bluuebunny/crossref_metadata_2025 huggingface dataset:
The 5‐HT syndrome in rats as tool for the screening of psychoactive drugs
Authors: Ortmann R.
Published: January 2005

The use of the behavioral 5‐HT syndrome in rats to characterize psychoactive drugs interacting with the central serotonin system is described. The potentiation of L‐5‐HTP‐induced excitation can be used to detect drugs inhibiting central monoamine oxidase (MAO) A or the 5‐HT uptake system and to define their mechanism of action. In addition to their potency, the biological half‐life of these types of drugs can also be measured. The mechanism of action by which β‐adrenoceptor agonists like salbutamol or clenbuterol potentiate behavioral effects of L‐5‐HTP is discussed. The 5‐HT syndrome is also a convenient behavioral test system to screen for central 5‐HT antagonists and 5‐HT agonists. Different procedures to characterize the 5‐HT specificity of behavioral effects induced by putative 5‐HT agonists are described and their relevance discussed.
Effects of imipramine, bupropion, chlorpromazine, and clozapine on differential‐reinforcement‐of‐low‐rate (DRL) > 72‐Sec and > 36‐sec schedules in rat
Authors: Howard James L. , Pollard Gerald T.
Published: January 2005

The hypothesis that a DRL schedule requiring a long pause (> 72 sec) specifically identifies antidepressant drugs was evaluated in rats pressing a lever for food reinforcement. The tricyclic antidepressant imipramine decreased responses and increased reinforcements as previously shown. However, the antipsychotics chlorpromazine and clozapine had a similar effect, as did prefeeding, and the atypical antidepressant bupropion increased responses and decreased reinforcements. Because mean baseline reinforcement rate was lower than in previous studies showing drug class specificity, the DRL requirement was reduced to > 36 sec and the drugs were tested again; effects were qualitatively similar to those in DRL > 72 in the first part of the study. The results suggest that a drug‐induced reduction in responses could account for the increase in reinforcements, that if drug class specificity exists it may occur only when baseline response and reinforcement rates are confined to a narrow range, that the failure of previous studies to show antidepressant type effects with nonantidepressants could have resulted from choice of drugs and doses, and that the type of reinforcer could be an important factor.
Geriatric psychopathology: An overview of the ailments and current therapies
Authors: Crook Thomas
Published: January 2005

An overview is presented of the major psychopathologic disorders in the elderly population. Alzheimer's disease and related disorders are considered, and a review is presented of the drugs currently marketed to treat these disorders and the compounds currently under investigation. Similarly, the symptoms and pharmacologic treatment of depression, anxiety, and sleep disorders in the elderly are discussed. In general, geriatric psychopharmacology is seen as a challenging and rapidly developing field of scientific inquiry.
Effects of some typical and atypical antidepressants on schedule‐controlled responding in rats
Authors: Rastogi S. K. , McMillan D. E.
Published: January 2005

The effects of tricylic antidepressant drugs with diverse chemical structures were studied in rats on responding maintained under a multiple fixed‐ratio (30) fixed‐interval (5 min) schedule of food resentation. Bupropion, mianserin, and nomifensine increased responding during the first half of the fixed‐interval component and during the fixed‐ratio component of the multiple schedule. Higher doses decreased rates under both the fixed‐ratio component and during the second half of the fixed‐interval component. Trazodone and trimipramine also increased rates of responding during the first half of the fixed‐interval component. Higher doses of these drugs decreased rates under the fixed‐ratio component more than the approximately equal rates during the second half of the fixed‐interval component. Iprindole, protryptyline, fluvoxamine, fluoxetine, maprotiline, clomipramine, imipramine, lithium, and chlorpromazine did not increase rates of responding under the fixed‐ratio component or under either half of the fixed‐interval component. Among these drugs, only imipramine differentially affected the nearly equal rates of responding during the second half of the fixed‐interval component and during the fixed‐ratio component. The effects of antidepressants depended on both the control rate of responding and the schedule. Rate‐increasing effects tended to be associated with antidepressants that interact with dopaminergic systems, but in general, the correlation between behavioral and biochemical effects was low.
Anticonvulsant phosphorus analogs of GABA
Authors: Cates Lindley A.
Published: January 2005

