bluuebunny/crossref_metadata_2025 huggingface dataset:
Genesis of the retinal pigment epithelium in the macaque monkey
Authors: Rapaport David H. , Rakic Pasko , Yasamura Douglas , LaVail Matthew M.
Published: January 2005

The development of the retinal pigment epithelium (RPE) was studied in rhesus monkey (Macaca mulatta) fetuses, neonates, and juveniles exposed to a pulse of (3H‐TdR) between embryonic day (E) 25 and postnatal day (P) 204 and examined at short and long intervals after the injection of the isotope.

The RPE develops from the outer layer of the optic cup which by E45 consists of a multistratified epithelium. The outer layer appears immature near the retina's edge and gradually becomes monostratified and more mature centrally. Even at this early stage, all cells contain pigmented melanosomes, although peripherally the pigment is limited to the apical portion of the cells. Examination of autoradiograms from animals allowed to survive for several postnatal months shows that monkey RPE cell genesis begins just after E27, increasing to a peak frequency of 0. 38 cells/mm at E43. Between E30 and E85 the density of radiolabelled cells varies within a restricted range of from 0.2 to 0.4 cells/mm (mean = 0.25 ± 0.09). From the density of radiolabelled cells, and data on the overall density of RPE cells in the juvenile retina, we determined the labelling index. During the first half of gestation, between 0. 38% and 0. 99% (mean = 0. 65 ± 0. 22) of RPE cells are generated during the short interval of isotope availability after pulse injection. Approximately 5% of RPE cells were generated by E33, and 50% by E71. After E85, RPE cytogenesis begins gradually to decrease, and 95% of the cells have been generated by the time of birth. Continued, very low density (0. 01 cells/mm) cytogenesis in the RPE is seen at P17, and persists at least until seven months postnatally.

RPE cell genesis begin near the fovea, and proceeds towards the periphery. Cell division largely ceases in both foveal and perifoveal regions by E56, at which time labelled cells first begin to appear peripheral to the equator. Besides the timing differences, RPE genesis in the central retina differs from that in the peripheral retina in that it proceeds at a higher rate, and lasts for a shorter time period. A prolonged postnatal period of low density RPE cell genesis persists in both central and peripheral retina. Comparison of the pattern of expansion of the area containing radiolabelled cells in the RPE and neuroretina demonstrates a remarkable spatial and temporal correspondence. Close analysis suggests that at any point on the retina, the last cells are generated in the neuroretina slightly before the last cells in the RPE. © 1995 Wiley‐Liss, Inc.
Evidence for corticotropin‐releasing hormone projections from Barrington's nucleus to the periaqueductal gray and dorsal motor nucleus of the vagus in the rat
Authors: Valentino Rita J. , Pavcovich Luis A. , Hirata Harumitsu
Published: January 2005

The present study used anterograde and retrograde tract tracing and immunohistochemistry to determine the efferent projections of corticotropin‐releasing hormone (CRH) neurons of Barrington's nucleus in the rat. Injections of Phaseolus vulgaris‐leucoagglutinin into Barrington's nucleus resulted in anterograde labeling in the dorsal motor nucleus of the vagus, periaqueductal gray, medial thalamic nuclei, lateral hypothalamus, paraventricular nucleus of the hypothalamus, lateral preoptic area, and lateral septum. The retrograde tract tracer, fluorogold, injected into the lumbosacral spinal cord labeled many, but not all, CRH‐immunoreactive neurons in Barrington's nucleus. Moreover, some Barrington's neurons that were retrogradely labeled from the spinal cord were not CRH‐immunoreactive. Several CRH‐immunoreactive Barrington's neurons were retrogradely labeled by fluorogold injections into the periaqueductal gray, and these were located predominantly in the dorsal part of the nucleus. Additionally, some CRH‐immunoreactive Barrington's neurons were retrogradely labeled from fluorogold injections into the dorsal motor nucleus of the vagus. In contrast, fluorogold injections into the lateral hypothalamus, lateral preoptic area, or lateral septum did not result in double labeling of CRH‐immunoreactive neurons in Barrington's nucleus. These results suggest that many, but not all, CRH‐containing neurons of Barrington's nucleus project to the lumbosacral spinal cord. In addition to their previously documented projections to the spinal cord, these neurons may be a source of CRH in the periaqueductal gray and dorsal motor nucleus of the vagus. CRH projections of Barrington's nucleus may play a role in behavioral or autonomic aspects of stress responses, in addition to their proposed role in micturition. © 1995 Wiley‐Liss, Inc.
Monosynaptic projections from the medullary gigantocellular reticular formation to sympathetic preganglionic neurons in the thoracic spinal cord
Authors: Aicher Sue A. , Reis Donald J. , Nicolae Raluca , Milner Teresa A.
Published: January 2005

