostly mild and transitory. The therapeutic effects of CGP 4718 A, as judged by the changes in total Hamilton depression rating scores and global assessement, indicated beneficial action of the drug on the core symptoms of depression (except sleep disturbances). The therapeutic effect appeared to be dose‐related and particularly marked in neurotic and reactive depressions. These findings, in line with the predictions made on the basis of preclinical animal studies, encourage further clinical testing of this compound.
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

The 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

Centchroman (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

The 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

Newly 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

The 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

The 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

Platelets, 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

Serotonin 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

Intravenous 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

A 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

More 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

SK&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

Vinpocetine 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

Linogliride (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

The 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

Bolus 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

The 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.
Cholecystokinin octapeptide prevents extinction of active avoidance behavior in the rat
Authors: Itoh Shinji , Katsuura Goro
Published: January 2005

The effect of cholecystokinin octapeptide (CCK‐8) on the performance of platform‐jumping avoidance behavior was investigated in the rat. CCK‐8 was injected subcutaneously once in different doses immediately after training trials. The number of avoidance responses remained high 5 and 10 days after the CCK‐8 administration and the greatest effect was observed with doses of 10 and 100 ng/kg, while in control saline group the number of responses decreased after 5 days. Larger doses of CCK/8 were less effective, probably due to a sedative action.
New perspecties on the phusiology, chemistry, and pharmacology of memory
Authors: Lynch Gary , Larson John , Staubli Ursula , Baudry Michel
Published: January 2005

Considerable progress has been made in the analysis of learning and memory both at the level of the chemical processes involved in translating brief phusiological events into long‐lasting changes in synaptic efficacy and at the level of the location of the changes responsible of behavioral phenomenon of memory. This review focuses primarily on recent findings concerning the phenomenon of long‐term potentiation (LTP) of synaptic transmission elicited in hippocampal pathways by certain patterns patterns of electrial stimulation of various pathways. We first discuss the nature of the physiological events which are critically involved in LTP induction and indicate that these events are linked with naturally occurring patterns of activity in behaving animals. Detailed analysis of the physiological events taking place in the initial period of LTP induction points out a very specific sequence of biochemical/biophysical mechanisms that play a critical role in triggering LTP. We then briefly review the evidence indicting that LTP induction is accompanied by various types of structural modifications that have been proposed to be responsible for the long duration of the synaptic changes. This is followed by the description of a candidate biochemical mechanism that links the initial events triggered by LTP‐inducing stimulations and the long‐lasting modifications in synaptic structure and function. The final section presents our efforts to situate the analysis of the LTP phenomenon in the broader context of learning and memory and in particular indicates how the knowledge obtained at the biochemical and cellular level can be used to design new strategies for a pharmacological analysis of the memory processes.
Quantification of the morphine reversal activity of opioid agonists/antagonists and naloxone by using a rabbit tooth pulp procedure
Authors: Wynn Richard L. , Bergman Stewart A.
Published: January 2005

The rabbit tooth pulp procedure was used to determine the potencies and durations of morphine reversal by naloxone, buprenorphine, nalbuphine, butorphanol, and pentazocine. Cumulative doses (mg/kg) required to double the number of morphine‐depressed respirations per minute (RPM) (ED 2 X) and to reduce morphine‐elevated lick/chew (L/C) volts by one‐half (ED 1/2) were determined. These doses were naloxone 0.003, 0.013; buprenorphine 0.030, 0.130; nalbuphine 0.130, 0.520; butorphanol 0.120, 0.630; pentazocine 1.10, 0.150. The antinociceptive effects of these compounds were compared by determining the cumulative dose required to achieve the highest percentage maximum possible effect (% MPE) as determined by the elevation of lick/chew threshold volts from control volts in morphine‐free rabbits: naloxone 6% at 0.0005 mg/kg; buprenorphine 69% at 0.075 mg/kg; nalbuphine 32% at 0.150 mg/kg; butorphanol 32% at 0.150 mg/kg, and pentazocine 12% at 1.55 mg/kg. The durations (min) of reversal of morphine RPM and morphine L/C volts were also determined: naloxone 33, 30; buprenorphine 240, 240; nalbuphine 120, 120; butorphanol 90, 45; pentazocine 60, 15. It is suggested that the rabbit tooth pulp assay is a sensitive and reliable assay to evaluate and quantitate compounds for opioid agonist/antagonist activity.
Small peptides and nerve growth: Therapeutic implications
Authors: Taylor J. E. , Moreau J. P. , DeFeudis F. V.
Published: January 2005

