bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuropharmacological assessment of the discriminative stimulus properties of the novel anxiolytic ipsapirone
Authors: Cunningham Kathryn A. 
Published: January 2005

AbstractThe novel anxiolytic ipsapirone appears to interact selectively with 5‐hydroxytryptamine1A (5‐HT1A) receptors. The present study investigated (1) the discriminability of ipsapirone using a two‐lever, water‐reinforced task and (2) the importance of 5‐HT1A and catecholamine systems in the ipsapirone cue. To this end, rats were trained to discriminate ipsapirone (7.5 mg/kg; N = 14) from saline. Dose‐response tests indicated that the ipsapirone cue was dose dependent. Buspirone and 8‐OH DPAT substituted while the dopamine (DA) D1 agonist SKF 38393, the DA D2 agonist quinpirole, and the α2‐adrenoceptor agonist clonidine engendered saline responding. Furthermore, the D1 antagonist SCH 23390, the D2 antagonist sulpiride, and the putative 5‐HT1A antagonist spiroxatrine did not block or mimic the ipsapirone cue. This research suggests that catecholamine systems do not play a prominent role in mediating the stimulus properties of ipsapirone. Moreover, while the substitution profile for ipsapirone suggests that this novel anxiolytic may be a selective 5‐HT1A agonist, blockade of the ipsapirone cue by a 5‐HT1A antagonist remains to be established.
General pharmacology of diprafenone, a new class lc antiarrhythmic agent, and 5‐hydroxydiprafenone, an active metabolite
Authors: Greenberg Stanley , Luisi Alan 
Published: January 2005

AbstractThis study compareo the effects of diprafenone, a new class lc antiarrhythmic agent, and 5‐hydroxydiprafenone (5‐OHDP), an active metabolite of diprafenone, to standard class l antiarrhythmic agents (propafenone, flecainide, or lidocaine), in several pharmacologic models, to ascertain the potential for side effects relative to the currently available class l antiarrhythmic agents. Diprafenone and propafenone decreased blood pressure and heart rate in anesthetized rabbits at 3 and 7 mg/kg, i.v., respectively. Neuromuscular transmission in rabbit gastrocnemius muscle was partially (38%) inhibited after 3 mg/kg of diprafenone and 7 mg/kg of propafenone. Diprafenone and 5‐OHDP (10−4M), but not lidocaine, inhibited aggregation of human platelets evoked by sodium arachidonate and adenosine diphosphate. Diprafenone, fleoainide, and 5‐OHDP (10−4M) inhibited the contractile responses of guinea pig vas deferens to norepinephrine and spontaneous and bradykinin‐evoked contractions of the guinea pig uteri. Diprafenone and 5‐OHDP, but not flecainide, relaxed rabbit bronchial smooth muscle contracted by acetylcholine. Diprafenone, 5‐OHDP and propafenone (10−5M and 10−4M) also depressed the contractile responses of canine mesenteric arteries to transmural nerve stimulation. Thus, high concentrations of diprafenone (10−5M and 10−4M) depress smooth muscle and neural function. The depressant effects occur with 4ndash;40 times the antiarrhythmic concentration of diprafenone and are shared by propafenone and, in part, by 5‐OHDP and flecainide. It is unlikely that major peripheral side effects will occur with therapeutic doses of diprafenone in man.
Phencyclidine acts as an N‐methyl‐D‐Aspartate agonist in vitro
Authors: Taylor Duncan P. , Behling Susan H. 
Published: January 2005

AbstractThe in vitro binding of the tricyclic compound (+)‐[3H]MK‐801 to membranes from rat brain cerebral cortex has been shown to be enhanced by L‐glutamic acid and inhibited by the noncompetitive N‐methyl‐D‐aspartate (NMDA) antagonist phencyclidine (PCP) and the competitive NMDA antagonist 3‐[(±)‐2‐carboxypiperazin‐4‐yl] propyl‐1‐phosphonic acid (CPP). We characterized these interactions in ligand saturation experiments. As noted by others, the KD was decreased by L‐glutamic acid. In addition, we noted a slight but significant increase in Bmax in the presence of the excitatory amino acid. PCP increased the KD in a fashion characteristic of competitive inhibition, but it also increased Bmax in a fashion which mimicked L‐glutamic acid. That this effect might be mediated by a direct action of PCP at the NMDA binding site was confirmed by the ability of CPP to block the PCP‐induced increase in Bmax. These data suggest that the chemical structure of PCP may represent a new starting point for the development of agents which interact with the NMDA receptor.
Effects of H2‐receptor antagonists on the central nervous system
Authors: Berlin Roger G. 
Published: January 2005