Microinjection of L‐glutamate into a restricted area of the medullary gigantocellular reticular formation, the gigantocellular depressor area (GiDA), lowers arterial pressure. Unlike the nuclei tractus solitarii and the caudal ventrolateral medulla, the two principle medullary vasodepressor areas, the GiDA projects directly to the spinal cord and not to the rostral ventrolateral medulla (Aicher et al. [1994] Neuroscience 60:761–779). We investigated whether neurons within GiDA directly innervate autonomic areas of the thoracic spinal cord. FluroGold injected into the thoracic spinal cord labeled neurons within functionally defined vasodepressor sites in the GiDA in the same animal.

To examine the morphology of GiDA efferents to the spinal cord, the anterograde tracer Phaseolus vulgaris‐leucoagglutinin was iontophoresed into the GiDA, and efferent processes in the intermediolateral cell column and nucleus intercalatus spinalis were examined by electron microscopy. Labeling was confined to axons and axon terminals (n = 144) that usually contained primarily small clear vesicles, contacted large and small dendrites, and formed symmetric (inhibitory) synapses.

To determine whether some of the postsynaptic targets of GiDA efferent terminals in the thoracic spinal cord were sympathoadrenal preganglionic neurons, these neurons were retrogradely labeled from the adrenal gland with Fluoro‐Gold in rats that had deposits of the anterograde tracer, biotinylated dextran amine (BDA), in the GiDA. Some BDA‐containing terminals formed symmetric synapses with dendrites containing Fluoro‐Gold. We conclude that a population of neurons in the GiDA monosynaptically innervates some sympathetic preganglionic neurons. The findings suggest the presence of a novel reticulospinal sympathoinhibitory projection originating in the GiDA. © 1995 Wiley‐Liss, Inc.
The physicochemical approach to drug design and discovery (QSAR)
Authors: Hansch Corwin
Published: January 2005

The study of physicochemical parameters to correlate mathematically chemical structure with biological activity induced by sets of congeneric drugs is now generally referred to as QSAR (quantitative structure‐activity relationships). The ways in which the QSAR paradigm are developing are becoming more varied and complex. Many kinds of parameters are under study in many different groups; various types of mathematical models have been proposed and are being evaluated. Drug researchers are turning more to enzyme modulation to control various biological processes. It is the study of enzyme‐ligand reactions of enzymes whose x‐ray crystallographic structure is known that affords us the means for developing a deeper understanding of QSAR and, at the same time, enhancing our ability to make drugs more selective for various forms of a given enzyme. The union of x‐ray crystallography, moleculargraphics, and QSAR is one of the most exciting new areas of drug development. This report is an introduction to how QSAR is being used to gain insight into the interaction of drugs with macromolecules and macromolecular systems.
450088‐S, a ring‐opened prodrug of a 1,4‐benzodiazepine, inhibited [3H]flunitrazepam labeling of rat cerebral cortex in vivo
Authors: Wong David T. , Bymaster Frank P.
Published: January 2005

