bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative study of central and peripheral histamine‐H1 receptor binding in vitro and ex vivo of non‐sedating antihistamines and of noberastine, a new agent
Authors: Leysen Josée E. , Gommeren Walter , Janssen Paul F. M. , Janssen Paul A. J. 
Published: January 2005

AbstractA new antihistamine, noberastine, and clinically used non‐sedating antihistamines, astemizole, mequitazine, terfenadine, loratadine, and cetirizine were investigated for in vitro and ex vivo binding to histamine‐H1 receptors in guinea‐pig cerebellums and lungs. In vitro, all the drugs dissociated slowly from histamine‐H1 receptors (half‐times ≥ 100 min), Ki,app‐values decreased with longer incubation times and for potent lipophilic agents (astemizole, mequitazine, and terfenadine) Ki,app‐values were lower with more dilute tissue suspensions. Because of the slow dissociation, true binding equilibrium cannot be attained during limited incubation times and because of the apparently high tissue adsorption for some of the drugs, the actual free drug concentration in solution is unknown. Therefore measured binding parameters are apparent; true equilibrium binding constants cannot be estimated. Noberastine showed the lowest Ki,app‐value in various assay conditions (0.55–0.15 nM). In optimized assay conditions astemizole and mequitazine were nearly as potent (Ki,app‐values 0.2 and 0.29 nM). Terfenadine, cetirizine, and loratidine bound with 30‐, 80‐ and 100‐times lower affinity. The in vitro receptor binding and neurotransmitter inhibition profile of these compounds revealed that they all primarily bound to histamine‐H1 receptors. The occupation of lung and cerebellar histamine‐H1 receptors was investigated after oral administration of different dosages of the drugs and at various times after drug administration using ex vivo binding techniques. Noberastine and astemizole were the most potent componds and showed complete differentiation between lung and cerebellar receptor occupation (with 0.63 mg.kg−1: 70% lung receptor occupancy, less than 10% cerebellar receptor occupancy). With mequitazine and terfenadine a 7‐times higher dose was required to reach the same effect. Astemizole was extremely long acting, noberastine, mequitazine and terfenadine were short acting. Loratidine and cetirizine differentiated very poorly or not at all between lung and cerebellar receptor occupation (at 2.5 mg.kg−1: 70% and 60% lung receptor occupation, 50% and 70% cerebellar receptor occupation). The physicochemical properties of the drugs were considered in the discussion of the data. It appeared that penetration into the brain is not directly related to lipophilicity. The study allowed a quantitative comparison of the receptor binding properties of the drugs. Noberastine, as a shorter acting agent, and astemizole, as a long acting agent, appeared to be the compounds of choice as non‐sedating antihistamines.
Reversal of stress‐induced arousal in sleeping rats by some imidazopyrimidine benzodiazepine receptor ligands
Authors: James Vernon , Gardner Colin R. 
Published: January 2005

AbstractFive selected imidazopyrimidine ligands for benzodiazepine receptors which show nonsedative anxiolytic behavioral profiles, were tested for their ability to reverse arousal induced by intermittent footshock stress in sleeping rats. RU32698, RU32759, RU33203, and RU33543 showed dose‐related inhibition of stress‐induced arousal in the dose range 2–10 mg/kg orally, as did chlordiazepoxide. After 14 daily doses there was little or no decrease in the magnitude of this effect with RU32759 and RU32698, respectively. In contrast, RU32514 only weakly reversed stress‐induced arousal at 10 mg/kg, a dose which is maximally active in a conflict procedure in rats. It is suggested that RU32514 possesses only weak agonist activity at benzodiazepine receptors and this is insufficient for it to be effective in this test. RU32698 and RU32759 show potential for development as non‐sedative anxiolytics and the sub‐acute dosing experiment suggests that they may not show marked tolerance.
Animal pharmacokinetics of selected imidazopyrimidine ligands for benzodiazepine receptors
Authors: Ager Ian R. , Doyle Anne B. , Hairsine Peter W. , McDonald Keith P. , Miller Peter , Parker Fred L. 
Published: January 2005

