bluuebunny/crossref_metadata_2025_split huggingface dataset:
Some neurochemical properties of a new antidepressant, bupropion hydrochloride (Wellbutrin™)
Authors: Ferris R. M. , White H. L. , Cooper B. R. , Maxwell R. A. , Tang F. L. M. , Beaman O. J. , Russell A. 
Published: January 2005

AbstractBupropion is a novel antidepressant agent. In the present study, an attempt was made to gain some insight into the mechanism of the drug's antidepressant activity. In vitro studies revealed that bupropion was a weak, competitive inhibitor of norepinephrine (NE) uptake into rat hypothalamic synaptosomes and of dopamine (DM) uptake into rat striatal synaptosomes, having IC50 values of 6.5 ± 0.6 × 10−6 M and 3.4 ± 0.4 × 10−6 M, respectively. At 1 × 10−5 M, the drug produced a 20 ± 3% inhibition of serotonin (5‐HT) uptake into rat hypothalamic synaptosomes. The drug was also a weak inhibitor of the ATP‐Mg+2 stimulated uptake of NE and DM into synaptic vesicles of whole rat brain, having IC50 values of 3.3 × 10−5 M and 6.0 × 10−5 M, respectively. Bupropion had no dose‐dependent effect on the spontaneous release of NE, DM, and 5‐HT from these synaptosomal preparations in concentrations as high as 1 × 10−4 M. Brain monoamine oxidase (MAO) activity in vitro was not affected by concentrations of the drug ranging from 10−7 M to 10−5 M. Bupropion was also without effect on brain MAO, 1 hr after i.p. doses in rats as high as 100 mg/kg. The ED50 value for bupropion necessary to inhibit the uptake of 3H‐catecholamines by 50% into synaptosomes incubated in the serum from rats treated with the drug was 40 mg/kg i.p., while its ED50 value for antidepressant activity, as judged by the ability of bupropion to reverse the immobile posture of “helpless” rats, was 8 mg/kg i.p. These neurochemical properties of bupropion on uptake of biogenic amines and on MAO activity serve to distinguish it from other antidepressant drugs of the tricyclic and MAO inhibitor classes.
Inhibition of Na,K‐ATPase activity and ouabain binding by sanguinarine
Authors: Pitts Barry J. R. , Meyerson Laurence R. 
Published: January 2005

AbstractSanguinarine, an isoquinoline alkaloid belonging to the benzophenanthridine class, has been found to be a time‐dependent inhibitor of cardiac Na,K‐ATPase activity. Enzyme inhibition depended on the concentration of enzyme in the assay. Dilution and centrifugation of the enzyme following incubation with sangunarine did not decrease inhibiton. Inhibiton of ouabain binding by sanguinarine was also time‐dependent and resulted in a reduction of the equilibrium level of ouabian bound to the enzyme preparation. This suggests the possibility that the positive inotropic effect of sanguinarine on the heart may be due to interaction with the cardiac glycoside receptor site on Na,K‐ATPase. Alternatively, sanguinarine may bind nonspecifically to phospholipids associated with the enzyme and exert its effects via conformational changes.
Alfentanil (R 39 209) — a particularly short‐acting intravenous narcotic analgesic in rats
Authors: Niemegeers C. J. E. , Janssen P. A. J. 
Published: January 2005

AbstractAlfentanil, N‐{1‐[2‐(4‐ethyl‐4,5‐dihydro‐5‐oxo‐1H‐tetrazol‐l‐yl)ethyl]‐4‐(methoxymethyl)‐4‐piperidinyl}‐N‐phenyl propanamide monohydrochloride monohydrate, is a chemically novel, potent, extremely short‐acting and safe intravenous morphine‐like agent in laboratory animals. As an analgesic in rats, alfentanil is 137 times as potent as pethidine (tail withdrawal reaction test: i.v. ED50 is 6.04 mg/kg for pethidine and 0.044 mg/kg for alfentanil). The safety margin in rats is 1,080 (LD50: 47.5 mg/kg i.v.). Alfentanil reaches its peak effect within 2 min after injection, and its duration of action is very short: at two times its lowest ED50 the drug has a duration of action of 10 min. This duration is 30–35 min for pethidine and fentanyl, and 120 min for morphine. The narcotic antagonist naloxone produces an immediate and complete reversal of all morphine‐like effects of alfentanil. In dogs, alfentanil is a potent antiemetic (ED50: 0.032 mg/kg i.v.) with a safety margin of over 850 (LD50: > 20 mg/kg i.v.).
The effects of colchicine derivatives on humoral antibody response in mice
Authors: Trottier R. W. , Fitzgerald T. J. 
Published: January 2005