AbstractHistamine functions as a neurotransmitter in the central nervous system (CNS), and H2‐receptor activation can modulate the activity of the CNS. H2‐receptor antagonists are known to penetrate the blood‐brain barrier and to cause neuropsychiatric effects. It appears that interactions with CNS H2‐receptors may account for many of these effects, although receptor interactions unique to certain H2‐antagonists may also play a role.
Loreclezole (R 72 063): An anticonvulsant chemically unrelated to prototype antiepileptic drugs
Authors: Wauquier Albert , Fransen Joannes , Melis William , Ashton David , Gillardin Jean‐Marie , Lewi Paul J. , Van Clemen Gust , Vaught Jeffrey , Janssen Paul A. J. 
Published: January 2005

AbstractThis study reports on the anticonvulsant profile of a chemically and pharmacologically new compound, loreclezole, as compared to prototype antiepileptics. The compound was tested in different species (mice, rats, guinea pigs, and dogs), in different seizure models, following p.o. or i.p. drug administration, and at different time intervals. Loreclezole was found to be active in a genetic model of reflex epilepsy (audiogenic seizures in mice) and in all models where seizures were elicited by chemical or electrical stimulation. In addition, loreclezole was active against both tonic (TON) and clonic (CLON) seizures and increased the threshold for behavioral as well as electroencephalographic (EEG) seizures. Loreclezole has a rapid onset of action (15 min in the quinolinic acid‐induced CLON seizures and barrel rotations) and a duration of action, in certain tests, of more than 24 hr (allylglycine test and s.c. pentylenetetrazol test in rats). There is a dissociation between the anticonvulsant doses and the induction of neurological side effects (in dogs, ratio > 25.5). Chronic administration for 5–7 days did not lead to tolerance to the anticonvulsant action of loreclezole. Also, as based on spectral map analysis, loreclezole both valproate and ethosuximide, suggesting that it might be effective against both grand mal and petit mald epilepsy.
Effect of exercise on disposition and pharmacokinetics of drugs
Authors: Somani Satu M. , Gupta Sundeep K. , Frank Stuart , Corder Clinton N. 
Published: January 2005

AbstractThe effect of various drugs on exercise in man and animal has been reported but there are very few reports which evaluate the effect of exercise on the disposition and pharmacokinetics of drugs. Exercise in general decreases the absorption after oral administration and increases absorption after intramuscular and subcutaneous administration. Exercise decreases the distribution and excretion of flow‐limited drugs and increases the distribution and excretion for capacity‐limited drugs. Treadmill or running wheel, but not swimming exercise diminishes or elevates the Phase I metabolism and glucuronidation. The effect of exercise on drug metabolism may be substrate specific, suggesting alterations in isozymes of Cyt P‐450. Exercise also decreases glutathione concentration. Effect of exercise on drug disposition is also related to the other factors including temperature, pH, drug permeability, and barometric pressure; the most critical factor, however, appears to be altered blood flow which occurs with exercise. There is a wide inter‐ and intraindividual variation in the metabolism and pharmacokinetics of drugs due to exercise. It remains to be determined what factors play a major role in drug disposition as a consequence of exercise. Exercise influences the amount of drug reaching the receptor site, which has significant affect on pharmacodynamic activity. This aspect of pharmacology has great implications in therapeutics particularly for drugs which have a low margin of safety.
Human immunodeficiency virus protease: A target for aids therapy
Authors: Debouck Christine , Metcalf Brian W. 
Published: January 2005

AbstractHuman immunodeficiency virus, also called HIV, is the etiologic agent of acquired immune deficiency syndrome (AIDS). This retrovirus produces a small, dimeric aspartyl protease which specifically cleaves the precursor forms of the structural proteins and enzymes of the virus. This proteolytic activity is absolutely required for the production of mature, infectious viral particles and is therefore an attractive target for therapeutic intervention. Peptide analogues containing transition‐state mimics were synthesized and shown to inhibit the activity of the purified HIV protease in vitro to various extents. Most interestingly, the most potent inhibitors were shown to effectively block the protease in HIV‐infected cells and to impair the viral life cycle. Other approaches to interfere with the viral protease activity or production are also discussed.
Pharmacology of Cl‐966: A potent GABA uptake inhibitor, in vitro and in experimental animals
Authors: Taylor Charles P. , Vartanian Mark G. , Schwarz Roy D. , Rock David M. , Callahan Michael J. , Davis M. Duff 
Published: January 2005

