bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dopaminergic dysregulation in schizophrenia: A target for new drugs
Authors: Davis Kenneth L. , Fiori Michael , Davis Bonnie M. , Mohs Richard C. , Horvath Thomas B. , Davidson Michael 
Published: January 2005

AbstractThe dopamine hypothesis postulates that at least some schizophrenic symptoms are a reflection of central nervous system hyperdopaminergia. The evidence for this model is briefly reviewed and its shortcomings highlighted. The dysregulation hypothesis of schizophrenia should be a useful reformulation. Rather than conceptualizing a static hyperdopaminergic state, schizophrenia might be better understood as a reflection of a relative failure of dopaminergic regulation. Evidence for such dysregulation is examined and possible mechanisms are presented. Avenues of future drug research are proposed.
Pharmacokinetic and ‐dynamic studies in elderlies with a potential antihypoxidotic/nootropic drug tenilsetam utilizing pharmaco‐EEG and psychometry
Authors: Saletu B. , Grünberger J. , Cepko H. 
Published: January 2005

AbstractIn a double‐blind, placebo‐controlled study, the pharmacokinetic, encephalotropic, and psychotropic properties of a new metabolically active thienyl‐piperazine derivative were studied in ten elderly subjects in their sixties by means of quantitative EEG and psychometric analyses. At weekly intervals, they received randomized single oral doses of placebo; 75 mg, 150 mg, and 300 mg tenilsetam (CAS 997); and 3.2 g piracetam as reference drug. Blood sampling EEG recordings, psychometric and psychophysiological tests, as well as the monitoring of blood pressure, heart rate, and side effects were carried out at 0, 2, 4, 6, 8, and 24 hr. Pharmacokinetic investigations showed that CAS 997 was rather well absorbed, as peak concentrations were observed consistently at 2 hr and were clearly dose‐dependent. The terminal half‐life was between 18 and 22 hr, as compared with 6 hr for the reference drug piracetam, which also exhibited plasma peaks at 2 hr. Computer‐assisted spectral analyses of the EEG showed a significant CNS effect of CAS 997 as compared with placebo, characterized by an increase of alpha activity, decrease of delta activity, and fast beta activity, as well as by tendency towards an augmentation of total power and decrease of the centroid and centroid deviation of the total beta activity. Partly similar though less pronounced alterations were exhibited by 3.2 g piracetam. Such changes were described previously by us after several other antihypoxidotics/nootropics and are indicative of improvement in vigilance. Dose/treatment–efficacy calculations demonstrated 75 and 150 mg CAS 997 superior both to placebo and the reference compound but also to the highest given dosis (300 mg CAS 997). Time–efficacy calculations showed two pharrnacodynamic peaks: one in the 4th and another one in the 8th to 24th hour. The time lag between pharmacokinetic and ‐dynamic changes may be due to the penetration of the drug through the blood brain barrier to a deep compartment receptor as well as to the formation of active metabolites. Psychometric investigations showed only small and inconsistent psychotropic effects after single doses of CAS 997 in elderlies. Evaluation of pulse rate, blood pressure, and side effects showed a good tolerability of both drugs.
Benzodiazepine receptor occupation and pharmacological effects of metaclazepam, a new benzodiazepine
Authors: Jochemsen Roeline , Kato Gabor , Ruhland Michael 
Published: January 2005

AbstractThe time course of benzodiazepine receptor occupation in mouse brain in vivo and the time courses of three pharmacological activities (anxiolytic/anticonvulsant, sedative, and muscle relaxant) were determined for metaclazepam and two of its putative minor metabolites, KC 3756 and KC 3757. Similar experiments were performed with diazepam as a reference compound. It was found that the in vivo receptor binding potency and the pharmacological activities of metaclazepam were three to four times less than those of diazepam, although the in vitro affinity of metaclazepam for the benzodiazepine receptor was only 1/100 that of diazepam. The in vivo benzodiazepine receptor binding potency and pharmacological activities of KC 3756 and KC 3757 were high (five to six times that of diazepam) and in good agreement with the in vitro affinity, Ki=0.93 and 1.4 nM, respectively. These findings suggest that the pharmacological activity of metaclazepam is partly regulated by the gradual formation of small quantities of highly active metabolites.
Beta‐1 antagonist and cardiostimulatory effects of celiprolol in anesthetized dogs
Authors: Barrett John A. , Smith Ronald D. , Wolf Peter S. , Pruss Thaddeus P. 
Published: January 2005