AbstractThe kinetics of imidazopyrimidines selected for development were investigated in the rat, dog, and cynomolgus monkey using high pressure liquid chromatography (HPLC) measurements of levels. These data were compared with levels estimated by benzodiazepine radioreceptor binding assays and with the in vivo binding of the compounds to these receptors in the brain. RU 32698, RU 33203, and RU 33543 were found in relatively high peak levels in the plasma of rats (1–6 μg/ml at 10 min‐1 hr after 10–100 mg/kg orally [p.o.]), dogs (4–12 μg/ml at 2 hr after 20 mg/kg p.o.), and monkeys (0.4–10 μg/ml after 150–500 mg/kg p.o.). HPLC analysis showed one further prominent peak for either RU 33203 or RU 33543 which had similar characteristics in all three species and may represent a common route of metabolism. In the rat these putative metabolites were at low levels in the brain when compared with parent levels. Nuclear magnetic resonance (NMR) and mass spectra of these isolated metabolites identified them as the hydroxymethyl derivatives on the oxadiazole ring. The synthesised metabolites showed two to six times less affinity for 3H‐flunitrazepam‐labelled benzodiazepine receptors, and the RU 33203 metabolite, RU 34149, did not displace in vivo benzodiazepine receptor binding after administration to mice, despite high plasma levels. This, coupled with little activity in several in vivo pharmacological models, suggests that this metabolite only poorly crosses the blood brain barrier. A pharmacological effect in the stress‐induced ultrasounds model is consistent with this view as the rat pups used have a poor blood brain barrier. Daily dosing of low, pharmacologically effective doses of all three compounds (25 or 30 mg/kg p.o.) in rats showed little change in the plasma levels of parents after the 14th dose. There were slight increases in the levels of the metabolites of RU 33203 and RU 33543. Higher doses showed some decrease of parent levels on day 14 but a clear increase in the metabolite levels, particularly with RU 33543, suggesting enhanced metabolism on repeated dosing. No marked differences in overall plasma level time courses of parent or metabolites were observed when comparing the first or last (28–30 days) daily dose in monkeys (150–500 mg/kg p.o.).
Characterization of central H2 receptors mediating cardiovascular activity by means of three histamine H2 receptor antagonists: MK‐208, BMY‐25368, and cimetidine in the rat
Authors: Poulakos Jennifer J. , Gerges Elizabeth N. , Gertner Sheldon B. 
Published: January 2005

AbstractStimulation of central histamine H1 and or H2 receptors with histaminergic drugs results in a dose‐related pressor response and bradycardia in conscious, freely‐moving rats. Two recently developed peripheral histamine H2 antagonists, MK‐208 and BMY‐26368, as well as cimetidine, were evaluated with respect to their ability to block the cardiovascular actions of central histamine H2 receptors. These drugs do not readily cross the blood brain barrier, therefore, they were administered intracerebroventricularly (i.c.v.). The ability of these agents to attenuate the cardiovascular effects of the H2 agonist impromidine was studied in conscious, freely‐moving rats. Blood pressure and heart rate were monitored directly via indwelling carotid catheters, and drugs were administered i.c.v. through permanently implanted cannulae. All of the H2 antagonists tested induced a transient hypertensive response that lasted approximately 15 min. MK‐208 (30 μg) partially blocked the central cardiovascular actions of impromidine. Unlike other histaminergic agents, MK‐208 produced a tachycardia and a profound hyperactivity which slowly developed into seizures. BMY‐25368 and cimetidine failed to antagonize the cardiovascular actions of impromidine. These results demonstrate that cimetidine and BMY‐25368, established peripheral H2 antagonists, did not block central H2 receptors, suggesting that central and peripheral H2 receptors may be pharmacologically distinct.
Psychopharmacological effects of an imino‐thiazolidine derivative antidepressant candidate, EGYT‐4201
Authors: Gyertyán István , Petöcz Lujza , Gacsályi István , Fekete Márton I. K. , Tekes Kornélia , Kápolnai László 
Published: January 2005