AbstractExperiments were performed to assess the pharmacology of a novel inhibitor of GABA uptake, Cl‐966 ([1‐[2‐[bis 4‐(trifluoromethyl)phenyl]methoxy]ethyl]‐1,2,5,6‐tetrahydro‐3‐pyridinecarboxylic acid, HCl salt; the molecular weight of the free acid is 473.8). Cl‐966 potently inhibits tritiated GABA uptake into rat hippocampal slices in vitro (lC50 = 304 nM). It has no appreciable effect on the uptake of other neurotransmitters tested (aspartate, dopamine, norepinephrine, serotonin) and has low activity in a broad range of neurotransmitter receptor binding assays. When given orally to mice, Cl‐966 prevents tonic extensor seizures from low‐intensity electroshock and prevents pentylenetetrazole‐induced clonic seizures (ED50 = 0.4–1.0 mg/kg). In addition, the hippocampal afterdischarge threshold in kindled rats is increased markedly (ED50 = 2.6 mg/kg p.o.). Despite anticonvulsant effects, higher doses of Cl‐966 reduce the intravenous dose of pentylenetetrazole needed to produce clonus in mice. In mice, rats, dogs, and monkeys, Cl‐966 interferes with normal behavior, causing ataxia, reduced responsivenes and myoclonus. In the hippocampus of anesthetized rats, Cl‐966 increases inhibition measured electrophysiologically. Overflow of endogenous GABA in the striatum (measured with in vivo microdialysis) was also increased. All of these observed effects with Cl‐966 may be explained by its inhibitory effect on GABA uptake.
Comparison of Somatuline (BIM‐23014) and somatostatin on endocrine and exocrine activities in the rat
Authors: Moreau Sylviane C. , Murphy William A. , Coy David H. 
Published: January 2005

AbstractThe actions of Somatuline (BIM‐23014), an Octapeptide analogue of somatostatin, and somatostatin have been compared on several endocrine and exocrine activities in the rat. A substantial difference exists between these two compounds with respect to potency, duration of action, and tissue‐selectivity. With regard to endocrine activities, Somatuline was about 300 times more potent than somatostatin in inhibiting growth hormone (GH) release 15 min after intravenous injection, and about 4 to 6 times more potent 15 min after subcutaneous administration. The inhibitory activity of subcutaneously‐administered Somatuline on D‐ALa2‐GRF‐stimulated GH release lasted for about 6 hr, whereas an action of somatostatin was not detected 30 min after injection. Somatuline was also more potent than somatostatin in inhibiting insulin‐stimulated glucagon secretion when both substances were administered intravenously, whereas they were about equipotent when given by the subcutaneous route. However, Somatuline was only about half as potent as somatostatin by the intravenous route in inhibiting glucose‐stimulated insulin release and inactive by the subcutaneous route. With regard to exocrine activities, Somatuline was about 300–500 times more potent than somatostatin in inhibiting the increase in plasma α‐amylase activity following ligation‐induced pancreatitis when both compounds were administered subcutaneously concurrently with pancreatic duct ligation. Somatuline was also about 20–400 times more potent that somatostatin in inhibiting gastric acid secretion when both compounds were administered subcutaneously prior to, or concurrently with, pentagastrin challenge, and about 100 times more potent than somatostatin when administered after pentagastrin challenge. Somatuline had a very weak inhibitory effect on the development of ethanol induced gastric ulcers, it did not induced diarrhea, and it had no effect on the course of diarrhea in rats subjected to castor oil gavage. The differences that have been shown to exist between Somatuline and somatostatin indicate that Somatuline may be more useful in treating certain disease states, such as diabetes mellitus, pancreatitis, and possible gastritis or bleeding gastric ulcers.
Cardioprotective effects of nicorandil on isoproterenol‐induced injury
Authors: Ohta Hideyuki , Azuma Junichi , Tanaka Yuya , Takihara Keiko , Hamaguchi Tomoyuki , Awata Nobuhisa , Sawamura Akihiko , Sperelakis Nicholas , Kishimoto Susumu 
Published: January 2005