AbstractCeliprolol is a new cardioselective beta adrenoceptor antagonist presently undergoing worldwide clinical traits. The present study was undertaken to further evaluate the beta antagonist and hemodynamic effects of celiprolol compared to the known beta antagonists propranolol, atenolol, and dichloroisoproterenol (DCI). The results show that celiprolol up to 1 mg/kg i.v. had no significant effect on contractile force (CF), heart rate(HR) or mean, arterial pressure (AP) in normal anesthetized dogs. In these animals, however, celiprolol produced a dose‐related decreases in the beta‐1 response to isoproterenol (ISO; ED50=0.01 for CF and 0.06 mg/kg, i.v. for HR) while having a lesser effect on the AP (beta‐2) responses to ISO (ED50 =1.8 mg/kg, i.v.). Celiprolol was equipotent to propranolol and atenolol in antagonizing the beta‐1‐mediated effects of ISO while being equipotent to atenolol and 300 times less potent than propranolol in antagonizing the beta‐2‐mediated effects. In mecamylamine‐pretreated dogs, celiprolol (1 and 3 mg/kg, i.v.) produced limited but significant increases in CF (25 ± 7 and 48 ± 10%, respectively) and HR (18 ± 1 and 22 ± 2%, respectively). DCI (0.1 mg/kg, i.v.) produced a more marked increase in CF (79 ± 9%) and HR (33 ± 7%). By contrast, atenolol 3 mg/kg i.v. and propranolol 1 and 3 mg/kg i.v. significantly depressed both CF and HR. None of the treatments had consistent effects on arterial pressure or aortic flow.In mecamylamine‐and propranolol‐pretreated dogs, celiprolol 1 or 3 mg/kg i.v. still produced a significant increase in CF (31 ± 9 and 21 ± 6%, respectively) and HR (15 ± 2 and 17 ± 3%, respectively). By contrast, the cardiostimulatory effects of DCI were completely abolished by propranolol. It is concluded that celiprolol is a potent and cardioselective beta adrenoceptor antagonist with mild cardiostimulatory effects only partially attributable to beta receptor stimulation.
Effects of α2‐agonists upon colonic propulsion
Authors: Pendleton Robert G. , Bendesky Robert J. , Cook Pat G. 
Published: January 2005

AbstractThe α2‐adrenoceptor agonists clonidine and lidamidine were found to be effective in decreasing colonic propulsion in conscious mice after oral administration. Propulsive activity was measured using evacuation of a rectally administered glass bead as the endpoint. The ED50's of clonidine and lidamidine in this assay were 55 μg/kg and 1.4 mg/kg, respectively. The effects of these compounds were selectively blocked by the α2‐antagonists SK&F 72223 and RX 781094 (idazoxan) but not by other standard receptor antagonists. Administration of lidamidine to cats over the same dosage range as was markedly active in mice icreased circular, but not longitudinal, colonic contractile activity, an effect that could be reversed by injection of idazoxan.
Effects of propranolol and tertatolol on cardiac output and regional blood flows in the rat
Authors: Rochette L. , Bralet J. , Rochat C. 
Published: January 2005

AbstractTertatolol (±)‐1‐(tert‐butylamino)‐3(thiochroman‐8‐yloxy)‐2‐propanol, hydrochloride is a noncardioselective beta‐adrenoceptor antagonist that is devoid of partial agonist activity. The effects of this substance on regional blood flows (RBF) in the rat were studied in comparison with those of propranolol. Rats were artificially ventilated with a mixture of 70% nitrous oxide and 30% oxygen. RBFs were assessed using radioactive microspheres of 15 ± 5 μm diameter, injected into the left ventricle. An initial injection of microspheres (57Co) was carried out 5 min before intravenous administration of propranolol (500 μg·kg−1), tertatolol (50 μg·kg−1) or physiological serum. A second microsphere administration (113Tin) was performed 10 min after injection of the test substances. The animals were sacrificed 3 min after the second injection of microspheres. Neither modifications in arterial pH, pO2, pCO2, nor in the arterial blood pressure were observed with either propranolol or tertatolol. In contrast, a decrease in heart rate was observed (−22% with propranolol and −14% with tertatolol). The reduction in cardiac output was 33% with propranolol and 29% with tertatolol. Propranolol reduced blood flow to the majority of structures and organs examined; such a reduction was 39% in the cerebral hemispheres, 31% in the brainstems and of greater than 20% in all the renal zones studied. With tertatolol, no significant modifications of RBF were observed in any of the cortical or medullary renal zones investigated, nor in any of the cerebral areas studied; only in several colonic areas and in the skin of the abdomen and back, were reductions in RBF observed. These results demonstrate a difference in the effects of these two substances on renal and cerebral haemodynamics.
Onset and duration of action of benzodiazepines as determined by inhibition of (3H)‐flunitrazepam binding
Authors: Sethy Vimala H. , Francis Jonathan W. , Elfring Grey 
Published: January 2005