AbstractThe imino‐thiazolidine derivative EGYT‐4201 exhibited marked activity in pharmacological tests characteristic for antidepressants. In the behavioral despair model and in antagonizing the effect of tetrabenazine its efficacy was considerably higher than that of several tricyclic and second generation antidepressant drugs. The compound also proved to be active in inhibiting the hypothermic effect of apomorphine. It potentiated the lethal effect of yohimbine, the hypermotility provoked by L‐dopa, and the stereotypy induced by D‐amphetamine. In contrast to amitriptyline and nomifensine, EGYT‐4201 showed neither sedative nor stimulant actions on spontaneous and conditioned behavior. The compound, similar to amitriptyline and viloxazine, exerted a moderate anticonvulsive effect against pentylenetetrazole, bicuculline, and picrotoxin. EGYT‐4201 did not exhibit significant anticholinergic activity on physostigmine induced lethality, oxotremorine evoked tremor, and isolated guinea pig ileum. In acute toxicity studies it proved to be more favourable than the reference compounds. EGYT‐4201 did not inhibit the enzymatic activity of the monoamino‐oxidase (MAO) enzyme, nor did it block the uptake of monoamines. The molecule was found to be inactive in binding studies of noradrenergic, dopaminergic, and serotonergic receptor types.
In vitro and in vivo studies on the effects of the alpha‐adrenoceptor blocker IP/66 (1‐(2‐ethoxy‐2‐(3′ ‐pyridyl)ethyl)‐4‐(2′‐methoxy‐phenyl)piperazine) on urethral tone in rats
Authors: Manzini Stefano , Perretti Francesca , Boni Paola , Barbanti Gabriele , Turini Damiano , Maggi Carlo Alberto 
Published: January 2005

AbstractIP/66 (1‐(2‐ethoxy‐2‐(3′‐pyridyl)ethyl)‐4‐(2′‐methoxy‐phenyl))piperazine is a newly synthetized and stereoselective alpha‐adrenoceptor blocking drug. This compound exhibits preferential blocking activity in postjunctional as compared to prejunctional alpha‐adrenergic responses. Furthermore, IP/66 inhibits phenylephrine‐induced motor response in human and rat prostatic tissue and phenylephrine‐, DMPP‐ and EFS‐induced motor responses in rat urethral tissues, being equieffective or even more potent than prazosin. Like prazosin, intravenous administration of IP/66, at doses at which no hypotensive effect is observed, induces a marked inhibition of phenylephrine or DMPP‐induced increase in urethral perfusion pressure, in anaesthetized pithed rats. Finally, IP/66 administration exerts beneficial effects in animals with surgically‐ or pharmacologically‐induced urethral outflow obstruction. As a whole, the pharmacodynamic profile of IP/66 is promising and this drug might be proposed for clinical setting evaluating its efficacy for the treatment of lower urinary tract dysfunctions.
Prepulse inhibition as a screening test for potential antipsychotics
Authors: Rigdon Greg C. , Viik Kaido 
Published: January 2005

AbstractStartle response amplitude is greatly reduced by a low intensity pulse presented 100 msec prior to the startle stimulus. The magnitude of this prepulse inhibition (PPI) is reduced in schizophrenic patients. In rats, apomorphine disrupts PPI; haloperidol antagonizes apomorphine's effects. We tested the antipsychotic drugs haloperidol, chlorpromazine, clozapine, and risperidone, and the non‐antipsychotic psychopharmacological agents diazepam, buspirone, and imipramine for their ability to antagonize apomorphine's effects on PPI of the acoustic startle reflex. Haloperidol, chlorpromazine, and risperidone antagonized apomorphine's blockade of PPI. Clozapine antagonized apomorphine's effect only at a dose that decreased startle amplitude by 82%. Imipramine and diazepam did not antagonize apomorphine's effect at behaviorally relevant doses. Buspirone weakly antagonized apomorphine blockade of PPI, but, like apomorphine, disrupted PPI when given alone. These results suggest that this PPI test may provide a useful screening procedure for compounds wtih antipsychotic activity. However, the lack of a robust clozapine effect needs to be investigated.
Medication property effects on expectations of action
Authors: Buckalew L. W. , Ross Sherman 
Published: January 2005

AbstractThis paper applied a psychological perspective, initiated from placebo research, on medication physical properties and related perceptions, expectations, and preferences. The purpose was to identify expectations of drug indications related to medication color and to identify any preferences for oral medication form. A census‐based (age, race, gender) sample of 102, screened for color vision, classified 29 different colored capsules as to physiological system(s) expected to be influenced. Medication form preferences were verbally obtained. Nonrandom distributions were found for 18 capsules, with 10 related to specific physiological indications to include “Unknown.” Capsules were clearly favored over pills and caplets. Age, gender, and race effects were minimal in sortings and preferences. Related research on perceptions of medications was reviewed and integrated with present data. Findings should have implications for drug development, drug effectiveness, and patient compliance. A theoretical framework was offered for understanding possible effects of preparation perceptual properties.
Heptaminol hydrochloride (hept‐a‐Myl®) facilitates a light‐dark discrimination task in a Y‐maze using electrical self‐stimulation as reinforcement
Authors: Cazala P. , Durantou F. , Pourrias B. 
Published: January 2005