Studies of the effects of small peptides (<10,000 Da), i.e., fragments of naturally occurring hormones (e.g., adrenocorticotrophic hormones [ACTH]: α‐melanocyte‐stimulating hormone [α‐MSH]), hypophysiotrophic factors (e.g., growth hormone‐releasing hormone [GHRH], thyrotropin‐releasing hormone [TRH]), other growth factors, and synthetic compounds on peripheral and CNS neuronal regeneration and behavior have been reviewed and analyzed. It seems apparent that certain hormonal fragments, growth factors, and some synthetic compounds (e.g., the ACTH/α‐MSH analogue Org 2766) can enhance peripheral, and possibly CNS, nerve regeneration. Further study of newer peptide‐analogues with increased potency, longer duration of activity, and greater selectivity of action might lead to the development of therapies for certain types of nerve injury and for neurodegenerative disorders.
Effect of ipratropium bromide on bronchospasm induced by inhalation of hypotonic solutions
Authors: Neria José Pérez , Montaño R. Luis Manuel , Monge L. Gilberto , Rubio M. Horacio , Selman L. Moisés
Published: January 2005

In order to determine the role of the cholinergic system in the bronchoconstriction induced by hypotonic solutions 30 subjects were studied: 15 asthmatic patients and 15 healthy volunteers to whom distilled water was administered by inhalation through ultrasonic nebulization. All asthmatic patients showed a 20% reduction of forced expiratory volume in 1 sec in relation to the initial value. Bronchospasm was not detected in any of the healthy subjects. After 24 hr, ipratropium bromide in aerosol was administered 1 hr before distilled water nebulization, and this prevented the bronchoconstriction response in 11 of the 15 asthmatic patients. These results suggest that such bronchospasm is mediated at least in part by vagal reflex.
Pharmacological evaluation of HP 370, a potential atypical antipsychotic agent: 1. In vivo profile
Authors: Szewczak Mark R. , Cornfeldt Michael L. , Dunn Robert W. , Wilker Jeffrey C. , Geyer Harry M. , Fielding Stuart , Glamkowski Edward J. , Chiang Yulin
Published: January 2005

HP 370 4,9‐Dibromo‐6‐(4 methyl‐1‐piperaziny(l)benzo((b)pyrrolo[3,2,1‐jk][1,4 benzodiazepine] demonstrated preclinical activity indicative of clinical atypical antipsychotic activity, which may provide an advantage over current therapeutic agents. It was effective in blocking apomorphine‐induced climbing behavior in mice (ED50 = 4.1 mg/kg i.p.; 1.6 mg/kg p.o), locomotion caused by direct application of dopamine to the nucleus accumbens in rats (ED50 = 15.4 mg/kg i.p.), intracranial self‐stimulation in rats (ED50 = 10.1 mg/kg i.p.), and pole‐climb avoidance in rats (ED50 = 4.0 mg/kg p.o. avoidance; 10.6 mg/kg p.o. escape failures). HP 370 was relatively inactive in blocking aporomorphine‐induced stereotypy in rats (50% at 40 mg/kg, 33% at 20 mg/kg i.p.), relatively inactive in causing catalepsy in rats (50% at 40 mg/kg i.p.)m and was completely inactive in blocking stereotypy caused by the direct application of dopamine to the corpus striatum of rats (up to 80 mg/kg i.p.). Chronic administration of HP 370 caused supersensitivity to apomorphine in the climbing mouse test and in dopamine‐induced locomotion in rats, but not in dopamine‐induced stereotypy in rats. Acute administration of HP 370 caused and increase in the numberof active dopamine neurons sampled in both the ventral tegmental area and substantia nigra of rats, whereas chronic administration resulted in singnificantly fewer dopamine neurons found in the ventral tegmental area with no change from control levels observed for the substantia nigra. In a measure of social interaction in rats, HP 370 significantly increased the time spent interacting without altering overall activity, suggesting favorable effects on negative symptomatology. No in vivo anticholinergic activity was seen in the physostigmine lethality test in mice. In vivo blockade of alpha noradrenergic receptors was suggested by the inhibition of norepinephrine lethality in rats (50= 0.6 mg/kg i.p.). HP 370 displays an in vivo profile consistent with that of an atypical antipsychotic agent and is predicted to be clinically effective with fewer side effects than currently available therapy.
Cardiovascular profile of the cardioselective beta‐adrenoceptor antagonist bisoprolol in anesthetized pigs
Authors: Verdouw Pieter D. , Schmeets Iiona O. L. , Rensen Rob J.
Published: January 2005