AbstractNicorandil, a new anti‐anginal drug, exerts a coronary vasodilation effect by mechanisms different from either nitrates or slow channel Ca+ + entry blockers. This agent has been demonstrated to increase membrane K+ conductance, elevate cyclic guanosine monophosphate content, and inhibit Ca+ + kinetics in vascular smooth muscle cells. In the myocardium, however, the direct effects of the agent have not been elucidated. We examined whether nicorandil could antagonize myocardial injury in chick hearts induced by a toxic dose of isoproterenol. Isoproterenol treatment (240 mg/kg subcutaneously twice a day for 4 days) caused a significant increase in heart/body weight ratio and induced a remarkable histological perturbation. A substantial accumulation of Ca+ + and a profound decrease of creatine kinase and lactate dehydrogenase activity were observed in the myocardium from isoproterenol‐treated chick. Oral administration of nicorandil (4 mg/day for 4 days, 15 min prior to each isoproterenol treatment) attenuated the deterioration induced by isoproterenol. The present study suggests that nicorandil partially protects the myocardium from the isoproterenol‐induced injury.
MK‐801 produces antianxiety effect in elevated plus‐maze in mice
Authors: Sharma Avadhesh C. , Kulkarni S. K. 
Published: January 2005

AbstractThe antianxiety effect of the non‐competitive NMDA receptor antagonist, MK‐801, was investigated in the present study in the elevated plus‐maze paradigm in mice. During a 5‐min session of the test, the number of entries the animal made in open/and closed arm, preference of the animal for first entry, and average time each animal spent in open and closed arm were noted as parameters for anxiety‐related movements. The effect of MK‐801 was further explored by studying its interaction with the specific anxiolytic agent, diazepam; the anxiogenic beta carboline agent, FG 7142; and the central benzodiazepine receptor antagonist, flumazenil (RO 15–1788). MK‐801 produced anxiolytic effects at all the doses investigated. It increased the preference of the animal for open arm in a dose‐dependent manner and the effect was potentiated by diazepam. Both FG 7142 and flumazenil reversed the effects of MK‐801 when these agents were concomitantly administered with MK‐801. The study revealed the anxiolytic effect of MK‐801, a non‐competitive antagonist of NMDA‐receptor, and also an interaction of the NMDA‐receptor and GABA/BZ‐receptor complex in anxiety‐related behaviour in mice.
Uptake of cicletanine by vascular smooth muscle
Authors: Silver Paul J. , Cumiskey Wayne R. 
Published: January 2005

AbstractCicletanine is an antihypertensive agent with vasorelaxant/natriuretic properties. The mechanism of vasorelaxation by cicletanine is unknown and may be related to effects on prostacyclin synthesis or cGMP phosphodiesterase inhibition. Direct links of vasorelaxation to biochemical mechanisms have been hampered by an approximate tenfold difference in potency between intact tissue and isolated enzyme systems. Therefore, the purpose of this study was to determine the relationship between cicletanine concentrations in vascular smooth muscle and in tissue bath superfusates. A high‐performance liquid chromatography (HPLC) method was developed that allowed for detection of 1–2 ng of cicletanine in vascular tissue. Incubation of denuded aortic smooth muscle rings from spontaneously hypertensive rats with vasorelaxant concentrations (10–100 μM) of cicletanine resulted in a seven‐ to 12‐fold accumulation of cicletanine in the tissue relative to the tissue bath. Uptake was maximal after 15 min of incubation and was maintained for at least 4 hr in the presence of continuous exposure to cicletanine. Uptake was not stereoselective, since both enantiomers of cicletanine were concentrated to the same extent and at a similar rate. In further studies, the rate of efflux of cicletanine from aortic rings was determined to be roughly the same as the rate of uptake, with a T1/2 of 3 min. These studies demonstrate that cicletanine can be concentrated within vascular smooth muscle to concentrations that are seven‐ to 12‐fold higher than those in a tissue bath. The mechanism responsible for this effect is not known but apparently is not related to differences in the rate of uptake/rate of efflux. These data further suggest that there may be a link between clinically attainable plasma concentrations of cicletanine (roughly 12–80 μM) and vasorelaxation.
Autoimmune mice as models for discovery of drugs against age‐related dementia
Authors: Lal Harbans , Forster Michael J. 
Published: January 2005

