bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clonidine in mania
Authors: Giannini A. James , Extein Irl , Gold Mark S. , Pottash A. L. C. , Castellani Sam 
Published: January 2005

AbstractHyperactivity of central noradrenergic neurotransmission has been implicated in the pathophysiology of mania. This theory suggests that clonidine, an antihypertensive medication that decreases the activity of central noradrenergic neurons by presynaptic inhibitory effect, has antimanic properties. We administered clonidine orally in a dosage of 17 μg/kg/day to 11 hypomanic or manic patients. Biegel‐Murphy Manic‐State Rating Scale scores were significantly decreased compared to pretreatment scores at day 10 and day 25 of clonidine treatment (P < .001). Sedation, hypotension, and depression were noted but were not limiting. Though the results of this study are only preliminary, clonidine alone or in combination with lithium may have advantages over neuroleptics in the acute stages of mania, including avoidance of extrapyramidal side effects and risk of tardive dyskinesia.
Clobazam and diazepam: The differential effects on psychomotor performance and subjective feelings in normal volunteers with high neuroticism level
Authors: Kawazu Yusuke , Nakano Shigeyuki , Ogawa Nobuya , Taeuber Karl 
Published: January 2005

AbstractThe purpose of this study was to investigate the possible differences between diazepam and clobazam with regard to their effects on psychomotor performance and subjective feeling in normal volunteers with high neuroticism levels. The study was designed as a double‐blind, crossover, single‐dose comparison of clobazam, diazepam, and placebo. Using the Maudsley Personality Inventory (MPI), 12 healthy male volunteers exhibiting high neuroticism scores were selected. Clobazam 10 mg, diazepam 5 mg, and placebo were administered orally. Measurements of psychomotor performance and subjective ratings of mood states were performed before and 1.5 and 6 hr after administration. Prior to the experiment the subjects were trained with the performance tests to minimize interference of learning effects with drug effects. Between the three treatments there were 1‐wk intervals. Both clobazam and diazepam significantly lowered choice‐reaction task performance as compared to placebo. Only clobazam lowered mirror‐drawing task performance significantly differently from placebo. Significant changes in subjectively rated mood states were also seen after clobazam only. These mood changes appeared to indicate some disinhibitory or stimulant effects. The demonstrated differences between the effects of both anxiolytics are discussed in the context of experimental design characteristics and the subjects' high level of neuroticism. Some of the observed effects may be due to an interaction of drug effects with neurotic tendencies rather than to generalized drug effects per se.
Occupation of brain receptors by benzodiazepines and β‐carbolines: Multiple mechanisms and responses
Authors: Hirsch James D. , Kochman Ronald L. 
Published: January 2005

AbstractHigh affinity for the brain benzodiazepine receptor can no longer be considered predictive of benzodiazepine‐like pharmacology in vivo. Studies of 3H‐diazepam (3H‐DZ) and 3H‐propyl‐β‐carboline‐3‐carboxylate (3H‐PrCC) binding were performed to investigate how occupation of the benzodiazepine receptor by these two high‐affinity ligands leads to their significantly different pharmacological effects. In mouse hypothalamus, there are four times as many 3H‐DZ binding sites as 3H‐PrCC binding sites (Bmax values = 1,025 and 265 fmol/mg protein, respectively) and both types of site form a distinct anterior‐to‐posterior gradient in this tissue. Physiological Ca+2 concentrations do not regulate 3H‐ligand binding in Ca+2‐depleted whole mouse brain membranes, but in the presence of increasing concentrations of guanosine 5′‐triphosphate (GTP), Ca+2 stimulates 3H‐DZ binding up to 25%. In contrast, 3H‐PrCC binding is unaffected by Ca+2 and GTP. Diazepam (DZ) and ethyl β‐carboline‐3‐carboxylate (βCCE) both stimulate 3H‐muscimol binding to GABA receptors in whole mouse brain membranes (DZ = +57%, βCCE = +27%), and βCCE partially blocks the effect of the benzodiazepine. Moreover, alkyl β‐carboline‐3‐carboxylates prevent a temperature‐induced thermodynamic transition in the benzodiazepine receptor that occurs in the presence of GABA. Studies of 8‐anilino‐1‐naphthalene sulfonic acid fluorescence (ANS) perturbation have also suggested that occupation of the receptor by a benzodiazepine results in a conformational change. Although benzodiazepines and β‐carbolines are high‐affinity ligands for the benzodiazepine receptor, these results suggest that their different pharmacological profiles may result from significant differences in binding mechanisms and receptor responses.
Behavioral and neurochemical studies on the anticonflict actions of buspirone
Authors: Weissman B. A. , Barrett J. E. , Brady L. S. , Witkin J. M. , Mendelson W. B. , Paul S. M. , Skolnick P. 
Published: January 2005