We report here that a peptidoaminobenzophenone (450088‐S), a ring‐opened prodrug of a 1,4‐benzodiazepine, effectively inhibited the labeling of receptors for 1,4‐benzodiazepines by [3H]flunitrazepam in vivo despite the lack of receptor affinity for 450088‐S in vitro. Labeling of cerebral cortex after an intravenous injection of [3H]flunitrazepam was inhibited by about 80% after an intraperitoneal injection of 450088‐S or diazepam. 450088‐S was found to be four times more potent than diazepam. The inhibition occurred within 5 and 10 min of administration of diazepam and 450088‐S, respectively. These findings demonstrate the occupancy of 1,4‐benzodiazepine receptors in brain upon administration of the prodrug 450088‐S in rats.
Clonidine in mania
Authors: Giannini A. James , Extein Irl , Gold Mark S. , Pottash A. L. C. , Castellani Sam
Published: January 2005

Hyperactivity 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

The 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

High 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

A 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

Clinical 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

CGS 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

Active 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

This 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

THIP (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

Animal 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

The 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

The 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

The 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

Subcutaneous 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

Various 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

The 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.
Effects of propentofylline on the micromechanical properties of red blood cells
Authors: Seiffge Dirk , Nagata L. Katsuyoshi
Published: January 2005

The hemorheological effects of the xanthine derivative propentofylline (HWA 285) were investigated in vitro and ex vivo. The following micromechanical methods were used: (1) Nuclepore filtration test; (2) Filtrometer MF 4 [Teitel, 1977]; (3) Singlepore Erythrocyte Rigidometer (SER) [Kiesewetter et al., 1982b] (4) Mini‐Aggregometer [Schmid‐Schönbein et al., 1973a]. A protective effect of HWA 285, starting at a dose of 10−5 mol/liter, against red blood cell (RBC) rigidification, induced by lactacidosis (pH 6.9) in the Nuclepore filtration test could be demonstrated. RBC deformability was shown to decrease in adjuvant arthritis (AA) in rats. We tested HWA 285 (1, 5.01, 10.0, 15.8, 31.5, and 50.0 mg/kg p.o. for 21 days) in AA rats for its effect on hemorheology. The drug neither had an effect on inflammation with respect to hematological parameters and plasma proteins nor caused a reduction in the increased RBC aggregation in AA rats. However, we could show with the first three methods that HWA 285 has a significant effect on improvement of RBC deformability.
A review: Diabetic retinopathy—pathophysiologic and therapeutic approaches
Authors: Tso Mark O. M.
Published: January 2005

Of the five million known diabetics in the United States, 5,000 become blind each year because of diabetic retinopathy. While the pathologic changes in the retina are well defined, the pathogenetic and pathophysiologic factors are not clear, and therapeutic approaches are empirical. The disease may be classified clinically and pathologically into four stages:(1) preretinopathy, characterized by disruption of the blood‐retinal barrier; (2) background retinopathy, exhibiting typical microangiopathic changes; (3) diabetic macular edema, resulting in gradual loss of central vision; (4) proliferative retinopathy, ending in retinal detachment and blindness. Many associated pathophysiologic factors have been described, but the critical pathogenetic mechanisms have not been established. The contributing factors include: (1) hyperglycemia and insulin control; (2) disruption of the blood‐retinal barrier; (3) retinal microangiopathy, including changes of pericyte and endothelial cell basement membrane; (4) formation of microaneurysms; (5) systemic diseases, including hypertension, blood alteration, hormonal changes, and genetic abnormalities; (6) ocular disorders such as optic atrophy, alteration in intraocular pressure, and eye surgery; and (7) retinal and vitreal neovascularization. A number of therapeutic approaches are being actively tested. Treatment with panretinal photocoagulation has been helpful to some patients, and the control of contributing systemic factors may delay progression of the disease. Vitrectomy with or without endoscopic panretinal photocoagulation has been useful in some advanced cases. Pituitary ablation has been effective for treatment of severe diabetic retinopathy, but severe complications have forced its abandonment. Aldose reductase inhibitors and other medications are currently being tested.
Inflammation of the external eye
Authors: Smolin Gilbert
Published: January 2005