AbstractThe effects of colchicine and two of its chemical derivatives (propyl and bromo substitutions on the acetamido group) were investigated on the sheep red blood cell (SRBC) humoral antibody response in mice. These drugs were shown to suppress SRBC antibody titres. Immunosuppression was dependent upon temporal relationships of antigen/drug administration, as well as on the dosage profile of the drugs. In these studies bromocolchicine was the most active agent tested. Possible pharmacologic mechanisms are discussed.
Effects of analgesics, endorphins, and other drugs in a 3H‐serotonin binding assay
Authors: Gay David D. , VonVoigtlander Philip F. 
Published: January 2005

AbstractAnalgesics of various classes, endorphins, and other psychotropic drugs were evaluated for activity in inhibiting 3H‐serotonin binding to a soluble serotonin binding protein (SBP) isolated from rat brain. Morphine, leu‐endorphin, and the narcotic antagonist, nalorphine, effectively inhibited binding, while other analgesics, including codeine, methadone, pentazocine, beta‐endorphin, and enkephalins were inactive. Amitriptyline partially inhibited binding, while stimulants did not. Inhibition of serotonin binding to SBP does not appear to be characteristic of narcotic analgescis or any one therapeutic class of compounds.
Antihistaminic effect of terfenadine: A new piperidine‐type antihistamine
Authors: Cheng Hsien C. , Woodward James K. 
Published: January 2005

AbstractThe antihistaminic effect of terfenadine was studied in the isolated guinea pig ileum, histamine skin wheals in guinea pigs and monkeys, and i.v. histamine‐induced death in guinea pigs. In the guinea pig ileum, terfenadine, 1 × 10−7 M, shifted the histamine dose‐response curve to the right in a parallel fashion without affecting the dose‐response curve of acetylcholine and barium chloride. However, as the dose of terfenadine was increased (3.16 × 10−7 and 1 × 10−6 M) the histamine dose‐response curves were displaced to the right with a depression of the maximum response and a reduction of the slope. Thus an unsurmountable type of antagonism was observed. Acetylcholine was also antagonized in a similar fashion by these two concentrations. In contrast, terfenadine appeared to displace the barium chloride dose‐response curve to the right in a parallel fashion. At 0.4 and 0.8 mg/kg p.o., terfenadine shifted the histamine skin wheal dose‐response curves to the right in a parallel fashion, but at 1.6 to 6.4 mg/kg, terfenadine antagonized the histamine wheal dose‐response curves with a depression of the maximum and the slope of the curve. These results were also similar to those of cyproheptadine but were different from those of chlorpheniramine, which produced parallel shifts. In monkeys, terfenadine produced a substantially greater effect on the histamine wheal than did chlorpheniramine (both administered at 30 mg/kg p.o.). Terfenadine also completely protected against i.v. histamine‐induced death in guinea pigs. Terfenadine produced no atropine‐like effect against pilocarpine‐induced salivation in rabbits, no demonstrable histamine H2 antagonism, no antiserotonin activity, no α or β antagonism, and no untoward cardiovascular effects. Most significantly, terfenadine had no overt central nervous system (CNS) effects in mice, rats, guinea pigs, or monkeys; whereas chlorpheniramine produced tremors and convulsions in mice and monkeys when tested at much lower doses than those used for terfenadine. It is concluded that terfenadine is an effective and specific antihistaminic compound with the potential advantage of a lack of CNS sedative effects.
The trypanocidal activity of various aromatic bisguanylhydrazones in vivo
Authors: Ulrich Peter C. , Grady Robert W. , Cerami Anthony 
Published: January 2005