AbstractThe discovery and development of drugs to treat Alzheimer's disease and other age‐associated dementias constitute an important goal of research in the pharmaceutical industry. Suitable animal models are routinely sought to expedite the discovery and development processes. The current review proposes new animal models based upon research findings from both clinical and animal investigations which suggest a neuroimmunologic component in certain age‐associated dementias. Several clinical studies are discussed which suggest associations between dementia and brain‐reactive autoantibodies in patients with Alzheimer's disease. In addition, studies of mice suggest that neuroimmunological, neuropathological, and behavioral characteristics of aging are accelerated in genetically autoimmune‐prone mice. The learning and memory deficits of autoimmune mice are qualitatively similar to those of normal aged mice, and these deficits show similar sensitivity to pharmacologic interventions involving cholinergic and GABNbenzodiazepine systems. However, the appearance and progression of these changes with age occur more rapidly and with greater reliability in the autoimmune mice when compared with non‐autoimmune strains. The studies reviewed suggest that autoimmune mice may provide a useful animal model for identification and evaluation of new drugs against learning and memory dysfunctions. In addition, the accelerated decline of learning/memory in autoimmune mice may expedite evaluation of chemical interventions designed to prevent the occurrence or arrest the progress of Alzheimer's disease and other age‐associated dementias. The autoimmune models may be especially appropriate in identifying novel drugs with the immune system as a primary target.
Pharmacological studies of a rat spatial delayed nonmatch‐to‐sample task as an animal model of dementia
Authors: Deacon Robert Michael John 
Published: January 2005

AbstractA variation of the delayed nonmatch‐to‐sample task in rats has recently been described in which the spatial positions of retractable levers are used as the sample and response cues. The pharmacology of this task has been investigated, with the aim of developing models relevant to the search for compounds active in dementia, particularly Alzheimer's disease. Scopolamine and atropine decreased the accuracy of responding. This was attenuated by physostigmine and THA. Mecamylamine, 8‐OH DPAT, CPP, MK‐801, and pentobarbital all produced marked accuracy deficits. Diazepam and sodium valproate affected accuracy rather less. Subthreshold doses of mecamylamine and scopolamine given together produced a significant accuracy deficit. All the drugs tested decreased the total trials performed. Prior satiation experiments demonstrated that this rate decrease in itself did not necessarily cause the decrease in accuracy. CPP and MK‐801 appeared to produce the largest decrease in accuracy, with the least effect on rate. This selectivity, combined with the emerging role of the NMDA receptor complex in learning, memory, and dementia, encourages the development of this model or similar models in the search for compounds with the potential to treat dementia.
Subacute toxicity of aldicarb: Prevention and treatment with memantine and atropine
Authors: Gupta Ramesh C. , Kadel Wade L. 
Published: January 2005

AbstractDaily administration (i.p.) of aldicarb in male Sprague‐Dawley rats at various dosage levels for 21 days revealed (1) 0.1 mg/kg, nontoxic dose; (2) 0.2 mg/kg, moderately toxic dose; and (3) 0.4 mg/kg, severely toxic dose, Inhibition of acetylcholinesterase (AChE) in discrete brain regions and diaphragm muscle was dose dependent. Toxic signs were premdominantly peripheral even though AChE inhibition was significantly higher in the brain (except striatum). Besides AChE inhibition, marked inactivation of carboxylesterases (false targets) was observed, suggesting a protective mechanism especially against low dosage by reducing free concentration of aldicarb. After 30 min following the 7th, 14th, or 21st dose of aldicarb, the degree of inhibition of esterase(s) remained the same, and consequently no tolerance developed to aldicarb. On day 21, administration of memantine HCl (18 mg/kg, i.p.) and atropine sulfate (16 mg/kg, i.p.) 30 min and 15 min, respectively, prior to aldicarb (0.4 mg/kg) injection provided complete protection. Therapeutic administration of these antidotes completly reversed the clinical manifestations of intoxication. The present findings indicated that memantine provided protection and reversal of AChE from inhibition in addition to reversible blockage of hyperneuromuscular activity.
Pharmacological effects of Hoe 249: A new potential antidepressant
Authors: Alpermann Hans Georg , Schacht Ulrich , Usinger Patricia , Hock Franz J. 
Published: January 2005

AbstractThe 1‐(2‐hydroxy‐1‐phenylethyl)‐imidazole derivative Hoe 249 has a profile which suggests the compound is a promising candidate for clinical evaluation as an antidepressant drug. In pharmacological tests commonly considered predictive of antidepressant activity, e.g., reserpine‐ and tetrabenazine‐antagonism, reversal of oxotremorine‐ and apomorphine‐induced hypothermia, and potentiation of yohimbine toxicity, Hoe 249 is equipotent to nomifensine, but does not meet excitation and stereotypic behavior in a comparable dose range. Hoe 249 shows weak anticonvulsant activity against pentylenetetrazole‐induced seizures and it causes a slight dose‐dependent prolongation of hexobarbital narcosis. Biochemical studies characterize Hoe 249 as an inhibitor of synaptosomal dopamine and norepinephrine uptake, whereas serotonin uptake is not influenced. © 1992 Wiley‐Liss, Inc.