The pathophysiology and therapeutic approaches currently in use for inflammation of the external eye are discussed in detail. The general principles of inflammation are explained in detail as well as their specific application to the external ocular tissues.
The pharmacology of ketanserin, the first selective serotonin S2‐antagonist
Authors: Awouters Frans
Published: January 2005

The quinazolinedione derivative ketanserin was studied in many known and newly introduced tests to obtain its detailed pharmacological profile. Ketanserin was a potent, orally very effective antagonist of endogenous serotonin (5‐HT): 0.15 mg/kg (ED50 s.c. and p.o.) protected rats from the gastric lesions induced by the mast cell activator compound 48/80. Many other in vivo observations, such as antagonism of tryptamine‐induced cyanosis in rats (ED50 s.c., 0.056 mg/kg), inhibition of mescaline‐induced head twitches in rats (ED50 s.c., 0.097 mg/kg), and inhibition of 5‐HT‐induced effects in various species, revealed the potent antagonist activity of ketanserin on vasoconstrictor and bronchoconstrictor actions of serotonin. When compared to other compounds with 5‐HT‐antagonist activity, the pharmacological profile of ketanserin corresponds to that of a potent, peripherally acting serotonin antagonist with weak associated α‐adrenergic blocking and antihistamine activity. In addition, binding experiments and studies on isolated tissues and platelets disclosed the high selectivity of ketanserin's serotonin antagonism. Serotonin S2‐receptors of the rat frontal cortex were labeled by low concentrations of ketanserin (Ki = 0.39 nM), and affinity of drugs for S2‐receptors highly correlated with their activity against serotonin‐induced contractions of blood vessel preparations (e.g., of the rat caudal artery, A2‐value of ketanserin: 0.83 nM) and serotonin‐induced platelet aggregation. In these experiments, ketanserin was devoid of serotonin! ‐binding, of agonist activity on vascular smooth muscle, of inhibition of 5‐HT uptake into platelets, and of 5‐HT antagonism on gastrointestinal smooth muscle. The absence of all these secondary activities is pharmacologically characteristic for ketanserin when compared to known serotonin‐antagonists. On the basis of this profile of pure and selective serotonin S2‐antagonism, ketanserin was studied in experimental hypertension and in many spontaneous and induced circulatory dysfunctions. A prolonged antihypertensive effect can be obtained with ketanserin in the absence of distinct compensatory mechanisms. Vascular dysfunction can start at low, sensitizing concentrations of serotonin and be almost completely corrected by ketanserin, despite the involvement of other mediators. Ketanserin is a very effective antagonist of the mixture of vasoactive substances released by aggregating platelets. In experimental thrombosis, sustained ketanserin treatment prevents the impairment of blood flow and the associated organ deficiency. When deviations from normal hemorrheology are long‐standing, as in aged spontaneously hypertensive dogs, acute ketanserin administration is distinctly antihypertensive and reduces hemorrheological abnormalities. At the conclusion of these extensive studies, serotonin appears to act at peripheral S2‐receptors as the primary pathological mediator of vascular congestion.
Effect of propentofylline on cerebral metabolism of rats
Authors: Stefanovich V.
Published: January 2005

