Determination of functionally-relevant serum levels of MJ 13859-1 in the dog: relationship to blockade of amphetamine stereotypy.

The ability of drugs to block dopamine-agonist induced stereotypy in animals has proven to be a reliable in vivo predictor of antipsychotic efficacy in man. Assessment of a drug's potency at displacing [3H]spiperone from rat striatal membranes is an in vitro test which also has predictive validity for antipsychotic actions. Methods are described for assessing stereotyped behavior in the dog, and for measuring the ability of serum samples taken from treated animals at behaviorally interesting time points, to displace [3H]spiperone from washed synaptic membranes of rat striata.

Flunarizine and verapamil: effects on central nervous system and peripheral consequences of cytotoxic hypoxia in rats.

Flunarizine is a calcium entry blocking drug possessing antihypoxic activity in animal models of cerebral and peripheral ischemia-anoxia and has clinical usefulness in circulatory disorders of both central and peripheral origin. This report compares the activity of flunarizine and verapamil, another calcium entry blocking drug, on the central nervous system (CNS) and peripheral consequences of cytotoxic hypoxia induced by high and low doses of KCN. The lethal effect of KCN (6 mg/kg, i.

Neuropharmacology of buspirone.

Buspirone is a clinically effective anxiolytic with a unique structure and pharmacology which distinguishes it from the benzodiazepines. It has been termed anxioselective because it lacks anticonvulsant, sedative, or muscle-relaxant properties. Preclinical evidence suggests it lacks potential for abuse or physical dependence and interacts minimally with CNS depressants such as alcohol.

Effect of fenoterol on immunological release of leukotrienes and histamine from human lung in vitro: selective antagonism by beta-adrenoceptor antagonists.

The inhibitory effects of fenoterol, a beta 2-adrenoceptor agonist, on the release of SRS-A leukotrienes and histamine from chopped human lung tissue were measured and selective beta-adrenoceptor antagonists used to investigate the nature of the receptors involved. Fenoterol 0.01-1.

The selectivity of beta-adrenoceptor antagonists on isoprenaline-induced changes in heart rate, blood pressure, soleus muscle contractility and airways function in anaesthetized cats.

The beta-adrenoceptor antagonist of propranolol, metoprolol, atenolol and butoxamine in anaesthetized cats has been measured and compared with the activity of four synthetic phenylethanolamine derivatives. The effects of isoprenaline on four parameters in the anaesthetized cat: heart rate, blood pressure, soleus muscle contractility and airway reactance, were measured and the modification of the isoprenaline dose-response relation by each of the antagonist drugs assessed. Parallel shifts in log dose-response curves for isoprenaline were caused by propranolol for all parameters, by metoprolol and atenolol for each parameter except blood pressure, and butoxamine for each except soleus muscle and heart rate.

Prognostic parameters in recurrent malignant melanoma.

In 361 patients with recurrent malignant melanoma, the clinical stage was the strongest determinant of subsequent survival (P less than 0.01). In Stage IV, the number of initial, distinct lesions was important.

The determination of beta-adrenoceptor antagonist cardioselectivity "in vivo": atenolol in anaesthetized cats.

A study has been carried out to establish the best method for determining the cardioselectivity of beta-adrenoceptor antagonists in vivo, exemplified by atenolol in the anaesthetized cat preparation. Using three beta-adrenoceptor agonists: terbutaline (beta 2), dobutamine (beta 1), and isoprenaline and monitoring atenolol's antagonism of the agonist effects on heart rate, airway elastance and soleus muscle tension, parallel shifts in dose-response curves for each agonist were observed on each parameter. The cardioselectivity of atenolol was determined with each agonist by comparison of DR10 values from Schild plots and mean dose-ratio shifts.

Surfactant deficiency in rats without a decreased amount of extracellular surfactant.

Low volume ventilation without periodic large inflations leads to diminished alveolar stability and to the accumulation of increased amounts of airway disaturated phosphatidylcholine (DSPC) in large aggregates that sediment at 1,000 g; surfactant in this form lowers surface tension less rapidly than surfactant present in the 1,000-g supernatant fraction. These observations led to the present work in which we tested the notion that alveolar instability may develop in the presence of an undiminished quantity of total airway surfactant, if the amount of surfactant found in the 1,000-g supernatant fraction is diminished. Pulmonary compliance fell and the alveolar-arterial O2 gradient widened in normothermic rats during constant ventilation in the resting tidal volume range, and, in hyperthermic rats (approximately 39 degrees C) similarly ventilated but with the addition of periodic sighs.

Buspirone analogues. 1. Structure-activity relationships in a series of N-aryl- and heteroarylpiperazine derivatives.

A series of analogues of buspirone was synthesized in which modifications were made in the aryl moiety, alkylene chain length, and cyclic imide portion of the molecule. These compounds were tested in vitro for their binding affinities to rat brain membrane sites labeled by either the dopamine antagonist [3H]spiperone or the alpha 1-adrenergic antagonist [3H]WB-4101. Compounds were also tested in vivo for tranquilizing properties and induction of catalepsy.

