bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anticonvulsant activity of (+)‐5‐methyl‐10, 11‐dihydro‐5H‐dibenzo[a, d]cyclohepten‐5, 10‐imine (MK‐801), a substance with potent anticonvulsant, central sympathomimetic, and apparent anxiolytic properties
Authors: Clineschmidt Bradley V. , Martin Gregory E. , Bunting Patricia R. 
Published: January 2005

AbstractMK‐801 prevented tonic extensor seizures in the rat induced by bicuclline with the ED50 being 23 μg/kg p.o. Clonazepam, phenobarbital, diazepam, phenytoin, γ‐acetylenic GABA, sodium valproate, and trimethadione were all less potent. In mice, MK‐801 was likewise the most potent (ED50 = 0.35 mg/kg p.o.) compound in protecting against tonic seizures induced by electroshock. Clonazepam (ED50 = 0.41 mg/kg p.o.) and MK‐801 (ED50 = 0.67 mg/kg p.o.) were by far more potent than any of the other anticonvulsants tested versus bicuculline‐elicited seizures in mice. Besides being a potent anticonvulsant, MK‐801 demonstrated selectivity, since much higher doses were required in mice to block clonic convulsions produced by pentylenetetrazol (ED50 = 11 mg/kg p.o.) and tonic seizures caused by strychnine (ED50 > 15 mg/kg p.o.) than were needed against electroshock or bicuculline.The anticonvulsant (electroshock) effect of MK‐801 in mice was unaffected by pretreating the animals with various receptor antagonists (atropine, mecamylamine, chlorpheniramine, tripelennamine, cyproheptadine, cinanserin, methysergide, cimetidine, and propranolol). MK‐801 was slightly, but significantly, antagonized by methergoline, naloxone, and theophylline, whereas haloperidol and especially α‐adrenoceptor blockers (prazosin, HEAT, phenoxybenzamine) markedly reduced the anticonvulsant effect of MK‐801. Haloperidol was selective for MK‐801, not affecting the anticonvulsant actions of phenytoin or phenobarbital. Prazosin antagonized phenytoin and phenobarbital, but to a much lesser extent than it antagonized MK‐801.MK‐801 is an extremely potent and selective anticonvulsant acting at least partly via a catecholaminergic mechanism.
Restoration of shock‐suppressed behavior by treatment with (+)‐5‐methyl‐10,11‐dihydro‐5H‐dibenzo[a, d]cyclohepten‐5, 10‐imine (MK‐801), a substance with potent anticonvulsant, central sympathomimetic, and apparent anxiolytic properties
Authors: Clineschmidt Bradley V. , Williams Michael , Witoslawski John J. , Bunting Patricia R. , Risley Edwin A. , Totaro James A. 
Published: January 2005

AbstractMK‐801 was evaluated in rats for “antipunishment” and “anticonflict” activity in two procedures: (1) A conditioned emotional response (CER) test involving the suppression of lever‐pressing by unaviodable shock and (2) a simple conflict test in water‐deprived animals that were shocked for licking water. The effect of MK‐801 in both procedures was qualitatively similar to the benzodiazepines. Lever‐pressing in the CER test was increased by MK‐801 at doses ranging from 50–400 μg/kg administered orally (p.o.) at either 0.5 or 2 hours prior to testing. The number of shocks received in the “thirsty rat” conflict procedure was increased by MK‐801 at doses from 110–1,000 μg/kg p.o., providing the compound was given 2 or more hours before test. MK‐801 was without anticonflict activity when administered 1 hour prior to study.In squirrel monkeys trained in a response‐contingent conflict paradigm, a specific anticonflict effect for MK‐801 (50–400 μ/kg p.o.) was not demonstrable. As assessed by observing the overt behavior of squirrel monkeys, MK‐801 at doses greater than 100 μg/kg p.o. caused apparent “taming” or “tranquilization.” Chlordizepoxide and diazepam given, respectively, at doses above 1 and 2 mg/kg p.o. had a similar “taming” action. The benzodiazepines possessed a greater separation between doses producing “taming” and those causing ataxia than did MK‐801.The mode of action for the antipunishment effect of MK‐801 in rats is not known, but it was found that naloxone (2 or 5 mg/kg SC) antagonized the anticonflict actions of both MK‐801 and chlordiazepoxide. In vitro, MK‐801 was inactive (IC50 > 2 μM) with respect to competing for binding to rat brain tissue by various radioligands (diazepam, muscimol, apomorphine, spiroperidol, serotonin, LSD, WB‐4101, dihydroalprenolol, QNB, and 2‐chloroadenosine). An increase in 3H‐diazepam binding in vitro in rat brain tissue was detected following acute, but not chronic, treatment in vivo with MK‐801.
Viloxazine and amitriptyline in endogenous depression
Authors: Petrie William M. , Wilson William H. , Jamieson Robert C. , Ban Thomas A. 
Published: January 2005