AbstractSeven aromatic bisguanylhydrazones and two related compounds were screened against Trypanosoma brucei (EATRO 110M) in mice. The four most active were then screened against T. congolense (TREU 1183) in mice and rats. Eradication of parasitemia through 28 (T. brucei) or 42 days (T. congolense) resulting from a single dose of drug administered IP either 4 or 24 hours (respectively) after infection was used as the criterion of activity. 1,3‐Diacetylbenzene bisguanylhydrazone dihydrochloride cleared T. congolense from 50% of the animals (ED50) at a dose of approximately 10 mg/kg and from mice infected with T. brucei at approximately 15 mg/kg. This drug was also active when given 5 days after infection with T. congolense (ED50 ≅ 15 mg/kg). The isomorphous pyridine derivative, 2,6‐diacetylpyridine bisguanylhydrazone dihydrochloride, was active against T. brucei in mice (ED50 ≅ 8 mg/kg), but noncurative against T. congolense. At therapeutic doses of these two compounds, reversal and clearance of parasitemia was often not observed for 2–4 days, suggesting a delayed mode of action. Moreover, 1–2 days after drug treatment, the infectivity of parasites obtained from treated animals was significantly reduced, if not abolished. These findings indicate that more intensive screening of aromatic bisguanylhydrazones against various species of trypanosomes is warranted.
A cholinergic link in the centrally mediated actions of angiotensin II
Authors: Moore Alan F. , Drexler Anne P. 
Published: January 2005

AbstractThis study was designed to determine the role of brain cholinergic mechanisms in the centrally mediated blood pressure and drinking responses to angiotensin II (ANG II). Atropine (10 mg/kg, IV), but not methyl atropine (8 mg/kg, IV), significantly inhibited drinking and BP responses to ANG II intracerebroventricularly (ICV). BP responses to IV ANG II were not inhibited. Both atropine (20 mg/kg, IP) and methyl atropine (20 mg/kg, IP) inhibited cellular‐dehydration thirst induced by injection of hypertonic saline. Hemicholinium (80 μg/kg, ICV) had similar effects to atropine on BP and drinking responses to ICV ANG II. Phentolamine (0.5 mg/kg, IV) had a small but significant inhibitory effect on the drinking but not the BP response to ANG II ICV. It is concluded that brain cholinergic mechanisms contribute both to the drinking and pressor response to ICV ANG II, and to the drinking response to cellular‐dehydration thirst. There may also be a peripheral cholinergic component to cellular dehydration but not ICV ANG II‐induced thirst.
Role of beta‐adrenergic receptors in the mechanism of action of second‐generation antidepressants
Authors: Sethy Vimala H. , Harris Douglas W. 
Published: January 2005

AbstractThe effect of chronic intravenous infusion of desmethylimipramine (DMI), amitriptyline, mianserin, bupropion, alprazolam, or diazepam on the density of beta‐adrenergic receptors in the rat cerebral cortex has been investigated in this study. DMI and amitriptyline significantly decreased the density of beta‐adrenergic receptors. Mainserin, bupropion, alprazolam, and diazepam had no significant effect on the density of beta‐adrenergic receptors. Results of this study indicate that mechanisms other than beta‐adrenergic receptors may be involved in the antidepressant activity of these drugs.
Air‐induced writhing: A rapid broad spectrum assay for analgesics
Authors: VonVoigtlander Philip F. , Lewis Richard A. 
Published: January 2005