Hazards of battery ingestion.

A 12-year-old boy ingested a mercury battery from a watch as a part of an alleged poisoning attempt by an uncle. The battery apparently ruptured spontaneously in the child's stomach less than 36 hours after ingestion. At surgery one battery terminal was found embedded in gastric mucosa thought to be progressing toward gastric perforation.

Buspirone: an anxioselective alternative for the management of anxiety disorders.

Buspirone HCl (Buspar) is a novel anxiolytic agent unrelated to the benzodiazepines or other psychotherapeutic agents. Animal studies support an anxioselective profile, i.e.

Plasma prednisolone concentrations and kinetics in renal transplant patients.

Plasma prednisolone concentrations were measured in 26 renal transplant (RT) patients and five control subjects. A linear relationship was found between prednisolone dosage in mg/kg and area under the plasma concentration time curve in seven stable RT patients (r = 0.98) and in all subjects (n = 19) with estimated prednisolone clearance rates (CLp) between 0.

Buspirone: chemical profile of a new class of anxioselective agents.

Buspirone is a lipophilic, dibasic heterocyclic with no structural resemblance to other anxiolytic or antipsychotic agents. Neurochemical binding studies suggest that buspirone has both dopamine agonist and antagonist properties. Structural comparisons with (+)-butaclamol indicate that buspirone possesses features required for binding at the postsynaptic dopamine receptor site.

In vitro experiments on chloroquine and pyrimethamine absorption in the presence of antacid constituents or kaolin.

A study was made in vitro of the effect of five gastrointestinal medications on the absorption of chloroquine and pyrimethamine, the two most commonly used antimalarial agents in the Sudan. Activated dimethicone did not appreciably affect the absorption of either antimalarial drug. All other agents tested significantly decreased the absorption of both chloroquine and pyrimethamine.

Effect of benoxaprofen on release of slow-reacting substances from human lung tissue in vitro.

1. macroscopically normal human lung tissue was obtained from operative specimens removed for lung cancer and challenged with antigen or calcium ionophore. The release of histamine and slow-reacting substances was measured by fluorimetric and bioassay techniques respectively.

The effect of magnesium trisilicate and kaolin on the in vivo absorption of chloroquine.

An in vitro study indicated that certain antacids and adsorbents may decrease the oral availability of th two widely used antimalarial agents chloroquine and pyrimethamine. To determine if this data was applicable to the clinical (in vivo) situation, plasma levels of one of the antimalarial agents (chloroquine) were followed in six Negro--Arab volunteers both when given alone and when taken with separate doses of two of the implicated interactants (magnesium trisilicate and kaolin). This in vivo work confirmed the in vitro findings; chloroquine area under the plasma concentration-time curve data were decreased by both magnesium trisilicate (18.

Antiallergics: 3-(1H-tetrazol-5-yl)-4H-pyrimido[2,1-b]benzothiazol-4-ones.

A short series of the title compounds was prepared and evaluated for both antiallergic and bronchodilator activity. Members of the series exhibit good oral activity in the rat PCA test, the most potent being the parent compound, 3-(1H-tetrazol-5-yl)-4H-pyrimido[2,1-b]benzothiazol-4-one, and its 8-chloro derivative. The latter two compounds are considerably more potent than either disodium chromoglycate or theophylline as antiallergic agents and also show significant bronchodilator activity.

The modification by ketotifen of respiratory responses to histamine and antigen in guinea-pigs.

Aerosolized solutions of histamine or ovalbumin were administered to control or ovalbumin-sensitized guinea-pigs. The time to onset of respiratory distress (preconvulsion time) during challenge with these agents was measured using a force-displacement transducer on the animal's back. The preconvulsion time for each guinea-pig was compared with and without ketotifen pretreatment.

The use of buccal partitioning as a model to examine the effects of aluminium hydroxide gel on the absorption of propranolol.

1 A buccal partitioning model showed no absorption interaction between propranolol and aluminium hydroxide gel in three volunteer subjects. 2 The previously reported in vivo interaction is therefore not due to propranolol adsorption to, or complexation with the antacid but is more probably due to a decreased gastric emptying rate caused by the antacid. 2 Buccal partitioning has proved useful in the examination of the mechanism of the propranolol/aluminium hydroxide absorption interaction and may also be a suitable in vivo bioavailability screening model for other drugs which can be partitioned in the buccal membranes.

Dopamine and antianxiety activity.

Clinical trials have indicated that buspirone (Buspar) is effective in the treatment of anxiety with efficacy and dosage comparable to diazepam. Until recently it has been thought that antianxiety drugs must alter benzodiazepine receptor binding in vitro. However, buspirone lacks any structural similarity to te benzodiazepines and does not interact with the benzodiazepine/gamma-aminobutyric acid (GABA) axis.