AbstractIn a double‐blind clinical trial carried out on 20 outpatients with the diagnosis of endogenous depression, amitriptyline (75–225 mg) was found to be somewhat faster in its therapeutic effects on depression than viloxazine (150–450 mg), whereas viloxazine was somewhat faster in its therapeutic effect on anxiety. Cardiovascular adverse effects were only encountered with amitriptyline, whereas gastrointestinal side effects were present with viloxazine.
The role of brain acetylcholine in cardiovascular regulation and hypertension: A minireview and therapeutic implications
Authors: Brezenoff Henry E. , Coram Willie Mae 
Published: January 2005

AbstractAcetylcholine in the central nervous system exerts a significant influence on cardiovascular parameters and appears to be involved in some aspects of hypertension. Stimulation of central muscarinic receptors with direct‐acting cholinomimetics or with acetylcholinesterase inhibitors evokes a rise in blood pressure in unanesthetized cats, dogs, rats, and humans. Anesthetics may significantly modify this response. Concomitant with the pressor response is a potentiation of reflex bradycardia, inhibition of reflex tachycardia, and enhancement of the pressor reflex to carotid artery occlusion. Administration of atropine or intracerebroventricular injection of hemicholinium‐3 reduces blood pressure in spontaneously hypertensive rats (SHR) but not in normotensive rats. Preliminary results are presented showing that systemic or central injection of N‐(4‐diethyl‐2‐butynyl)‐ succinimide, a muscarinic receptor antagonist specific for central receptors, also reduces blood pressure in SHR but not in normotensive animals.
Successful treatment of ballism with diazepam
Authors: Becker Robert E. , Lal Harbans , Alexander Paul , Karkalas John , Kucharski Thomas 
Published: January 2005

AbstractTwo patients with ballism were treated successfully with diazepam. It is suggested that diazepam acted as an indirect GABAmimetic drug to correct a functional GABA deficiency secondary to hyperactivity of the dopamine system in the subthalamic nucleus as a cause for ballism.
Physical dependence liability of TR5379, a novel narcotic antagonist analgesic
Authors: Howes John F. , Bousquet Ann R. 
Published: January 2005

AbstractTR5379 is a novel morphinan with potent antinociceptive activity in the mouse abdominal constriction procedure. It is a narcotic antagonist with a potency similar to that of butorphanol. In rats and monkeys, TR5379 does not appear to induce any physical dependence. Following a 6‐day chronic administration of TR5379 to rats, no indications of withdrawal were observed. TR5379 did not substitute for morphine in either the physically dependent rat or the physically dependent monkey. In the chronically morphinized rat, an acute dose of TR5379 caused the rapid onset of a marked withdrawal syndrome.
The in vivo pharmacological profile of histamine (H1) antagonists in the rat
Authors: Niemegeers C. J. E. , Awouters F. H. L. , Janssen P. A. J. 
Published: January 2005

AbstractThirteen known H1‐antagonists were studied in a series of pharmacological in vivo tests in rats. Antihistamine activity, oral absorption, and duration of action were determined in the compound 48/80 test. The dissociation between the activity in the compound 48/80 test and in the other tests was used as a measured of antihistaminic specificity. Properties common to several H1‐antagonists were: antimuscarinic (diphenhydramine, promethazine, mequitazine, azatadine, cyproheptadine, chlorphenriamine, clemastine, pyrilamine) and anti‐serotonin activity (mianserin, pizotifen, cyproheptadine, prometazine, diphenhydramine, pyrilamine). Sedative effects of H1‐antagonists were not detected by the pharmacological tests used here. Astemizole, ketotifen, and terfenadine were found to be very specific H1‐antagonists. For ketotifen and terfenadine, oral activity (1/5 and 1/25 of astemizole, respectively) and oral absorption (1/50 and 1/7 respectively) were poor, and the duration of action (4 and 6 hr, respectively) was relatively short. Astemizole was as potent orally as it was subcutaneously (ED50 = 0.11 mg/kg) and appeared to have a duration of action as long as 24 hr.
Comparison of the minimal lethal doses, cardiac toxicities, and cardiodepressor effects of tricyclic antidepressants and UP 614‐04, a potential antidepressant
Authors: Cazes M. , Witchitz S. , Provost D. , Versigny A. , Renard M. , Sebe B. 
Published: January 2005