AbstractThe present study examine ex vivo percent inhibition of (3H)‐flunitrazepam ((3H)‐FNZ) binding to brain tissue homogenates obtained from rats or mice at various time intervals after intravenous administration of benzodiazepines. The peak effect of benzodiazepines was observed within 1–10 min, and their intensity and duration of action could be increased by raising the dose administered. The benzodiazepines were found to differ with respect to onset of peak effect, duration of maximum effect, total length of action, and brain half‐life. The ex vivo determination of (3H)‐FNZ binding is thought measure benzodiazepine‐like activity produced by the parent compound and its active metabolites.
Protease‐antiprotease imbalance in the pathogensis of emphysema and chronic bronchial injury: A potential target for drug development
Authors: Snider Gordon L. 
Published: January 2005

AbstractThe hypothesis that emphysema might be caused by an imbalance between proteases and antiproteases in the lungs arose shortly after the discovery of the premature and familial occurrence of emphysema in persons with homozygous alpha‐1‐protease inhibitor deficiency. Experimental evidence for support of this hypothesis has come from experimental induction of emphysema in animals by proteases. The ability of proteases to induce emphysema is proportional to their elastolytic potency. The importance of elastin degradation as a cause of the development of emphysema has also come from experiments of genetic models in which elastin crosslinking is prevented. The neutrophilis believed to be the most likely source of elastase in the induction of the emphysema of smokers. Alpha‐1‐protease inhibitor is the most important antiprotease. Alpha‐1‐antiprotease is susceptible to oxidative inactivation by cigarette smoke or by endogenous oxidants. Oxidants from cigarette smoke may also interfere with proper elastin repair. Serine proteases have also been shown to produce secretory cell metaplasia in the central intrapulmonary bronchi of hamsters. The discovery of secretory leukoprotease inhibitor in sputum and its production by bronchial secretory cells raises the possibility that secretory cell metaplasia in humans may also be caused by an imbalance between proteases and antiproteases. Although evidence for the validity of the proteaselantiprotease hypothesis of the phogenesis of emphysema and chronic bronchitis in human smokers is still indirect, the development of supplemental antiprotease therapy seems rational for the prevention of progression of these diseases in persons who are unable to stop smoking.
Effects of toluene inhalation on fixed‐ratio liquid‐reinforced behavior in rats
Authors: Ghosh Tushar K. , Pradhan S. N. 
Published: January 2005

AbstractThe effect of toluene inhalation was studied on an operant behavior maintained by a fixed‐ratio (FR‐24) schedule of liquid reinforcement in rats. A dynamic (flow‐through) inhalational behavioral chamber was used to expose rats to toluene vapor. Rats were exposed successively to three graded concentrations (105, 214, 382 ppm) of toluene vapor each for 2 hr in range‐finding experiments during 6 1/4‐hr sessions. The reinforcement rate was not altered at hours 1 and 2 but was decreased at hours 3 and 5 of exposure. However, at hours 4 and 6 the reinforcement rate showed recovery from depression. In 2‐hr exposure experiments with four different concentrations of toluene on separate days, the reinforcement rate was decreased at hour 1 during exposure to 142, 211, and 496 ppm, but exposure to 121 ppm had no effect. There was also no effect when rats were exposed to 115 ppm of toluene during a 5‐hr session. The experiment with 2‐hr daily exposures to 212 ppm of toluene for 5 consecutive days indicated the development of tolerance to the decreased reinforcement rate during 4th and 5th days of exposure. This study thus shows a minimum effective concentration of 142 ppm of toluene, which would produce no effect on FR liquid‐reinforced behavior, and indicates that tolerance develops to the behavioral effect of toluene.
Direct effects of platelet activating factor (PAF) on cardiac function in isolated guinea pig heart
Authors: Tanniére Marianne , Rochette Luc 
Published: January 2005