The dimethyl (I), diethyl (II), and di‐isopropyl (III) esters of 3‐amino‐phenylphosphonic acid and diethyl 2‐acetamidophenylphosphate (IV) were tested for inhibition of seizures induced by maximal electroshock (MES) and subcutaneous pentylenetetrazol (Metrazol) (scMet) and for neurotoxicity. Compound I was further tested for inhibition of seizures induced by subcutaneous bicuculline (scBic) and picrotoxin (scPic). Protective indices (P.I.) were compared with those reported for valproic acid (VPA) against MES and scMet and, in the case of I, with VPA, ethosuximide, trimethadione, and phenobarbital (scBic and scPic). The P.I. values of I are comparable to those of trimethadione, equal to VPA against scMet, but higher by factors of 2.6, 1.8, and 1.3 against MES, scPic and scBic, respectively.
Evidence that 5β‐progestins produce uterine relaxation by diminishing cellular calcium permeability
Authors: Kubli‐Garfias Carlos , Ortega‐Suárez Pilar , Hoyo‐Vadillo Carlos , Ponce‐Monter Héctor
Published: January 2005

This report presents the relaxant effect of progesterone and some of its 5β‐derivatives on the tonic contractions induced in isolated rat uterus by high K+ (40 mM) and high K+Na+‐free depolarizing solutions. Experiments were recorded with a polygraphic system. Contractions were countered by the action of progesterone (101 μM), pregnanedione (41 μM), pregnanolone (25 μM), and epipregnanolone (47 μM). The relaxant effect of progestins was, however, significantly more effective against the contraction produced by high K+ alone than that produce by high K+Na+‐free solutions. These different results suggest the ability of 5β‐reduced progesterone metabolites to block the sensitive‐to‐voltage Ca2+ channels (which are activated by K+) and also agree with the existence of a Na+/Ca2+ interchanger in the myometrial membrane. It can be concluded that 5β‐progestins induce relaxation of the uterus probably by blocking the calcium entrance into the cell.
Atherosclerosis: An overview
Authors: Comai K. , Feldman D. L. , Goldstein A. L. , Hamilton J. G.
Published: January 2005

Atherosclerosis is a generalized disease of the arterial system that develops slowly and is symptomless until lesions have become sufficiently large and complicated to cause ischemia. The personal and economic costs of atherosclerosis are enormous. There is a consensus among experts and data from recent long‐term studies to indicate that reduction in the primary risk factors (elevated plasma cholesterol, elevated blood pressure, and smoking) leads to effective management of asymptomatic individuals at risk. Research has also led to an understanding of cholesterol metabolism and clearance pathways from some tissues. However, the factors regulating cholesterol influx and efflux from the arterial wall are currently poorly understood. The role of the monocyte/macrophage in the genesis of the atherosclerotic lesion is receiving renewed attention. The secretory products of the macrophage contain proteases and growth factors capable of causing tissue destruction and cell proliferation, two important components of advanced lesions. Recent advances in cell culture technique have allowed the in vitro growth and/or passage of all the cell types implicated in the development of the lesion. The efficacy of antiatherosclerotic agents must ultimately be proven in man. However, a battery of animal models has been developed over a period of 30 years, which when used appropriately might predict the utility of a drug in man.
Modulation of hepatic and extrahepatic LDL receptors: Involvement in the progression of atherosclerosis
Authors: Newton Roger S.
Published: January 2005

Extensive investigation over the past 2 decades has led to a far better understanding of the role of lipoproteins in the etiology and progression of atherosclerosis. Paramount to this understanding has been the elucidation of how cells recognize these macromolecular complexes and metabolize the lipids and proteins they transport. Because of their elevation in plasma of many individuals with premature coronary heart disease, low‐density lipoproteins (LDL) have received particular attention. As primary transporters of cholesterol to cells in mammalian tissues, LDL particles are removed from blood via specific cell surface receptors that facilitate their uptake. Once internalized and exposed to lysosomal enzymes, LDL particles are degraded, “freeing” their cholesterol to regulate cellular cholesterol synthesis and modulate the number of LDL receptors on the cell membrane. This high‐affinity, high‐capacity process has been termed the LDL receptor pathway and is functional in most tissues of the body, especially in liver where over 50%percnt; of the total body LDL degradation occurs. Liver is the target organ of bile acid sequestrants (cholestyramine/colestipol) and HMG‐CoA reductase inhibitors (compactin/mevinolin), both of which induce increased expression of LDL receptors by affecting hepatic cholesterol availability. Unlike liver, the arterial wall under normal conditions is not very active at degrading LDL via the classical LDL receptor pathway. However, when hypercholesterolemia occurs, especially when there is an LDL‐receptor deficiency, the arterial wall removes 20‐‐fold more LDL than normal and with a greater fractional catabolic rate. Thus other endocytotic pathways exist by which LDL can enter cells of the arterial wall. These pathways are not as actuely regulated as the classical LDL receptor pathway, and, as a result, the arterial wall cells, particularly smooth muscle cells and resident macrophages, accumulate cholesteryl esters. In this brief review, the importance of these receptors to the etiology and progression of atherosclerosis is discussed in detail and sites of possible pharmacological intervention are identified.
CGS 10078B: A novel antihypertensive agent with multiple mechanisms
Authors: Cavaliere Thomas A. , Huebner Charles F. , Watkins Barry E. , Weiss George B.
Published: January 2005