AbstractA series of behavioral and neurochemical studies were performed in order to determine if buspirone (or an active metabolite of this compound) could perturb a component of the γ‐aminobutyric (GABA)‐benzodiazepine receptor‐chloride ionophore complex. In confirmation of previous findings, buspirone was shown to have anticonflict actions in both the rat and monkey. However, in these tests, buspirone was not as efficacious as benzodiazepines in producing an anticonflict action. The benzodiazepine receptor antagonists CGS 8216 and Ro 15–1788 did not reverse the anticonflict actions of buspirone. Small but statistically significant increases in the binding of [3H]diazepam to brain were observed in vivo after doses of buspirone which are active in the “thirsty rat conflict” test. However, a similar change was not observed in the ex vivo binding of [3H]flunitrazepam. These observations suggest that a metabolite of buspirone may perturb some component of the GABA‐benzodiazepine receptor‐chloride ionophore complex in an indirect fashion. Further work is necessary to determine whether a causal relationship exists between the changes in [3H]diazepam binding observed in vivo and the anticonflict actions of buspirone.
Changing concepts of the biochemical action of the anxioselective drug, buspirone
Authors: Taylor Duncan P. , Allen Lloyd E. , Becker Jerry A. , Crane Margaret , Hyslop Deborah K. , Riblet Leslie A. 
Published: January 2005

AbstractClinical trials have demonstrated that buspirone (BusparTM) is effective in the treatment of anxiety with efficacy and dosage comparable to diazepam or clorazepate. Buspirone is chemically distinct from the benzodiazepines as well as other psychoactive drugs. More importantly, buspirone presents a clinical pharmacologic profile which is “anxioselective”; that is, it relieves anxiety without the accompanying ancillary properties of benzodiazepines (sedation, muscle relaxation, seizure control). Biochemical investigations have not conclusively identified any direct interaction of buspirone with the benzodiazepine‐γ‐aminobutyric acid (GABA)‐chloride ionophore complex. It has been known that buspirone possesses some pharmacologic properties that are shared by dopamine antagonists. However, these properties are not characteristic solely of this class of agents. In contrast to dopamine antagonists, buspirone does not produce catalepsy. In fact, buspirone reverses catalepsy induced by dopamine antagonists. Recent investigations have demonstrated that chronic administration of dopamine antagonists increases dopamine receptor binding in experimental animals. Chronic treatment with buspirone does not have this effect. In conjunction with other observations, it has now become obvious that buspirone does not possess the postsynaptic dopamine antagonism characteristic of antipsychotic drugs. However, the mechanism by which buspirone alleviates the clinical manifestations of anxiety continues to be undefined.
Antihypertensive assessment of two new angiotensin‐converting enzyme (ACE) inhibitors: CGS 13945 and CGS 13934
Authors: Miller Donald , Watkins Barry E. , Hopkins Marlene F. , Tonnesen Stanley T. , Van Orsdell Donna 
Published: January 2005

AbstractCGS 13945 (1‐(4‐(ethoxycarbonyl)‐2,4‐dimethyl‐2R,4R‐butyryl)‐2,3‐dihydro‐2S‐indole‐2‐carboxylic acid) and CGS 13934 (its dicarboxylic acid derivative) are nonthiol angiotensin‐converting enzyme (ACE) inhibitors which have antihypertensive properties. Acute administration of CGS 13945 lowers systolic pressure in spontaneously hypertensive rats (SHR) and sodium depletion enhances the blood pressure reduction; the acute antihypertensive effects of CGS 13934 are minimal. Acute administration of CGS 13945 or CGS 13934 also elevates plasma renin activity, especially in sodium‐depleted SHR. CGS 13945 reduces systolic blood pressure of SHR in a dose‐dependent manner following oral administration on each of 4 consecutive days, whereas the antihypertensive effect of CGS 13934 is not apparent until the third day of drug administration. After 3 consecutive daily doses, 30 mg/kg (PO) of CGS 13945, CGS 13934 or captopril produce equal antihypertensive effects. CGS 13945 also reduces systolic blood pressure of sodium‐depleted normotensive rats. Daily oral administration of CGS 13945 to either sodium‐replete or ‐deplete perinephritic hypertensive dogs does not appreciably affect mean arterial pressure. Results suggest that CGS 13945 must be endogenously de‐esterified to the free acid form for endowment of optimal biological activity to inhibit the ACE. While the rat is apparently capable of such hydrolysis, the dog's capacity for endogenous hydrolysis appears to be quite limited.
A social interaction model of anxiety sensitive to acutely administered benzodiazepines
Authors: Gardner C. R. , Guy A. P. 
Published: January 2005