Propentofylline (HWA 285) [3‐methyl‐1‐(5′‐oxohexyl)‐7‐propylxanthine] is in in vitro experiments a good inhibitor of cAMP and cGMP phosphodiesterases in the rat brain and cerebral microvessels. In in vivo experiments it modulates cAMP and cGMP systems and GABA concentration in four examined structures of rats: cortex, hypothalamus, cerebellum, and striatum. Propentofylline (5 mg/kg i.v.) doesn't influence levels of cerebral energy reserves in normal rats but prevents to a significant degree some of the changes in metabolite levels caused by anoxia (30 s of nitrogen breathing). This antianoxic effect occurs at 5 min and disappears 20 min after administaration of the drug. Caffeine (5 mg/kg i.v.) shows a trend toward further aggravation of anoxia. The modulating effect of propentofylline on cAMP and cGMP systems, GABA levels, and especially cererbral enery metabolism in anoxia is possibly related to the potential therapeutic effect of this drug.
Biochemical evidence for a new benzodiazepine receptor antagonist
Authors: Kenneth Koe B. , Kondratas Elena , Lebel Lorraine A. , Minor Katherine W.
Published: January 2005

1‐(3‐Chlorophenyl)‐3‐diethylcarbamoyl‐1 H‐1,2,4‐triazole (CP‐32,961) inhibited [3H]diazepam binding to rat cortical membrances and [3H]flunitrazepam binding to mouse brain in vivo. Its inhibition of the binding of [3H]Ro 15‐1788 (benzodiazepine receptor antagonist) to these membranes was not facilitated by added GABA; CP‐32,961 exhibited a GABA ratio of 0.84 compared to 2.44 for diazepam. Cerebellar cyclic GMP content in rats was raised by CP‐32,961, which also further elevated the increased cyclic GMP levels induced by isoniazid. These neurochemical actions are similar to those shown by ethyl β‐carboline‐3‐carboxylate (β‐CCE) and suggest that CP‐32,961 is a benzodiazepine receptor antagonist with inverse agonist activity.
Levocabastine (R 50547): The prototype of a chemical series of compounds with specific H1‐antihistaminic activity
Authors: Stokbroekx Raymond A. , Luyckx Marcel G. M. , Willems Johan J. M. , Janssen Marcel , Bracke Johan O. M. M. , Joosen Robert L. P. , van Wauwe Jean P.
Published: January 2005

The synthesis and the histamine H1 antagonism of four racemates of 1‐[cyano‐4‐(4‐ fluorophenyl)cyclohexyl]‐3‐methyl‐4‐phenyl‐4‐piperidinecarboxylic acid, termed R 48756, R 49389, R 49429, and R 49549, are described. R48756 (cabastine) was found to be the most potent compound, with oral ED50 values of 0.002–0.003 mg/kg in both the histamineinduced lethality test (guinea pigs) and the compound 48/80 assay (rats). Upon resolution of cabastine into its two optical isomers, levocabastine (R 50547) after oral administration in guinea pigs was about four times (1 hr) to 90 times (24 hr) more potent than dextrocabastine (R 50554). Protection from dyspnea, induced by histamine aerosols, was obtained with 0.005 mg/kg of levocabastine, whereas a dose of 2.5 mg/kg, failed to protect guinea pigs from dyspnea induced by serotonin or acetylcholine aerosols.
Comparative pharmacological profile of ritanserin and ketanserin
Authors: van Nueten Jan M. , Schuurkes Jan A. J. , De Ridder Walter J. E. , Kuyps Jan J. M. D. , Janssens Walter J.
Published: January 2005