CGS 10078B is a potent orally effective antihypertensive agent with β‐adrenergic antagonist as well as other vasodilatory mechanisms. In spontaneously hypertensive rats, CGS 10078B (3 and 30 mg/kg, p.o.) caused rapid and significant dose‐related reductions in blood pressure that were sustained at 24 hr and accompanied by moderate reductions in heart rate. In conscious hypertensive dogs, CGS 10078B (3 mg/kg, p.o.) produced decreases in blood pressure that were of greater magnitude than those obtained with propranolol and better maintained than those obtained with nifedipine at comparable dosage. Radioligand binding assays indicated that CGS 10078B antagonizes α1‐, β1‐, and β2‐adrenoceptors and inhibits nitrendipine binding at sites associated with Ca++ channels. These biochemical results correlate well with in vitro cardiovascular studies, demonstrating that CGS 10078B possesses antagonist activity at β1‐receptors (guinea pig left atria), β2‐receptors (guinea pig trachea), β1‐receptors (rabbit aorta), and voltage‐sensitive Ca++ channels (responses to K+ or Ca++ in rabbit aorta), and on Ca++ uptake and retention (45Ca in rabbit aorta). In vivo studies with dogs treated with CGS 10078B (30 mg/kg, p.o.) also identified nonselective β‐antagonism and no interference with orthostatic reflexes. In summary, the multiple modes of action of CGS 10078B may afford a distinct clinical advantage in the treatment of hypertension.
Phencyclidine‐ type catalepsy in the pigeon: An update on chen's work
Authors: Leander J. David , Ray Wood C. , Zimmerman Dennis M. , Dykstra Linda A.
Published: January 2005

Chen [1965] described a specific form of catalepsy produced by phencyclidine and related arylcyclohexylamine analogues in pigeons. The present study expanded those observations to a variety of compounds identified as having phencyclidine‐like subjective effects in man or in drug discrimination experiments in laboratory animals. Besides phencyclidine and ketamine, etoxacrol, dexoxadrol, dextrorphan, cyclazocine, and a series of benz(f)isoquinolines produced phencyclidine‐like catalepsy, thus correlating with drug discrimination data from pigeons using phencyclidine‐like drugs. A variety of opioid agonists and mixed agonists/antagonists, along with nefopam, amantadine, baclofen, and THIP, did not produce phencyclidine‐like catalepsy. Opioid antagonists, haloperidol, and α‐methylparatyrosine did not antagonize the phencyclidine‐like catalepsy. These results emphasize the specificity of phencyclidine‐like catalepsy as a test for determining the presence or absence of phencyclidine‐like activity in compounds during drug development.
Lidamidine's effects on the lower gastrointestinal tract: A review
Authors: DiJoseph John F. , Mir G. Nabi
Published: January 2005

Lidamidine is a new, nonnarcotic, nonanticholinergic drug intended for the treatment of diarrhea. In preclinical test models, it compares favorably in both potency and duration of action with marketed antidiarrheal drugs. Lidamidine's intestinal antisecretory effects are mediated through the activation of peripheral alpha‐2 adrenoceptors. Lidamidine crosses the blood brain barrier poorly and is therefore devoid of the centrally mediated alpha‐2 effects that have limited the use of other alpha‐2 adrenoceptor agonists in the intestinal tract. Lidamidine relaxes circular and longitudinal smooth muscle in the intestinal tract and may be useful for treatment of certain intestinal motility disorders. In clinical trials, lidamidine has proven to be effective for the management of diarrheal diseases.
The effect of piroxicam on locomotor activity in rats with adjuvant‐induced arthritis
Authors: Seymour Patricia A. , Larson David L. , Browne Ronald G.
Published: January 2005