AbstractThe cardiotoxic and hemodynamic effects of intravenously administered UP 614‐04, imipramine, clomipramine, and amitriptyline were compared using guinea pigs and dogs. In guinea pigs, determinations of minimal lethal dose and electrocardioraphic changes indicated that UP 614‐04 was much less cardiotoxic than the three tricyclic antidepressants tested. In dogs, both imipramine and clomipramine exerted more pronounced effects than UP 614‐04 on hemodynamic parameters. However, all three agents had qualitatively similar dose–response characteristics in that low doses produced slight increases in systolic blood pressure and heart rate, intermediate doses did not alter haemodynamic parameters, and high doses produced marked cardiodepressor effects. Imipramine and clomipramine were also much more potent than UP 614‐04 in potentiating the pressor action of intravenously administered norepinephrine. Taken together, these results have indicated that UP 614‐04 is about five times less cardiotoxic and about four to eight times less potent as a cardiodepressor than imipramine or clomipramine.
Comparative toxicity of oral all‐trans‐retinoic acid and the aromatic retinoids Ro 10‐9359 and Ro 12‐7554 in rats: Hematologic and biochemical studies
Authors: Teelmann Kampe 
Published: January 2005

AbstractReduced bodyweight gains and bone fractures are the most obvious effects in rats after repeated ingestion of high doses of vitamin A derivatives. These effects are dose dependent and well reproducible. Doses of different retinoids causing similar reductions of bodyweight gain and comparable frequencies of bone fractures can be called equitoxic in this respect. The following study was performed with approximately equitoxic doses of all‐trans‐retinoic acid (15 mg/kg/d) and the aromatic retinoids Ro 10‐9359, etretinate (7.5 mg/kg/d), and Ro 12‐7554 (2 mg/kg/d) administered as dietary admix to 18 rats/sex/group for 4 weeks. An additional group of 18 rats/sex remained untreated and served as controls. The aim of this experiment was to investigate and compare the toxic effect of these retinoids on additional parameters such as red blood counts, hemoglobin, alkaline phosphatase, cholesterol, and serum proteins known to be altered in rats exposed to this class of compounds. Under the conditions of this study, using doses which were approximately equitoxic as regards weight gain and bone fractures, the most pronounced changes on the additional parameters mentioned above were caused by retinoic acid. Less influence was shown by etretinate. The degree of compound‐related effects was lowest in the rats treated with the newly developed aromatic retinoid Ro 12‐7554.
Effects of punishment‐attenuating drugs on deprivation‐induced drinking: Implications for conflict procedures
Authors: Leander J. David 
Published: January 2005

AbstractVarious drugs which increase the rates of punished operant responding were studied for their effects on deprivation‐induced drinking of water. Chlordiazepoxide, diazepam, lorazepam, pentobarbital, amobarbital, phenobarbital, and SQ‐20,009 increased deprivationinduced drinking. Drugs which did not increase drinking include ethanol, cyproheptadine, methysergide, and baclofen. This grouping of drugs as to their effects on deprivation‐induced drinking is similar to the grouping of drugs on punishment procedures using deprivationinduced drinking, rather than punishment procedures using operant responding. This suggests that the effects of drugs on punished drinking reveal more about the effects of drugs on deprivation‐induced drinking than they do about the effects of drugs on punished behavior in general.
Tissue blood flow and cephalic arteriovenous shunting in cats following administration of indalpine, a selective inhibitor of 5‐hydroxytryptamine uptake
Authors: Saxena Pramod R. , Tangri Krishna K. 
Published: January 2005