The cardioselective beta‐adrenoceptor antagonist bisoprolol ((±)−1‐[4‐(2‐isopropoxyethoxy‐ymethyl)‐phenoxy]3‐isopropylamino‐2‐propanol‐hemifumarate, EMD 33512) was studied for its effects on cardiac performance in ten anesthetized open‐chest pigs. Radioactive labelled microspheres (15 ± 1 μm) were used to determine regional blood flows. In doses of 4, 16, 64, 256, and 1,024 μg · kg−1 (arterial plasma concentrations 1.65 ± 0.07 to 569 ± 22 ng · ml−1) the drug caused dose‐dependent decreases in cardiac output (4–31%, P < .05) that were primarily due to a negative chronotropic action as heart rate, which had already been slowed down by 9% (p < .05) after the lowest dose, decreased up to 22% (p < .05). Stroke volume was not significantly affected at any dose, although it tended to decrease after the highest dose of hisoprolol (−10%, p < .05). Myocardial it tended to reflected by maxLVdP/dt, fell dose dependetly from 12% (after 4μg · μg·Kg−1, P < .05) up to 46% (after 1,024 μg · −1, P < .05). Raising the heart rate to predrug levels revealed that this reduction in maxLVdP/dt was not related to the bradycardic action of the drug. Mean arterial blood pressure decreased slightly (<15%, P < .05) after the highest three doses, but a larger fall was prevented by a mild vasoconstriction of the systemic arterial vascular bed as systemic vasular resistance increased up to 28% (P < .05). Pulmonary artery pressure was not affected, because pulmonary vasuclar resistance increased with the highest doses. Left ventricular blood flow, which had already decreased significantly with the lowest dose (11%, P B < .05), also decreased dose dependently (up to 44% after 1,024 μg · kg−1, P < .05). These decreases were equally distributed over all myocardial layers as the endolepi blood flow ratio (1.13 ± 0.04) was not affected. Myocardial 02 consumption was not affected by the lowest dose, but decreased progressively up to 43% (P <
.05) with the higher doses. These changes occurred parallel to those in blood flow as myocardial O2 extraction did change. Cerebral blood flow was well preserved but decreases in perfusion of some other organs and tissues (kidneys, stomach, and skeletal muscle) were similar to those in cardiac output.