To evaluate the effectiveness of piroxicam, a clinically effective, long‐acting, nonsteroidal antiinflammatory drug, in a potential animal model of chronic nociception, the locomotor activity of arthritic rats was monitored over long periods of time by computer. Rats injected with complete Freund's adjuvant (CFA) displayed locomotor deficits as measured by both horizontal and vertical activity. In experiment 1, to test the effectiveness of piroxicam therapy in severely arthritic animals, administration of piroxicam (1‐‐10 mg/kg/day) was initiated 14 days after CFA injection and activity was recorded for 5 days. It was found that a single treatment significantly increased the mobility of the arthritic animals and the 4 additional days of treatment induced continued improvement in mobility and reduction in paw swelling. In experiment 2, to assess the effect of piroxicam on the development of the immobility associated with CFA‐induced arthritis, piroxicam administration (0.3‐‐3.3 mg/kg/day) was initiated prior to CFA injection and locomotor activity was monitored for 16 days. It was demonstrated that the activity of CFA‐injected rats severely and progressively decreased and that piroxicam significantly increased the activity of the arthritic rats, while having no effect on the activity of the nonarthritic control animals. These studies demonstrate the efficacy of piroxicam in arthritic rats and, although further investigation is necessary, demonstrate that the measurement of locomotor activity in arthritic rodents may be an important tool for the identification and evaluation of antiinflammatory/analgetic agents.
Species and vascular bed responses of veins and arteries to endothelial‐derived relaxing factor in dog and pig
Authors: Greenberg Stan , Diecke Friederich P. J. , Tanaka Toshio P.
Published: January 2005

The vascular endothelium is a source of a mediator of vascular smooth muscle (VSM) relaxation known as endothelial‐derived relaxing factor (EDRF). Endothelial‐dependent relaxation is dependent on the type of vessel under study (artery vs. vein) and on the vascular site from which the blood of vessels are derived. EDRF is released by bradykinin, adenosine, and adenosine triphosphate, substance P, serotonin, arachidonic acid, thrombin, and other relaxant substances. EDRF appears to be a labile substance with a six‐second half‐life that contains a labile ketone or carbonyl moiety in its active site. EDRF appears to be selectively inhibited by ouabain, pyruvate, and metabolic inhibitors and inactivated by potassium and sodium borohydride. EDRF appears to act by stimulating an increase in cyclic GMP in the smooth muscle cells of porcine tissues and possibly by other mechanisms in canine tissues. Canine veins possess receptors for porcine aortic EDRF but may not make EDRF itself or may have a different endothelial‐derived substance than canine arteries. Little is known concerning the factors that release or affect the action of EDRF, its mechanism of action or its chemical composition, especially in the pulmonary vasculature. The differences between release of EDRF from artery and vein and the responses to, and composition of, EDRF in vein and artery remain an area for further research.
Radioimmunoassay procedures for astemizole and metabolites in plasma
Authors: Woestenborghs Robert , Geuens Ivo , Michiels Marcel , Hendriks Rik , Heykants Jozef
Published: January 2005

A sensitive radioimmunoassay is described for the determination of astemizole in human plasma. Immunization of rabbits with an astemizole hapten, conjugated with bovine serum albumin, resulted in the production of antiserum, capable of detecting less than 0.05 ng/ml of astemizole. Because of the cross‐reactivity of the antibodies with structurally related metabolites, plasma samples had to be submitted to two distinct extraction procedures prior to radioimmunoassay. The most selective procedure enabled the measurement of unchanged astemizole as confirmed by high‐performance liquid chromatography. The other extraction procedure allowed the determination of the fraction astemizole plus hydroxylated metabolites, which consisted mainly of astemizole and its major metabolite desmethylastemizole.
Drug‐receptor dissociation time, new tool for drug research: Receptor binding affinity and drug‐receptor dissociation profiles of serotonin‐S2, Dopamine‐D2, histamine‐H1 antagonists, and opiates
Authors: Leysen Josée E. , Gommeren Walter
Published: January 2005