AbstractThe effects of intraperitoneal injections of heptaminol hydrochloride (hept‐a‐myl®) on a light‐dark discrimination task in a Y‐maze using intracranial self‐stimulation (ICSS) in the lateral hypothalamus (LH) as reinforcement were studied in BALB/c mice. At the two doses injected (34.6 and 60 mg/kg) heptaminol facilitated the discrimination between the arm reinforced by LH stimulation and the neutral arm, during the acquisition and reversal phases of the task. However, mice injected with the dose of 34.6 mg/kg performed the best discrimination performance (i.e., made the lowest number of discrimination errors). Moreover, heptaminol greatly decreased the latency to initiate LH stimulation, whereas the latency to terminate it was not modified.These results suggest that heptaminol (1) can be considered as a cognitive enhancing agent which is able to improve the discrimination performance whatever the complexity of the learning task and (2) modulates the activity of certain neuronal mechanisms involved in ICSS regulation.
Evidence for a unique interaction of loreclezole with the GABA receptor complex
Authors: Vaught Jeffry L. , Wauquier AlBert 
Published: January 2005

AbstractThe interaction of loreclezole (a structurally novel non‐benzodiazepine anticonvulsant), diazepam, phenobarbital sodium, and ethosuximide with the benzodiazepine antagonists β‐CCE, Ro 15‐1788, and CGS 8216 and the purine antagonist aminophylline were examined in the rat i.v. metrazol seizure test. The anticonvulsant activity of loreclezole was inhibited by β‐CCE and CGS 8216 but not by Ro 15‐1788 or aminophylline. The inhibition produced by CGS 8216 was dose dependent (ID50 = 0.04 mg/kg i.p. CGS 8216) and surmountable. When the interactions of the various antagonists with loreclezole were compared to those of diazepam, phenobarbital sodium, and ethosuximide, a clear differentiation of activity was evident. β‐CCE blocked the anticonvulsant activity of all four compounds whereas Ro 15‐1788 blocked only the anticonvulsant effects of diazepam. CGS 8216 blocked the anticonvulsant effects of diazepam and loreclezole in a similar manner while being much less effective against the anticonvulsant effects of ethosuximide and ineffective against phenobarbital sodium. Aminophylline blocked the anticonvulsant effects of only ethosuximide. Based on these data and the anticonvulsant profile of loreclezole, we suggest that loreclezole represents a new class of agents which modulate GABAergic transmission via a unique interaction with the GABA receptor complex.
Effects of Ginkgolide B and Ginkgo biloba extract on local cerebral glucose utilization in the awake adult rat
Authors: Lamour Yvon , Holloway Harold W. , Rapoport Stanley I. , Soncrant Timothy T. 
Published: January 2005

AbstractThe effects of the extract of the leaves of Ginkgo biloba and of one of its major components, Ginkgolide B, on local cerebral glucose utilization (LCGU) have been studied in the awake adult rat. Ginkgolide B (10 mg/kg i.p.) had no significant effect on LCGU in 38 brain regions studied. In contrast, the Ginkgo biloba extract (150 mg/kg i.p. in 3 divided doses) produced significant and widespread decreases in LCGU in 21 brain regions (range 3–26% reduction). These results demonstrate that Ginkgo biloba is able to reduce brain glucose utilization, but that the substance responsible for this effect may not be Ginkgolide B.
Effect of fentanyl on the electrophysiological recovery following incomplete global cerebral ischemia
Authors: Vasthare Usha S. , Rubin Sharon , Riina Howard A. , Rosenwasser Robert H. , Carlsson Christer , Tuma Ronald F. 
Published: January 2005

AbstractThe effects of two commonly used doses of the opioid fentanyl (50 and 100 μg/kg) on the electrophysiological outcome following global cerebral ischemia were studied in rats. The somatosensory evoked responses (SSER) and EEG activity were utilized to assess neurophysiological outcome. Prior to ischemia, there was no difference in the latency of the cortical peak of the SSER between groups. During the ischemic period, SSER and EEG activity were abolished in both groups. During the reperfusion period, however, the cortical peak of the SSER returned within 30 min in the animals anesthetized with 50 μg/kg of fentanyl, whereas in the animals anesthetized with 100 μg/kg fentanyl the cortical peak did not return by 60 min. This suggests that the animals anesthetized with a high dose of fentanyl are more susceptible to ischemic damage and that a high dose of fentanyl may exacerbate neurological damage following an ischemic insult to the brain.
Subcortical arteriosclerotic encephalopathy (Binswanger's disease): Clinical observations and therapeutic implications
Authors: Bogucki Andrzej , Prusiński Antoni , Szymańska Róźa , Lorenc Józefa 
Published: January 2005