AbstractA number of observations indicate that a decrease in plasma 5‐hydroxytryptamine (5‐HT) level may lead to a diminished tissue perfusion and an opening of arteriovenous (AV) anastomoses in the head during migraine headaches. Indeed, some antimigraine drugs and the amine itself decrease the shunting of radioactive microspheres over the cephalic circulation in the experimental animals. Since indalpine selectively inhibits 5‐HT uptake mechanisms and increases plasma 5‐HT level, we have investigated the effects of the drug (1, 2, and 4 mg·kg−1) on tissue blood flow and on AV shunting using the radioactive microsphere method in anesthetized cats. Indalpine caused minimal systemic hemodynamic effects; only a moderate (14%) hypotension resulted with the highest dose. Regionally, the drug increased blood flow to brain, intestines, mesentery + pancreas, and skeletal muscles. Both total peripheral AV‐shunting (as indicated by the microsphere content of the lungs) and jugular venous AV‐shunting (as measured by microspheres in the jugular venous blood) were decreased by the drug. These hemodynamic changes resemble those occurring during 5‐Ht infusions. It is suggested that indalpine may be of therapeutic value in migraine since it decreased AV‐shunting across the cephalic circulation.
The effect of pirenzepine (LS 519), a specific antimuscarinic drug, on cortisol levels in man
Authors: Alagna Sergio , Masala Antonio , Satta Andrea , Faedda Rossana , Devilla Luisa , Rassu Sergio , Rovasio Pier Paolo 
Published: January 2005

AbstractThe authors investigated the effect of a single 75‐mg oral dose of pirenzepine, a drug which selectively blocks the muscarinic receptors and does not cross the blood‐brain barrier, on the function of the HPA axis. A significant decrease in basal cortisol values following the administration of the drug was observed in comparison with a placebo test. Moreover, the adrenal response to exogenous adrenocorticotropin (ACTH) administration was unchanged following a 5‐day course of the drug, ruling out direct action of pirenzepine at the adrenal level. These data suggest that cholinergic muscarinic hypothalamic and/or pituitary systems may be involved in the regulation of ACTH‐cortisol secretion.
Treatment with antidepressants and down regulation of beta‐adrenergic receptors
Authors: Pandey Ghanshyam N. , Davis John M. 
Published: January 2005

AbstractThe effect of chronic and acute treatment with several antidepressant drugs and electroconvulsive shock (ECS) on the responsiveness of norepinephrine (NE) receptor coupled adenylate cyclase and beta‐adrenergic receptor binding sites in rat brain has been studied by several groups of investigators. It has been consistently reported that chronic administration (2 to 4 weeks of treatment) of antidepressant drugs or ECS causes a decreased accumulation of NE stimulated cyclic AMP accumulation in rat brain. It has also been reported that chronic treatment with antidepressant drugs or ECS causes decreased binding of [3H]dihydroalprenolol (DHA) or [125I]hydroxybenzylpindolol (I‐HYP) (ligands used for studies of beta‐adrenergic receptors) in rat brain. However, such effects are not observed after acute or single administration of these drugs or ECS. Since there appears to be a close correlation between the time course of the effects of these drugs on NE receptor coupled adenylate cyclase and beta‐adrenergic receptor binding, and since most of the antidepressant drugs tested thus far produce such effects, it has been suggested that down regulation or decreased responsiveness of beta‐adrenergic receptors may be related to the therapeutic effects manifested by antidepressant drugs. These observations offer the possibility that determination of beta‐adrenergic receptor responsiveness after chronic treatment with drugs may prove useful in the preclinical screening of potential antidepressant drugs. In this paper, studies related to down regulation of beta‐adrenergic receptors, including our own, are reviewed.
Enhancement of benzodiazepine binding by a diaryltriazine, LY81067
Authors: Wong David T. , Bymaster Franklin P. , Lacefield William B. 
Published: January 2005

AbstractLy81067, a diaryltriazine, represents a new class of compounds to enhance [3H]flunitrazepam binding to membranes of rat cerebral cortex. The enhancement induced by LY81067 exceeds that induced by γ‐aminobutyric acid (GABA) and is partially abolished by the GABA antagonists bicuculline and picrotoxin. Scatchard analysis on the saturable binding of [3H]flunitrazepam reveals that LY81067 at 10 μM increases mainly the affinity for the [3H]ligand, due to a reduced rate of dissociation of the receptor‐bound [3H]flunitrazepam. A dependence on chloride anions was demonstrated in the enhancement of [3H]flunitrazepam binding by LY81067. These findings suggest that the diaryltriazine LY81067 enhances [3H]flunitrazepam binding by exerting its effect at or near the picrotoxinsensitive anion recognition sites of the GABA/benzodiazepine receptor complex.
The use of a microcomputer for collecting screening data and for conducting range finding experiments on muscle relaxant drugs
Authors: Thut Paul D. , Polansky Gregg , Rudo Frieda G. 
Published: January 2005