In conclusion, bisoprolol has a cardiovascular profile similar to that of other beta‐adrenoceptor agents. The finding that no serious adverse cardiovascular affects are observed over a wide dose range warrants further studies in models of myocardial is‐chemia and hypertension.
Preventive effect of cholecystokinin octapeptide on scopolamine‐induced memory impairment in the rat
Authors: Itoh Shinji , Takashima Akira , Katsuura Goro
Published: January 2005

In a passive avoidance response, intraperitoneal administration of scopolamine (0.5 mg/kg) at 15 min before the training trials produced a marked impairment of memory in the rat. However, pretreatment with cholecystokinin octapeptide (CCK‐8) either given subcutaneously or intracerebroventriculary (i.c.v.) prevented the scopolamine‐induced amnesia. Continuous i.c.v. infusion of CCK‐8 (1 ng/day) for 7 days significantly prevented the amnesia. The results support our previous findings that CCK‐8 has a protective effect against experimental amnesia in the rat.
New potential antipsychotic drug BMY 20661: A profile of its effects on midbrain dopamine neurons
Authors: Henry Douglas J. , White Francis J.
Published: January 2005

The new potential antipsychotic drug BMY 20661 was subjected to a series of electrophysiological tests to determine its effects on midbrain dopamine (DA) neurons in the rat substantia nigra pars compacta (A9) and ventral tegmental area (A10). Acute intravenous (i.v.) administration of BMY 20661 exerted little effect on the basal spontaneous firing rates of either A9 or A10 DA neurons. Following suppression of DA unit activity by the DA agonist apomorphine (APO), BMY 20661 consistently increased the firing of A10, but not A9, DA cells. However, the rates of A10 DA cells seldom recovered to pre‐APO basal levels following BMY 20661 administration. The ability of BMY 20661 to partially reverse the APO‐induced rate suppression was apparently not due to blockade of DA receptors since pretreatment with BMY 20661 (6.3 mg/kg, i.v.) only slightly (nonsignificantly) reduced the ability of APO to inhibit the firing of A10 cells. Surprisingly, BMY 20661 significantly attenuated the effects of APO on A9 DA cells. These findings suggest that BMY 20661 influences A10 DA neurons by a non‐DA mechanism. Because BMY 20661 has been reported to bind to 5‐HT1A receptors, the acute effects of this compound were compared to those of 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT), a known 5HT1A agonist. These compounds demonstrated similar profiles in their ability to reverse APO‐induced suppression of A10 DA cells but, unlike BMY 20661, 8‐OH‐DPAT was also active on A9 DA cells. Repeated administration of BMY 20661 for 28 days (either 5 or 10 mg/kg/day) failed to alter significantly the number of spontaneously active A10 DA cells but caused a small, but statistically significant, increase in the number of A9 DA cells/track. Because the ability to decrease the number of spontaneously active A10 DA cells has been proposed as a predictive model for antipsychotic drug action, the results obtained following repeated administration of BMY 20661 fail to support a potential antipsychotic profile for this new compound.
Neurochemical and behavioural profile of Lu 17‐133, (±)‐trans‐4‐[3‐(3,4‐dichlorophenyl)‐indan‐1‐yl]‐1‐piperazineethanol, an inhibitor of the uptake of dopamine and noradrenaline
Authors: Hyttel J. , Arnt J. , Bøgesø K. , Christensen A. V. , Larsen J.‐J , Lembøl H. L. , Meier E. , Sánchez C.
Published: January 2005

The neurochemical and behavioural profile of Lu 17‐133, (±)‐trans‐4‐[3‐(3,4‐dichlorophenyl)‐indan‐1‐yl]‐1‐piperazineethanol has been characterized and compared with that of a series of inhibitors of biogenic amine uptake. Lu 17‐133 inhibits the uptake of dopamine and noradrenaline in the nanomolar range, but it has only a weak effect on serotonin uptake. Blockade of receptors for dopamine (D‐1, D‐2), noradrenaline (α1, α2), histamine (H1), acetylcholine (muscarinic), and serotonin (5‐HT2) was absent or seen only at micromolar concentrations. The biochemical profile is close to that of GBR 13.069, GBR 12.921, and Lu 19‐005 (INN name, Indatraline). Lu 17‐133 shows only weak behavioural effects. In high doses, it potentiates apomorphine and 5‐HTP and reverses the effect of tetrabenazine in mice. It has minimal stimulatory property, as it increases very weakly the locomotor activity in mice and does not induce stereotypy (either low‐component or oral stereotypy) in rats. It does not induce ipsilateral circling behaviour in 6‐OHDA‐lesioned rats, although in combination with scopolamine, a full ipsilateral rotation is seen. Lu 17‐133 has no anticataleptic effect and does not generalize to the discriminative stimulus properties induced by d‐amphetamine. Experiments have shown that there is no clear correlation between inhibitory effect on dompamine uptake and in vivo effects in the models detecting dopamine‐stimulating compounds; nor is there any obvious correlation between effects in different in vivo test models. The neurochemical and behavioural characteristics of Lu 17‐133‐inhibition of dopamine‐ and noradrenaline‐uptake in vitro with low stimulatory properties in vivo make it an interesting candidate as a new antidepressant drug.
Prevention of scopolamine effect on the decrease of acetylcholine content by peripherally administered cholecystokinin octapeptide in some regions of the rat brain
Authors: Takashima Akira , Itoh Shinji
Published: January 2005