AbstractActive social interaction (SI) and aggression (AGG) were recorded separately during 5‐min observation periods of pairs of male Wistar rats. There was little difference between the levels of SI in undrugged animals across ten different experimental conditions, involving the manipulation of environmental and social stimuli. When animals were housed and tested together, no increases in SI were observed with acute administration of chlordiazepoxide (CDZP, 8 mg/kg PO) irrespective of other environmental changes. When the only potentially anxiogenic stimulus used was a novel partner, a large increase in SI was observed with CDZP. With the exception of strong lighting, combinations of this and other stimuli resulted in smaller increases. When animals were housed and familiarized together but tested with a novel partner, the large increase in SI induced by CDZP was not associated with changes in locomotor activity and was maintained after subacute dosing when decreases in motor activity were absent. Furthermore, similar increases were observed with other benzodiazepines after acute administration in this protocol. This modified method of SI in the rat is more sensitive to the anxiolytic activity of benzodiazepines leading to their detection after acute administration.
1,4‐Dihydropyridine Ca2+channel antagonists and activators: A comparison of binding characteristics with pharmacology
Authors: Janis Ronald A. , Triggle David J. 
Published: January 2005

AbstractThis comparison of the binding characteristics and pharmacology of 1,4‐dihydropyridines indicates that the high‐affinity binding sites studied in cardiac and smooth muscle cells represent a major site of action of these drugs, and that this site is the Ca2+channel or a closely related protein. Electrophysiological studies suggest that the effects of both Ca2+channel inhibitors and activators are voltage dependent. The apparent lack of agreement between the equilibrium dissociation constants for [3H]1,4‐dihydropyridines and their potency in cardiac muscle may be due to conformational modifications that occur in the 1,4‐dihydropyridine binding site as a result of voltage or other changes during membrane isolation. The selective effect of 1,4‐dihydropyridines for vascular smooth muscle relative to cardiac muscle may be explained, in part, by differences in membrane potentials and Ca2+channel regulatory mechanisms and, in part, by differences in receptor structure. 1,4‐Dihydropyridine antagonists and activators appear to bind to a common site that is not the same as the binding site for nondihydropyridine Ca2+channel antagonists.
Evaluation of THIP in standard tests for analgesic activity: Occurrence of antinociception and hyperalgesia
Authors: Hynes Martin D. , David Leander J. , Frederickson Robert C. A. , Peter P. K. Ho , Johnson Douglas W. , Archer Robert A. 
Published: January 2005

AbstractTHIP (4,5,6,7‐tetrahydroisoxazolo[5,4‐c]pyridin‐3‐ol), a structurally rigid analog of the GABA‐agonist muscimol, was investigated for antinociceptive activity in a variety of preclinical tests for analgesic activity. Antinociceptive activity was observed in the mouse writhing, mouse hot plate, rat tail flick, rat inflamed paw, and monkey shock titration tests. In the mouse writhing, mouse hot plate, and rat tail jerk experiments, periods of significant hyperalgesia were noted either prior to or following the occurrence of THIP‐induced antinociception. At those times when an antinociceptive effect of THIP could be demonstrated in the test systems employed in this study, a variety of unfavorable effects were noted including sedation, ataxia, myoclonic jerks, and vomiting. These side‐effects of THIP first appeared near the dose that produced antinociception in 50% of the animals (ED50 value) and became progressively more intense as the dose increased. Neither the narcotic antagonist naloxone, the cholinergic antagonist atropine, nor the GABA‐antagonists bicuculline or picrotoxin blocked the antinociceptive activity of THIP. The synthesis of prostaglandins was not inhibited by THIP. The antinociceptive activity of THIP is an interesting lead in the search for a novel analgesic that lacks the undesirable effects of opiates. However, the occurrence of hyperalgesia and marked side‐effects at doses near the effective analgesic dose may limit THIP's therapeutic potential.
Vasopressin and cognition: An analysis and perspective
Authors: Strupp Barbara J. , Weingartner Herbert 
Published: January 2005