AbstractThe direct effects of platelet activating factor (PAF) (2.5 nM) on isolated guinea pig heart were studied: first, on Langendorff model perfused hearts, using the radiolabelled microspheres technique, we found that PAF reduced the myocardial flow homogenously. Secondly, using isolated “working” heart preparations, the direct effects of PAF on the coronary and aortic flows, heart rate, and systolic ejection volume were evaluated. PAF markedly reduced coronary and aortic flows. Systolic ejection volume (SEV) was significantly decreased and the reduction, which was maximal at 3 min, persisted at 20 min. Some of the direct cardiac effects of PAF were antagonized by addition of GBE to the medium (10 mg/l). These data demonstrate the direct effects of PAF on cardiac function. The possible of PAF in the mediation of the episodes of coronary spasm may be suggested.
Endothelium‐derived relaxing and contracting factors: New concepts and new findings
Authors: Greenberg Stan , Diecke F. P. J. 
Published: January 2005

AbstractThe vascular endothelium is a source of both relaxing and contracting factors. These yet to be identified substances have been termed endothelium‐derived relaxing factor(s) (EDRF) and endothelium‐derived contracting factor(s) (EDCF). The family of EDRF(s) appear to be important mediators of vascular relaxation and platelet disaggregation. Destruction of the endothelium or modulation of its structure, as occurs with coronary artery disease and atherosclerosis, results in impaired coronary and systemic arterial relaxation, vasospasm, and enhanced platelet aggregability. Acute and chronic hypertension blunts EDRF‐induced vascular relaxation. Thus, EDRF appears to represent an endogenous modulator system of vascular smooth muscle‐endothelium‐platelet interaction in humans. Recent evidence supports the possibility that one EDRF may be nitric oxide, whereas a second EDRF may stimulate sodium‐potassium ATP'ase. EDCF may be a family of at least three substances. One substance appears to be a low molecular weight polypeptide, is produced by hypoxia, and promotes a long‐acting vasoconstriction associated with increased calcium influx into vascular smooth muscle. The second EDRF is of unknown origin, is diffusable, released by anoxia and hypoxia, and may facilitate the action of the leukotrienes and lipoxygenase products on vascular smooth muscle. The remaining EDCF may be derived from the actions of lipoxygenases on arachidonic acid and appears to be released by vasoconstrictor agonists, stretch and potassium ion. Further research is required to elucidate the functional role and nature of EDCF(s) on vascular smooth muscle.
CI‐911: A placebo‐controlled study in patients with primary degenerative dementia
Authors: Dysken Maurice W. , Anton‐Johnson Susan , Klein Linda , Kuskowski Michael , Schut Lawrence J. , Miles Steven H. , Maletta Gabe J. , De Jong Richard 
Published: January 2005

AbstractTwenty patients with primary degenerative dementia participated in a 6‐week, doseranging, double‐blind, placebo‐controlled study of Cl‐911, a cognition activator that enhances performance in animal models of impaired cognition. Cl‐911 was well tolerated in these patients, but it did not result in significant improvement on objective measures of cognition, social functioning, or self‐care.
Central nervous system effects of the imidazodiazepine Ro 15‐4513
Authors: Harris Cynthia May , Lal Harbans 
Published: January 2005

AbstractLigands for benzodiazepine receptors produce one of three types of effects: (1) diazepamlike; (2) opposite to diazepam; or (3) no direct effects, but blockade of the effects of the other ligands. Data refiewed in this paper demonstrate that the imidazodiazepine Ro 15‐4513 produces direct neuronal and behavioral effects of the type opposite to those of diazepam. These include electrophysiological and behavioural seizures, anxiety‐like behaviors, inhibition of aggression, and facilitation of learning and memory. In addition to its direct effects, Ro 15‐4513 also blocks the effects of benzodiazepines, barbiturates, and ethanol. This antagonism has been reported for a broad range of experimental approaches including biochemical, physiological, and behavioral measures. Because direct effects of Ro 15‐4513 are, in many cases, opposite to the effects of these sedative drugs, these direct effects may account for at least part of the ability of Ro 15‐4513 to antagonize sedative drugs. However, for some measures, such as exploratory activity and operant response rate, even under conditions in which the effect of Ro 15‐4513 is the same as that of the sedative drugs, Ro 15‐4513 still antagonizes the effects of the sedative drugs. Blockade of the effects of Ro 15‐4513 by both agonists and antagonists at the benzodiazepine receptor strongly supports the hypothesis that all of the effects of Ro 15‐4513 occur due to its action at the benzodiazepine receptor. Blockade of ethanol by very low concentrations of Ro 15‐4513 substantiates the role of the benzodiazepine receptor‐chloride ionophore complex in mediating neurobiological effects of ethanol and has stimulated efforts to develop alcohol antagonists with greater specificity and selectivity.
Time‐dependent sensitization as the cornerstone for a new approach to pharmacotherapy: Drugs as foreign/stressful stimuli
Authors: Antelman Seymour M. 
Published: January 2005