AbstractThe injection of air into the peritoneal cavity of rats produces reliable and quantifiable behavioral responses. These responses are blocked by compounds known to have analgesic properties, including opioid agonists, opioid agonist‐antagonists, cyclo‐oxygenase inhibitors, and amine potentiators. However, psychotropic agents were generally inactive at reasonable doses. The ability of this assay to identify a wide spectrum of analgesic agents in rats was superior to the hot plate, warm plate, and tail immersion assays.
Effects of the novel antipsychotics, RMI 81582 and clopipazan, on predictors of extrapyramidal liability in squirrel monkeys
Authors: Neale Robert , Gerhardt Susan , Liebman Jeffrey M. 
Published: January 2005

AbstractThe neuroleptic‐induced acute dyskinetic syndrome in primates has been proposed as a predictor for extrapyramidal side effects of potential antipsychotics. Another potential predictor in monkeys is the degree to which benztropine reverses antipsychotic‐induced inhibition of Sidman avoidance performance. Assessment of these models has been hampered by the scarcity of clinically effective antipsychotics that lack extrapyramidal side effects. Recently, however, RMI 81582 and clopipazan have been reported to exert antipsychotic activity in initial clinical trials without causing extrapyramidal side effects. Using squirrel monkeys, these drugs were tested in both procedures. RMI 81582 did not cause dyskinesias at any dose tested, and its blockade of avoidance could not be antagonized by benztropine. These results are consistent with the previously proposed clozapine‐like profile of RMI 81582. However, clopipazan, like haloperidol, induced dyskinesias and its effects on avoidance were reversed by benztropine. Possible clinical implications are discussed. These results support the predictive value of these two primate models for antipsychotic‐induced extrapyramidal dysfunction.
Preliminary report: Comparison of the potencies of clonidine, B‐HT 920, and B‐HT 933 in reversing reserpine‐induced ptosis in the mouse
Authors: Deniard Marie‐Jeanne , Meignen Joelle , DeFeudis Francis V. 
Published: January 2005

AbstractThe potencies of the α‐adrenoceptor agonists clonidine, B‐HT 920 (2‐amino‐6‐allyl‐5,6,7,8‐tetrahydro‐4H‐thiazolo‐[5,4‐d]‐azepin), and B‐HT 933 (2‐amino‐6‐ethyl‐4,5,7,8,‐tetrahydro‐6H‐oxazolo‐[5,4‐d]‐azepin; Azepexole) in reversing reserpine‐induced ptosis in male NMRI mice were determined. Reserpine (2.5 mg/kg, i.p.) was administered 4 hr before intraperitoneal injection of the α‐adrenoceptor agonists. All three α‐adrenoceptor agonists produced dose‐dependent reversal of ptosis, this effect being maximal at about 15–30 min after injection. At 30 min postinjection, on a mg/kg basis, clonidine‐HCl was about 23 times more potent than B‐HT 920‐2 HCl and about 375 times more potent than B‐HT 933 2‐HCl in reversing ptosis. Although reversal of reserpine‐induced ptosis in the mouse is not selective for α2‐adrenoceptor agonists, these results indicate that this test can be used to compare the relative potencies of three substances with pronouced α2‐adrenoceptor agonist activity.
Effects of N6‐cyclohexyladenosine (CHA) on responses to adrenergic and cholinergic nerve stimulation in the peripheral autonomic nervous system
Authors: Kitzen Jan M. , Schwenkler Mary A. , Moeller Janice E. , Hellyer Luther D. , Wilson Sandy J. 
Published: January 2005