The effect of ritanserin was determined on a variety of isolated smooth muscle tissues. The compound is a potent antagonist of serotonin‐induced contractions of isolated blood vessels (IC50‐, Ah‐ or A2−value between 5.6 × 10−11 and 3.3 × 10−10M) and trachea (IC50 = 1.6 × 10−8M) and of serotonin−induced bronchospasms in anaesthetised guineapigs (ED50 = 0.026 mg/kg i.p.). In most tests ritanserin was more potent than ketanserin (IC50‐ or A2‐value between 5.1 × 10−10 and 2.6 × 10−9M) as a serotonergic antagonist. In these vascular and tracheal preparations, serotonin induced contractions via S2‐serotonergic receptor sites. Ketanserin acted as a competitive antagonist. In contrast, ritanserin was un unsurmountable, apparently non‐competitive S2‐serotonergic antagonist, except at the rabbit femoral artery where the serotonergic antagonism was of the competitive type. Its resistance to wash‐out suggests a long duration of action. Both compounds had little or no effect on serotonergic responses mediated through M‐ or D‐receptors in gastrointestinal tissues. In the femoral artery of the rabbit, ritanserin and ketanserin inhibited H1‐histaminergic responses at concentrations 20 times and 4 times higher, respectively, than those required for S2‐serotonergic antagonism. No other effects of ritanserin were observed unless at much higher concentrations. For instance, in the femoral artery of the rabbit, concentrations approximately 200 times higher (A2‐value = 2.8 × 10−8M) were needed for alpha1‐adrenergic antagonism than were required for S2‐serotonergic antagonism (A2‐ value = 1.3 × 10‐10M), while this ratio was 9 for ketanserin for the same preparation. In the rat tail artery, these ratios, based on IC50‐values, were 666 and 39 for ritanserin and ketanserin respectively.

In conclusion, as an S2‐serotonergic antagonist, ritanserin is more potent and more specific than ketanserin. The mode of interaction with the S2‐serotonergic receptor and the relation between time and antiserotonergic activity are different for the two compounds.
Development and clinical use of the new gastrointestinal prokinetic drug cisapride (R 51 619)
Authors: Reyntjens André , Verlinden Marleen , Aerts Tonny
Published: January 2005

Cisapride is a new gastrointestinal prokinetic substance that is devoid of antidopaminergic and direct muscarinic activity. This was evidenced by a lack of effect on prolactin release and gastric secretion. In man, cisapride stimulates lower esophageal, gastric, small intestinal, and colonic motility. Accordingly, cisapride significantly improves esophageal reflux disorders, gastroparesis, and constipation and has been successfully used in the treatment of clinical conditions that result from a deficient motor coordination.
Nucleoside transport inhibition and the release of purine metabolites from hypoperfused isolated guinea pig hearts
Authors: van Belle Herman , Wynants Jozef , Goossens Frans
Published: January 2005

Hypoperfusion elicited a marked but transient release from isolated guinea pig hearts of inorganic phosphate, nosine, hypoxanthine, xanthine, and uridine, but had no effect on the release of uric acid, uracil, and adenosine. Lack of increased formation of adenosine, as well as a clearcut effect of hypoperfusion on uridine release, suggest that the purine catabolites did not originate from either cyclic AMP or from ATP released with catecholamines during ischemia. They merely point to a particular sensitivity of some cells to ischemia whereby the nucleotides are rapidly degraded and released into the interstitium.

Inclusion at low concentrations (5 × 10−8 M) of a nucleoside transport inhibitor, such as the water soluble analogue of mioflazine, drastically reduced the basal release of most of the metavolites and completely suppressed the effect of hypoperfusion. This effect is specifically ascribed to nucleoside‐transport inhibition since no marked change was observed on the release of inorganic phosphate.
Selectivity of agonists and antagonists at D2dopamine receptors compared to D1 and S2receptors
Authors: Seeman Philip , Grigoriadis Dimitri E. , Niznik Hyman B.
Published: January 2005

The common dopamine agonists (dopamine, apomorphine, ADTN, and N‐propylnorapomorphine) are not selective D1 or D2 dopamine receptors, affecting both simultaneously. SK&F 38393 is selective for D1, while bromocriptine and (D2)D2LYD2171555 are selective for D2. The neuroleptic with the highest D2/S2 selectivity is eticlopride with an affinity 3,200‐fold higher for the D2 dopamine receptor compared to the S2 serotonin receptor. Such selective neuroleptics may be clinically useful and may also help in measuring the elevated D2 density in vivo by positron emission tomography in the brains of schizophrensis.