AbstractThis report describes a method that has been developed to use an Apple II Plus microcomputer in data collection, data analysis, and transfer of raw and summary data to a data base that is maintained on a larger computer. The compounds being screened are potential skeletal muscle relaxants acting at the neuromuscular junction. The microcomputer produces a CRT (cathode ray tube) display resembling the data sheets previously used in a drug screening project. It prompts the user to enter the following data through the keyboard: compound number, date, drug solution, animal weight, desired compound dose. From the entered data, the microcomputer calculates and displays the appropriate injection volume so that a technician will be shown the exact dose that is to be injected into the test animal. Following injection, the mouse is immediately placed on an inclined screen as described by Pradham and De [1953]. Times to onset and offset of muscle paralysis are entered and displayed on the CRT. For lower doses, the effects of the drug on respiration are recorded. After these primary data are recorded, all other relevant data are elicited by a menu of appropriate pharmacological questions. Data from each animal are stored in a random access file on a 5.25‐in. floppy disk. From these files tabular and narrative reports of the drug's effects can be automatically generated. The data are also sent by telephone modem to a data base that is maintained on a larger computer for access by chemists in structure–activity studies. This method has greatly increased the speed and efficiency of data collection and report generation. Furthermore, it has allowed the raw data to be easily searched and reviewed in subsequent structure–activity studies. Because this data collection system is small and self‐contained, it may be mobed easily to different testing sites.
Comparative anticholinergic activity of oxaprotiline and amitriptyline
Authors: Roffman Mark , Gould Eugene , Brewer Samuel , Lau Helen , Sachais Barry , Dixon Nina , Kaczmarek Linda , Le Sher Anne 
Published: January 2005

AbstractAs part of a double‐blind multicenter trial comparing oxaprotiline with amitriptyline and placebo in 308 outpatients with moderate depression, objective (salivary flow) and subjective (dry mouth, blurred vision/visual disorder, and constipation) determinants of anticholinergic activity were assessed. Both active treatments, but not placebo, induced approximately a 40% reduction in salivary flow after one week of treatment with 75 mg/day h.s. Whereas amitriptyline caused a further reduction (26%) in salivary flow by the end of the trial (week 5), no such reduction was noted with oxaprotiline. With regards to subjective complaints, more patients experienced dry mouth and blurred vision/visual degree of sedation is related to the degree of anticholinergic effects per se. Rather, the sedation may be related to a specific anticholinergic effect, such as changes in salivary flow.
Putative endogenous ligands to the benzodiazepine receptor: What can they tell us?
Authors: Davis Leonard G. , Manning Robert W. , Dawson William E. 
Published: January 2005

AbstractThe endogenous ligand for the benzodiazepine receptor has not been convincingly demonstrated, nor is it clear what role this drug receptor actually plays in brain function. A number of putative endogenous ligands for the benzodiazepine receptor have been identified and reported in the literature. These putative ligands, at various stages of purification, have been typically identified by their ability to displace 3H‐diazepam in a radioreceptor binding assay. Taken together, these studies provide useful information on the role that the benzodiazepine receptor and its ligand might play in brain function. The purpose of this paper is to review this area of research and attempt to provide a unifying hypothesis. In summary, calling this bioactive site the benzodiazepine receptor may be a misnomer, as it appears to effect both anxiogenic and anxiolytic activities involved in the maintenance of homeostatic levels of vigilance. Moreover, it can be suggested that endogenous ligands of reciprocal action could exist, mediating each function (relaxation and vigilance) and, thereby, maintain a balance of neural activity.
The action of structural analogues of γ‐aminobutyric acid on binding sites in mouse brain
Authors: Tunnicliff Godfrey , Welborn Kathy L. 
Published: January 2005

AbstractNineteen structural analogues of γ‐aminobutyric acid (GABA) and the anxiolytics buspirone and diazepam were tested for their ability to modify GABA function in vitro. Each compound was added to the GABA receptor binding assay, the flunitrazepam receptor binding assay, the sodium‐dependent GABA binding assay, and the assay for GABA aminotransferase. It was anticipated that some of these analogues would substantially affect several of these assays. The most interesting compound to emerge was phenylthiohydantoic acid. This not only inhibited GABA receptor binding (Ki = 121 μM) but also stimulated flunitrazepam binding and inhibited the activity of GABA aminotransferase. In light of the evidence that a reduced GABA function can be a factor in anxiety, phenylthiohydantoic acid has the potential to be a GABA‐mimetic and thus be useful in the treatment of anxiety.