AbstractSubcortical arteriosclerotic encephalopathy (SAE), or Binswanger's disease, is one of the forms of vascular dementia. In SAE arteriosclerotic changes affect subcortical arteries and arteroles. Atherosclerosis of large cerebral arteries is common among SAE patients. As dyslipoproteinemias are risk factors for atherosclerosis we studied blood lipids and lipoproteins in patients with clinical diagnosis of SAE. In 11 patients diagnosis of the disease was established on the basis of CT scans and clinical course consistent with SAE. In the studied group a tendency to increased total cholesterol and apolipoprotein B and to decreased HDL cholesterol (HDL‐CH) were found. The levels of LDL cholesterol (LDL‐CH) and the CH/HDL‐CH and HDL phospholipides/HDL‐CH ratios were significantly higher in SAE patients when compared to controls.
Cyclo(leu‐gly) reverses the permanent dopamine receptor up‐regulation induced by ovariectomy
Authors: Fields Jeremy Z. , Wichlinski Lawrence J. , Ritzmann Ronald F. , Drucker George E. , Gordon John H. 
Published: January 2005

AbstractSeveral neuropsychiatric diseases, including tardive dyskinesia and schizophrenia, are thought to involve increased neurotransmission at dopaminergic synapses. Although many animal models of this dopaminergic hyperactivity have been studied, the ovariectomized (OVX) rat model, which we recently developed, appears to be unique. The brain D2 DA receptor up‐regulation (increases in receptor number) and the behavioral hypersensitivity to dopamine (DA) agonists that develop in this model after a few months appear to be permanent. Using this model, it is now possible to screen for agents that can reverse a permanent dopaminergic supersensitivity. In this report, we document such a reversal by cyclo(leu‐gly) (CLG), a dopaminergic neuromodulator, in the OVX model. Female Fisher rats were ovariectomized and allowed to recover for 3 months. Following a challenge dose of apomorphine (0.45 mg/kg, i.p.) OVX rats showed significantly more stereotypic sniffing (+ 175%) than sham controls. Following lower doses of APO (125 and 150 μ/kg, i.p.), OVX rats showed significantly more locomotor activity (+ 105 and + 365%). CLG (4 daily doses, 8 mg/kg, s.c.) reversed these hypersensitive responses. In parallel, OVX rats showed a significant increase (+ 35%) in [3H]‐spiroperidol binding (Bmax) in corpus striatum relative to sham rats; this dopamine receptor up‐regulation was also reversed by CLG. We conclude (1) that the long‐term OVX rat is useful for modelling the permanent or irreversible aspect of supersensitivity to DA; and (2) CLG may be useful in the treatment of dopaminergic diseases.
Histamine‐induced wheal, flare, and pruritus: Inhibition by cetirizine, terfenadine, and placebo
Authors: Coulie P. J. , Ghys L. , Rihoux J. P. 
Published: January 2005

AbstractTwelve adult volunteers were enrolled in a four‐session, double‐blind, crossover, randomized study. On each session, two capsules were administered in the morning and contained the pulverised products of either placebo (P) + P, terfenadine (T) 60 (mg) +P, T 60 + T 60, or cetirizine (C) 10 + P. On the evening of each experimental day, two capsules were taken at 0800 pm either as P + P or as T 60 + P or as P + P, or as P + P. We thus have four groups called, respectively, placebo, terfenadine 60 bid, terfenadine 120, and cetirizine 10. Pricks (100 mg/ml histamine) were performed before drug intake and 5, 12, 17, and 24 hr after drug intake. Ten minutes after each prick, wheal areas were underlined and transfered onto a transparency to be measured later. One volunteer gave up the trial due to the appearance of a serious disease not related to the trial. Regarding initial wheals, cetirizine 10, terfenadine 60 bid, and terfenadine 120 significantly (P < 0.01) reduced the wheal at H5, H12, H17, and H24 (except NS at H17 for T120). At H5, H12, and H17, cetirizine 10, terfenadine 60 bid, and terfenadine 120 were significantly more potent than P (P < 0.03). At H24, only cetirizine 10 and terfenadine 60 bid were significantly more potent than placebo. Pairwise global comparison shows a significant difference (P = 0.03) in favour of cetirizine regarding terfenadine 120. Side effects under active drugs were not different from those under placebo.