AbstractThe adenosine derivative N6‐cyclohexyladenosine (CHA), was studied in various cardiovascular and autonomic experiments. In hemodynamic studies in dogs, CHA 0.5 mg/kg, i.v., caused moderate hypotension and bradycardia. Additional studies in dogs showed that a portion of the bradycardia was the result of an inhibitory effect on the sympathetic nerves to the heart since the chronotropic reponses to cardioaccelerator nerve stimulation were inhibited while the responses to isoproterenol were slightly potentiated. CHA was more potent than adenosine in this experiment and caffeine, 3 mg/kg, i.v., antagonized the effects of CHA. CHA was also found to inhibit the pressor effects of lumbar sympathetic nerve stimulation in rats while responses to intraarterial norepinephrine(NE) were potentiated. In the isolated stimulated guinea pig ileum, both CHA and adenosine inhibited the stimulation‐evoked twitches, with CHA being the more potent. Caffeine, 0.1 mM, antagonized the inhibitory effects of both compounds. CHA had no significant effect on the negative chronotropic responses to vagus nerve stimulation in dogs. These findings indicate that CHA is qualitatively similar to adenosine but is more potent and longer lasting. CHA, like adenosine, appears to alter reponses to both adrenergic and cholinergic nerve stimulation.
Comparison of the effects of slow Ca2+ channel blockers and other agents on passive cutaneous anaphylaxis in the rat
Authors: Hertz F. , Ranson M. , DeFeudis F. V. 
Published: January 2005

AbstractThe actions of five slow Ca2+ channel blocking agents (nifedipine, verapamil, diltiazem, mesudipine, and D 600) were compared with those of several substances that are used clinically in treating asthma (e.g., theophylline, isoproterenol, disodium cromoglycate, and clemastine) and several other agents that are used in cardiovascular therapy (e.g., disopyramide, clonidine, cibenzoline), using the passive cutaneous anaphylaxis (PCA) reaction in the rat. High doses of all slow Ca2+ channel blockers produced a partial inhibition of the PCA reaction. Isoproterenol, theophylline, prazosin, cyproheptadine, ketotifen, phentolamine, and disodium cromoglycate produced dose related inhibition of PCA reaction, their maximum effects being greater than those of the slow Ca2+ channel blockers. As nifedipine, verapamil, and diltiazem were about as potent as the H1 antagonist clemastine in inhibiting the PCA reaction, it seems possible that certain slow Ca2+ channel blockers might be of value in treating asthma or other allergic disorders in man.
U‐48,753E: A potent, structurally novel antidepressant‐like agent
Authors: Vonvoigtlander Philip F. , Triezenberg Herman J. , Losey Elizabeth G. , Gay David D. 
Published: January 2005

AbstractU‐48, 753E (trans‐3,4‐dichloro‐N‐(2‐(dimethylamino)‐cyclopentyl)‐propionanilide maleate) was compared to imipramine in a number of tests of antidepressant‐like activity and mechanisms of action. Although not structurally related to imipramine or other nontricyclic antidepressants, U‐48,753E was considerably more potent than imipramine in tests of norepinephrine potentiation, tetrabenazine antagonism, and behavioral despair. U‐48,753E displayed only moderate anticholinergic and no monoamine oxidase inhibitory activities. In vivo measurements of biogenic amine uptake indicated that U‐48,753E blocks norepinephrine, epinephrine, and serotonin uptake and that it is much more potent than imipramine, particularly regarding epinephrine uptake. U‐48,753E is most markedly distinguished by its potency in a test of alpha2‐adrenergic desensitization. Extremely low repeated doses and single doses of U‐48,753E were effective at antagonizing the hypothermia induced by the alpha2 agonist, clonidine. In contrast, imipramine required much higher, repeated doses to display similar activity. The alpha2 desensitization by U‐48,753E is also manifest by a reduced biochemical sensitivity to clonidine; clonidine‐induced slowing of norepinephrine synthesis is antagonized by U‐48,753E pretreatment. Thus, U‐48,753E shares many antidepressant‐like properties with imipramine, but generally has greater potency and a much greater predilection for blocking epinephrine uptake and altering alpha2‐adrenergic sensitivity.
Inosine and N6‐substituted adenosine analogs lack anxiolytic activity in the pentylenetetrazol discrimination model of anxiety
Authors: Spencer David G. , Gherezghiher Tseggai , Lal Harbans 
Published: January 2005