AbstractAnimal research concerning vasopressin's putative role in cognitive processes has been in progress for nearly two decades, yet the extent and nature of this role remain poorly understood. Methodologically, the reliance on extinction rate as an index of memory and the virtually exclusive use of avoidance tasks have limited the conclusions that can be drawn. In addition, from a theoretical perspective, the view of learning and memory as unitary phenomena may have contributed to an incomplete analysis of vasopressin's cognitive effects. The conclusions that may be drawn from the existing animal data are discussed in the context of the problems that arise in determining if any endogenous substance plays a role in cognitive processes. Recent research in both humans and experimental animals has demonstrated the importance of taking a differentiated approach to the study of cognition and has suggested that distinct cognitive processes may be driven by different biological mechanisms. This research approach has underscored the validity and fruitfulness of using animal models in this area and holds promise for unraveling the biological mechanisms involved in human cognitive processes in general and the role of vasopressin in particular.
Cognitive dysfunction in depression: Difference between depressed and nondepressed elderly patients and differential cognitive effects of nomifensine
Authors: Siegfried Klaudius R. , Jansen Winfried , Pahnke Klaus 
Published: January 2005

AbstractThe main aim of the study was to establish the degree of disturbance of the cognitive functions typical of the elderly depressed patients. The analysis was based on the results of a 4‐week, double‐blind, placebo‐controlled therapeutic study in which the effects and tolerance of the antidepressant nomifensine were tested in a randomized group of 100 patients. Half the patients were depressed and half nondepressed (a priori stratification, HAM‐D ≥ 18). Tests of central nervous arousal, attention, perceptual grouping, short‐term and long‐term memory, and complex reaction time were performed. The findings were analyzed as follows: First, baseline differences in cognitive performance, correlative of the stratification into depressed and nondepressed patients, were examined. Second, changes reflecting normalization of cognitive function resulting from the antidepressant treatment were analyzed. For antidepressant treatment, nomifensine, a noradrenaline and dopaminereuptake inhibitor, was used. Results showed that cognitive impairment in primary depression was fairly generalized over different cognitive functions. A global factor of cognitive impairment and a general cognitive improvement factor was found. Both factors are closely connected with the severity as well as the improvement in cardinal symptoms of depression. This relationship was interpreted as due to alterations in central nervous arousal.
Memory and benzodiazepines: Animal and human studies with 1,4‐benzodiazepines and clobzam (1,5‐benzodiazepine)
Authors: Koeppen D. 
Published: January 2005

AbstractThe amnesic effects of the 1,4 benzodiazepines make them useful as adjuncts to anesthesia. However, these effects are undesirable in the treatment of anxiety and epilepsy, especially in outpatients. The mode of action of the 1,4‐benzodiazepines on memory is not yet sufficiently identified. These compounds seem to affect the consolidation of information material; anterograde amnesic effects are common, while retrograde amnesia or impairment of short‐term memory have been reported only exceptionally. The 1,5‐benzodiazepine clobazam has shown minimal effects on memory in contrast to the 1,4‐benzodiazepines at therapeutically equipotent doses. These results tally with the less pronounced sedative action of clobazam compared to the 1,4‐benzodiazepines but do not seem to be connected by a causal relationship. The clinical relevance of these findings has to be clarified and the various factors modifying the effects of benzodiazepines on memory (e.g., benzodiazepine dose, type of memory task, individual encoding and decoding strategies, anxiety and neuroticism score) have yet to be characterized.
Hemodynamic effects of the serotonergic agent quipazine in the anesthetized dog
Authors: Vidrio Horacio , Mena Marco A. 
Published: January 2005