A new filter technique for in vitro measurement of the drug‐receptor dissocation time of unlabeled compounds was applied. The receptor binding affinity and drug‐receptor dissociation profiles were obtained for new and reference compounds belonging to the classes of serotonin‐S2, dopamine‐D2, and histamine‐H1 antagonists and of opiates. In vitro binding to the serotonin‐S2, dopamine‐D2, histamine‐H1, adrenergic‐α1 and ‐α2, cholinergic muscarinic and μ‐opiate receptors was studied. The binding affinity profiles provide indications about the specificity of the drugs; in each pharmacological class more selective drugs were found, whereas others cross‐reacted with various receptor sites. The drug‐receptor dissociation profiles revealed substantial differences amongst drugs in drug‐receptor dissociation times. For a particular receptor, drugs showed differences in dissociation time from half‐times of less than 1 min (e.g., alfentanil from opiate receptors) to several hours (e.g., lofentanil). In addition, drugs were found that dissociated very slowly from one receptor site and very rapidly from another receptor site (e.g., ritanserin: slow from serotonin‐S2, rapid from dopamine‐D2; spiperone: slow from dopamine‐D2, rapid from serotonin‐S2; astemizole: slow from histamine‐H1, rapid from serotonin‐S2 and adrenergic‐α1). Nevertheless, apparent binding affinities of these drugs for the receptor sites respectively were often found to be similar. Information on the drug‐receptor dissociation time allows re‐evaluation of apparent binding affinity data and gives better insight into the specificity of action of drugs. It can be applied at various levels of drug research: e.g., for interpretation of receptor binding data, drug effects on receptor regulation, functional effects of drugs, antagonizability of drug effects, and factors contributing to the in vivo duration of action of drugs. Finally, the information on drug‐receptor dissociation time may be an important factor for drug design and receptor modeling.
Conformational analysis of ketanserin
Authors: Tollenaere Jan P. , Moereels Henri , van Loon Marleen
Published: January 2005

An overview of the molecular modelling package Aid In Interactive Drug Analysis (AIDA) is presented. The current conformational analysis capability of AIDA is illustrated with an indepth study of the three‐dimensional characteristics of the selective S2‐receptor antagonist ketanserin. Both X‐ray crystallographic and NMR data are discussed in the light of the calculated conformational space involving three torsional angles. A procedure using AIDA to handle and inspect tens of thousands of conformations is described. On the basis of the conformational analysis the receptor‐preferred conformation of ketanserin is proposed.
Novel approaches to the pharmacotherapy of schizophrenia
Authors: Meltzer Herbert Y.
Published: January 2005

Numerous attempts to extend the pharmacotherapy of schizophrenia beyond conventional neuroleptics are reviewed. Clozapine and melperone are atypical neuroleptics that produce few extrapyramidal side effects during acute usage and possible less tradive dyskinesia with prolonged use. Decreasing dopamingeric activity with a tyrosine hydroxylase inhibitor or dopamine autoreceptor agonists may also be of value. Neuroleptics that block voltage‐sensitive calcium channels or calcium channel blockers per se have been advocated for treatment of negative symptoms or the deficit state. Among other possible clinical approaches reviewed are: beta adrenergic blockers, clonidine, tryptophan, 5‐hydroxytryptophan, fenfluramine, GABA drugs, including high dose benzodiazepines, lithium, carbamazepine, opioid agonists and antagonists, gamma‐endorphins, TRH analogs and vasopressin. Most studies indicate these agents produce inconsistent or slight‐to‐modest benefits, either in comparison with standard neuroleptic drugs or inaddition to neuroleptics, in groups of schizophrenic patients, including some double blind placebo‐controlled trials. Those individuals who do respond sometimes, but not always, fail to relapse when the experimental drug is discontinued or fail to respond to it in subsequent trials. Consistent with the presumed heterogeneity of schizophrenia, there is some evidence supporing non‐neuroleptic drug treatment for specific schizophrenic subtypes. The various stages of this usually life‐long disorder, together with the possible mutability of the underlying etiological factors over time, requires the utmost care in clinical trials.
Tardive dyskinesias and drugs
Authors: Kane John M. , Woerner Margaret , Lieberman Jeffrey A. , Kinon Bruce J.
Published: January 2005

Although considerable controversy remains as to the etiology and pathophysiology of tardive dyskinesia, epidemiologic evidence is compelling in supporting the role of neuroleptics as a major factor in the development of this syndrome. Current evidence suggests that tardive dyskinesia is a heterogeneous condition in terms of nature of onset, phenomenology, course, and response to specific treatments or pharmacologic probes. The point prevalence of tardive dyskinesia varies widely depending on the nature of the patient population and the criterion utilized to identify a “case.” The incidence of tardive dyskine‐sia among relatively young patients of varying diagnoses exposed to neuroleptics appears to be approximately 3–4% per year of cumulative neuroleptic exposure, at least for the first 6 years of such treatment. Age, vulnerability to acute extrapyramidal side effects, and a diagnosis of affective illness appear to be associated with increased risk of tardive dyskinesia development. There is clearly a need to take this aspect into consideration for new drug developments.
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

The 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

In 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

The 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

Celiprolol 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

The 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

Tertatolol (±)‐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

The 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

The 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

The 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

The 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

The 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

Twenty 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

Ligands 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

This 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

The 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

Up 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

In 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.