AbstractAlthough some in vitro studies have raised the possibility that endogenous purines mediate the therapeutic effects of the benzodiazepines, no behavioral studies have been performed to confirm or reject this hypothesis. Consequently, inosine and the adenosine A1 receptor agonists N6‐ (L‐phenylisopropyl) adenosine (L‐PIA) and 2‐chloroadenosine (2CA) were evaluated for diazepam‐like anxiolytic activity in the pentylenetrazol‐saline discrimination model of anxiety. Rats were trained to press one of two levers for food reward after pentylenetetrazol (PTZ) injection (20 mg/kg) and to press the other after saline injection. During testing in these rats, diazepam (10 mg/kg) blocked the PTZ‐induced selection of the PTZ‐appropriate lever (i.e., rats selected the saline‐correct lever). Inosine, L‐PIA, and 2CA neither blocked selection of the PTZ‐appropriate lever after PTZ administration nor did they reverse the diazepam blockade. It is suggested that adenosine or inosine may not act endogenously to mediate the anxiolytic effects of benzodiazepines.
Meeting the challenge of cardiovascular new drug discovery
Authors: Smith Ronald D. 
Published: January 2005

AbstractThe general challenge of new drug discovery is to translate a new idea in science or medicine into a useful therapeutic agent. The specific challenge of cardiovascular new drug discovery (CVNDD) is to translate a new idea in science or medicine into an agent for the treatment of cardiovascular disease such as hypertension, congestive heart failure, or ischemic heart disease. CVNDD has a fundamental and increasingly important role in providing a maturing world population with medicaments designed to assist the human organism adjust to aging and to changes in its environment. The economic impact of CVNDD is critical to the world pharmaceutical industry. The economic impact of CVNDD is insignificant, however, compared to the potential world health impact of successful CVNDD that generates effective new cardiovascular drugs.There can be no doubt that present cardiovascular drugs have enhanced the quality of life of millions of people worldwide and have contributed to a reduction in the morbidity and mortality of cardiovascular disease. Although the gains have been modest in some areas such as sudden cardiac death, they have been dramatic in other areas, such as stroke. The length and quality of life have been enhanced by the rational discovery, development, and therapeutic use of cardiovascular drugs. The future holds the promise of even more impressive gains through new generations of drugs—more efficacious, safer drugs [Fisher, 1980; Pletscher, 1980; Kaplan and Smith, 1981; Smith, 1983].
Cognitive analysis of neuropharmacological treatments
Authors: Weingartner Herbert , Strupp Barbara J. 
Published: January 2005

AbstractSeveral types of drug strategies have been investigated because they may be potentially valuable in the treatment of cognitive dysfunctions. Research efforts in this area have primarily considered how such drugs alter specific systems in the central nervous system and how these may relate to changes in behavior of laboratory animals. For the effective development of cognitively focused drug treatments, it is necessary that we appreciate the ways that drugs might alter different and specific cognitive systems. A number of methods of approach can be used to effectively define and contrast the psychobiological determinants of the cognitive response of drug treatments. These approaches are built upon findings that have shown that 1) cognitive failures in various syndromes are determined by different mechanisms 2) components of information processing are psychologically and biologically distinct; and 3) different types of nonspecific changes produced by a drug can differentially affect components of cognition.
High‐affinity (3H)‐dexoxadrol binding to rat brain membranes
Authors: Sethy Vimala H. , McCall John M. 
Published: January 2005

AbstractSpecific binding of (3H)‐dexoxadrol to rat brain membrane was saturable. The specific binding represented 74 to 82% of total binding. Scatchard analysis of the data demonstrated the existence of high‐ and low‐affinity binding sites. The kinetic constants for the corresponding binding sites were as follows: Kd1 = 1.68 nM, Bmax1 = 0.4 pmol/mg protein, Kd2 = 26.1 nM, and Bmax2 = 3.7 pmol/mg protein. Binding reached equilibrium within 5 minutes of incubation at 25°C. Optimum binding was observed between the pH range of 7.4 to 9. Binding was dependent on protein concentration and was reduced by denaturation of protein and by proteolytic enzyme. (3H)‐dexoxadrol binding was inhibited by drugs pharmacologically similar to phencyclidine (PCP) and bound (3H)‐dexoxadrol could be rapidly displaced by cold PCP.