Intraperitoneal injection of scopolamine at a dose of 0.5 mg/kg produced a marked decrease after 15 min in the acetylcholine (ACh) content of the frontal and temporal cortices and the hippocampus in the rat. In the parietal and occipital cortices and the striatum, the decrease in ACh content was less extensive. When rats were treated with cholecystokinin octapeptide 15 min before the scopolamine administration, the decrease in ACh was prevented in a dose‐dependent manner. The choline content was not affected significantly by these treatments.
Cholinergic systems and alzheimer's disease
Authors: Defeudis F. V.
Published: January 2005

Studies of central cholinergic mechanisms, cholinergic drugs, and Aizheimer's disease (AD) have been reviewed and analyzed. Although the pronounced cholinergic deficit that exists in the brains of AD patients is associated with memory loss and other cognitive dysfunctions, cholinergic “replacement therapy” is of limited benefit in trating AD. Recent findings concerning the roles of nerve growth factor, “excitotoxic” amino acids, and amyloid deposition in AD migh lead to mroe fruitful therapeutic approaches.
A double‐blind, placebo‐controlled study with oxiracetam in demented patients administered the Luria‐Nebraska Neuropsychological Battery
Authors: Mangoni A. , Perin C. , Smirne S. , Piccolo I. , De Filippi F. , Marchetti C. , Motta A. , Monza G. C.
Published: January 2005

A formal multicenter, double‐blind, between‐patient trial was carried out to evaluate the efficacy and tolerability of oxiracetam (OXIR) (800‐mg tablets), in comparison with placebo, each given twice daily for 24 weeks to patients suffering from probable or possible Alzheimer's disease (AD). Efficacy was assessed by the Inventory of Psychic and Somatic Complaints in the Elderly (IPSC‐E), administered at entry and after 8, 16, and 24 weeks of treatment, and by the Luria‐Nebraska Neuropsychological Battery (LNNB), administered at the beginning and at the end of the study. Thirty patients (16 on OXIR and 14 on placebo), 20 males and 10 females, mean age 62 years (range 52–79), were enrolled and completed the study. A significant (P < 0.01) difference between treatments in the total score of the IPSC‐E, as well as in some LNNB scales, was observed. In particular, patients on OXIR showed an improvement over time, while the condition of patients on placebo remained unchanged or tended to get worse. No difference in tolerability between the active drug and placebo was observed.
Effect of vinpocetine on monoamine receptor binding and synaptosomal uptake in the rat brain
Authors: Lee David K. H. , Geiger G.
Published: January 2005

The in vitro effect of vinpocetine on the various adrenergic, serotoninergic, and dopaminergic receptor systems was studied in the rat. At 1 μM concentrations, vinpocetine and its major metabolite, apovincaminic acid, did not exhibit inhibitory activity in any of the receptor binding assays, nor did vinpocetine show any significant inhibitory effect in the synaptosomal uptake assays at ten‐fold higher concentrations. The results suggest the unlikeliness that vinpocetine exerts its pharmacological effects through monoamine receptor binding or synaptosomal uptake mechanisms.