AbstractThis report begins by reviewing data showing that the effects of acute exposure to stressful situations can grow with the passage of time (time‐dependent sensitization; TDS) and then proceeds to suggest that the clinical syndromes of panic, delayed post‐traumatic stress disorder, and bulemia represent instances of stressor‐induced sensitization to subsequent stressors. Finally, it discusses data demonstrating that a host of pharmacological agents—including antidepressants, antipsychotics, and anxiolytics—also show TDS after a single or brief period of treatment and proposes that induction of this phenomenon is due to the foreign/stressful properties of drugs. The report concludes with the suggestion that the very widespread ability of drugs to trigger effects that then grow with the passage of time—independent of repeated treatment—can form the basis of a new and revolutionary approach to pharmacotherapy.
Electrophysiological and antiarrhythmic effects of the K‐channel opener, BRL 34915, in cardiac purkinje fibers
Authors: Liu Bo , Golyan Faraidoon , McCullough John R. , Vassalle Mario 
Published: January 2005

AbstractThe effects of BRL 34915 (6cyano‐3,4‐dihydro‐2,2‐dimethyl‐trans‐4‐[2‐oxo‐1‐pyrrolidyl]‐2H‐benzo[b]pyran‐3‐ol, to be referred to as BRL) on the electromechanical properties of superfused dog and sheep ventricular Purkinje fibers were studied in vitro. At 5 μM, BRL shortened the action potential and decreased contractile force; these effects were greater in dog than in sheep Purkinje fibers. BRL reduced the slope and amplitude of diastolic depolarization measured during interruptions of drive. BRL suppressed spontaneous activity and antagonized the enhancement of automatic discharge induced by norepinephrine (0.5 μM), barium (50 μM), or strophanthidin (0.5 μM). BRL reduced or abolished the oscillatory potentials induced by high [Ca2+]o (10.8 mM). It also antagonized the spontaneous responses in low [K+]o (1 mM) and hyperpolarized fibers depolarized in a K‐free solution. It is concluded that BRL modifies the action potential and force and has antiarrhythmic actions as it antagonizes abnormal pacemaker activity in Purkinje fibers by modifying potassium conductance and secondarily reducing intracellular calcium.
Pharmacokinetics and pharmacodynamics of acetylcholinesterase inhibition: Can acetylcholine levels in the brain be improved in alzheimer's disease?
Authors: Becker Robert E. , Giacobini Ezio 
Published: January 2005

AbstractUp to 20% or more of individuals who will be 80 years of age will develop senile dementia of the Alzheimer type (SDAT). In SDAT patients cholinergic neurons in the basal forebrain undergo profound damage, which is reflected in decreased acetylcholine synthesis, choline acetyltransferase activity, acetylcholinesterase activity, and choline uptake in cortical terminals. Physostigmine has been widely used to increase brain acetylcholine concentration by inhibiting acetylcholinesterase. The pharmacokinetics of physostigmine and its effects on acetylcholine concentration are not well studied. Our studies of physostigmine pharmacokinetics in dogs, rats, and humans suggest that a “slow‐release formulation” may be necessary to achieve increases in acetylcholine concentrations that will have therapeutic effects in SDAT. To investigate one potential “slow release formulation” of physostigmine we have studied direct injection into the lateral ventricles of the brain.
Neurotoxicity of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine: A model for parkinson's disease and its therapy
Authors: DeFeudis F. V. 
Published: January 2005

AbstractIn humans, ingestion of the meperidine‐analogue 1 ‐methyl‐4‐phenyl‐1,2,3,6‐tetrahy‐ dropyridine (MPTP) is known to cause parkinsonian symptoms and degeneration of the substantia nigra, effects that resemble the behavioral and pathological changes that characterize idiopathic Parkinson's disease (PD). Studies of the effects that this substance produces in animal models are reviewed and analyzed herein. Although the neurodegeneration induced by MPTP is less widespread than that which occurs in PD, primate models based on systemic administration of this substance should be useful in assessing the efficacies of antiparkinsonism drugs and might also provide information about the etiology of PD. Some limitations of the MPTP model might be overcome by using aged primates. In further defining the central mechanism of action of MPTP, it seems essential to determine which cell populations (e.g., nondopaminergic neurones, glia, vascular endothelial cells) contain the monoamine oxidase‐B that catalyzes its conversion to the neurotoxic metabolite 1 ‐methy‐4‐phenylpyridiniumion. Continued study along these lines could lead to the development of effective methods for controlling PD.