AbstractThe hemodynamic effects of quipazine, a serotonergic agent, were determined in pentobarbital‐anesthetized, open‐chest dogs administering the drug IV, either by bolus injection or by continuous infusion. Bolus injections of 0.1 and 1 mg/kg elicited transient increases in blood pressure, peripheral resistance, aortic flow, and stroke volume. Administration of 10 mg/kg decreased blood pressure, aortic flow, heart rate, cardiac contractility, and venous pressure, and increased stroke volume. Infusion of quipazine at a rate of 0.5 mg/kg/min for 30 min initially increased blood pressure and peripheral resistance and subsequently produced hypotension and decreased cardiac function. From the beginning of infusion, heart rate and venous pressure decreased, while stroke volume increased. Pretreatment with methysergide antagonized the hypotension and bradycardia, as well as the changes in venous pressure and stroke volume. It was concluded that quipazine elicits complex, dose‐related cardiovascular effects, some of which (hypotension, venodilatation, bradycardia) are mediated through methysergide‐sensitive central serotonin receptors. The arterial vasoconstriction produced by low doses of the drug was not mediated through these receptors and was probably the result of activation of a cardiogenic reflex.
Amitraz‐induced delay of gastrointestinal transit in mice: Mediated by α2‐adrenergic receptors
Authors: Hsu Walter H. , Lu Zheng‐Xing 
Published: January 2005

AbstractSubcutaneous injection of amitraz (0.3–3.0 mg/kg) produced a dose‐dependent delay of gastrointestinal transit in conscious mice. This effect of amitraz was antagonized by α2‐adrenergic blocking agents, e.g., yohimbine, piperoxan, and tolazoline. Other adrenergic antagonists without α2‐blocking activity (thymoxamine, prazosin, phenoxybenzamine, and propranolol) did not reduce the depressant effect of amitraz on gastrointestinal transit at the dosages studied. Furthermore, this effect of amitraz was not altered by a dopaminergic antagonist (haloperidol), a serotonergic antagonist (methysergide), a histamine H1‐antagonist (chlorpheniramine), a histamine H2‐antagonist (cimetidine), cholinergic antagonists (atropine and hexamethonium), a GABAergic antagonist (bicuculline), and an opioid antagonist (naloxone). Pretreatment of mice with 6‐hydroxydopamine failed to antagonize the effect of amitraz. These results suggest that amitraz‐induced delay of gastrointestinal transit is mediated by postjunctional α2‐adrenergic receptors and appears not to involve the activation of β‐adrenergic, dopaminergic, serotonergic, histaminergic, cholinergic, GABAergic, or opioid receptors.
Drugs that facilitate cognitive processes: Characterizing the response
Authors: Weingartner H. 
Published: January 2005

AbstractVarious types of drugs that have been proposed as treatments might alter cognitive processes. Programmatic research in this area is built upon knowledge about the psychobiological bases of learning, memory, and related cognitive processes. These efforts generally begin with promising research findings obtained from psychopharmacological studies of cognitive processes in lower animals. These findings are then integrated with what is known about the neuropathology of syndrome‐related types of cognitive failures in humans along with findings relating to the determinants of information processing in both impaired patients and unimpaired subjects. Experiments are then designed to test the cognitive response to some psychoactive drug treatment. Promising leads and preliminary claims and findings are frequently not supported by continued clinically focused research. A major reason is that studies do not adequately consider the differentiated nature of cognitive processes. This paper stresses a single theme—namely, cognitive processes are complex, differentiated, and determined by different psychobiological mechanisms and, therefore, are susceptible to change in relatively specific ways. A theoretical framework for the analysis of cognitive changes is proposed. This framework is used illustratively to profile how different types of cognitive responses may result from different types of drug treatment.
Cerebrovascular effects of a xanthine derivative propentofylline (HWA 285)
Authors: Grome John J. , Rudolphi Karl , Harper A. M. 
Published: January 2005

AbstractThe novel xanthine derivative propentofylline, 1‐(5′‐oxohexyl)‐3‐methyl‐7‐propylxanthine (HWA 285), was tested for its effects on cerebral blood flow and cerebrovascular resistance in the anaesthetised baboon. The intravenous administration of propentofylline (0.5 mg/kg/min) led to a small but significant increase in cerebral blood flow. In a separate group of baboons, propentofylline (0.1 mg/kg/min) was administered into the internal carotid artery to avoid interference by the peripheral actions of the drug. This produced a marked increase in cerebral blood flow combined with a fall in cerebrovascular resistance which oulasted the administration of the drug. Propentofylline did not produce any marked change in electroencephalographic (EEG) activity. Finally, the presence of the blood‐brain barrier did not appear important to these effects since disruption by hyperosmotic urea did not change the response of cerebral blood flow or cerebrovascular resistance to propentofylline administration. These data suggest that propentofylline produces an increase in cerebral blood flow mainly by dilatation of the cerebrovasculature.