bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ocular hypotensive effects of lofexidine, an alpha2‐adrenoreceptor agonist
Authors: Elko Edward E. , Tran Tung , Lal Harbans , Yorio Thomas 
Published: January 2005

AbstractThe present study examines the ocular hypotensive efficacy end pupillary response of the alpha2‐adrenergic receptor agonists lofexidine and clonidine. The topical administration of lofexidine to rabbit eyes in concentrations ranging from 0.25 to 5%, produced a dosedependent bilateral reduction in intraocular pressure (IOP), with the contralateral (untreated) eye exhibiting a significantly greater reduction in IOP than the ipsilateral (treated) eye, particularly at the lower concentrations. The maximum decrease in IOP was observed at 60 min postdrug with the IOP recovering gradually to predrug values with time. Pupillary dilatation was observed only in the durg‐treated eye. Unlike lofexidine, clonidine had no effect on pupillalry diameter. Clonidine decreaed IOP predominantly in the untereated contralateral eye at doses ranging from 0.625% to 5%, whereas a significant ocular hypertensive effect of clonidine was noted at the 7.5% dose in the treated ipsilateral eye. The present data provide evidence that topically administered lofexidine lowers IOP in normotensive New Zealand White (NZW) rabbits.
Species differences in high‐affinity adenosine A2 binding sites in striatal membranes from mammalian brain
Authors: Stone George A. , Jarvis Michael F. , Sills Matthew A. , Weeks Barbara , Snowhill Elaine W. , Williams Michael 
Published: January 2005

Abstract[3H]5′‐N‐Ethylcarboxamidoadenosine (NECA) labels both A1 and A2 adenosine receptors in mammalian brain tissue. In the presence of 50 nM N6‐cyclopentyladenosine (CPA), however, to block selectively the A1 component of binding, [3H]NECA labels two binding components in striatal tissue. Such binding is dependent on the presence of Mg2+ ions and the removal of endogenous adenosine, using the catabolic enzyme, adenosine deaminase. The two binding components were observed in six mammalian species–‐rabbit, man, rat, mouse, guinea pig, and calf–‐with dissociation constants varying between 3.2 and 9.6 nM for the higher‐affinity site and 54 and 232 nM for the lower‐affinity site. In rat brain tissue, specific binding was reduced by the presence of 5′ guanylyimidodiphosphate Gpp(NH)p, indicating the involvement of a G‐protein. Gpp(NH)p effects were attributable to a conversion of a proportion of high‐affinity to low‐affinity components, as determined by saturation experiments. These results, together with the observation that Gpp(NH)p shifted the inhibition curve for the agonist, 2‐chloro‐adenosine(2‐CADO), to the right indicate that the sites labeled by [3H]NECA in the presence of 50 nM CPA represent multiple affinity states rather than multiple receptor subtypes.Pharmacological examination of the higher‐affinity binding component using 2 nM [3H]NECA showed that binding was consistent with the labeling of an A2 adenosine receptor in all species. The order of activity for adenosine agonists was NECA > 2‐CADO > R‐phenylisopropyladenosine (R‐PIA) > N6cyclohexyladenosine ≥ CPA » S‐PIA. The activity ratios of the diastereomers of PIA (SIR) varied between 7.9 (mouse) and 14.5 (rat). The interaction of a series of 8‐phenyl‐substituted xanthines showed marked species differences with 1,3‐dipropyl‐8‐(2‐amino‐4‐chloro) phenylxanthine (PACPX) being the most active at 14‐15 nM in rabbit and man, 3‐fold less active in calf, and 24‐40‐fold less active in guinea pig, mouse, and rat. A similar trend was seen for 8‐phenyltheophylline (8‐PT), 8‐para‐sulfo‐phenyltheophylline (8‐PST), and 1,3‐diethyl‐8‐phenylxanthine (DPX), the relative order of activity of these adenosine antagonists being PACPX > 8‐PT 2 DPX 2 8‐PST. Caffeine and theophylline were much less active (1C50 > 10,000 nM), while the phosphodiesterase inhibitor 3‐isobutyl‐1 ‐methyl xanthine (IBMX IC50, 2,257‐4,410 nM) was 2‐3 times more potent in man and calf than in the other species studied.
Comparison of cocaine and procaine discriminative stimuli
Authors: Silverman Peter B. , Schultz Kem A. 
Published: January 2005

AbstractThe discriminative stimulus, abuse potential, and locomotor‐activating properties of cocaine have all been attributed to dopaminergic activity. Unexplained are findings that the local anesthetic, procaine, with little or no documented dopamine agonist activity, has stimulus properties similar to cocaine and is also self‐administered. The purpose of the work described here was to compare the discriminative stimulus properties of cocaine and procaine and the ability of procaine and other local anesthetics to induce rotational (circling) behavior in unilaterally 6‐hydroxydopamine‐lesioned rats. Rats were trained in a two‐lever, food‐reinforced, operant task to discriminate either cocaine (10 mg/kg, i.p.) or procaine (54.6 mg/kg, i.p.) from saline. Results show that cocaine and procaine have similar stimulus properties, administration of either resulting in partial generalization to the other. Cocainetrained animals generalized perfectly to the psychomotor stimulants amphetamine and methylphenidate. Haloperidol more effectively blocked cocaine than procaine. The alphaadrenergic blocker phentolamine was ineffective against either training drug. Apomorphine, caffeine, and nisoxetine yielded partial generalization to both of the training drugs. Upon acute administration, the local anesthetics other than cocaine showed no significant ability to induce rotation in lesioned rats.
Analysis of behavioral effects of drugs
Authors: Witkin Jeffrey M. , Katz Jonathan L. 
Published: January 2005

AbstractBehavioral pharmacology has largely replaced explanations of the behavioral effects of drugs in terms of hypothetical constructs with descriptions of the environmental or behavioral factors that modify drug effects and by characterization of behavioral mechanisms of drug action. The qualitative and quantitative modulation of behavioral effects of drugs by current and past behavioral and environmental variables has been amply demonstrated. However, fewer studies have been directed toward elucidation of behavioral mechanisms of drug action. The concept of behavioral mechanism implies that drugs can alter behavior in a manner functionally equivalent to the manner in which other variables alter behavior. Owing to the complexity of the determinants of behavior, a host of tactics is required for a comprehensive analysis of the behavioral effects of drugs. Detailed understanding of the various interpretations associated with the results of descriptive and mechanistic studies is essential to the development of adequate accounts of the manner in which drugs affect behavior. Studies elucidating the behavioral or environmental factors that influence the behavioral effects of drugs as well as studies of behavioral mechanisms of drug action may aid other disciplines within pharmacology and the neurosciences by ultimately pinpointing specific behavioral substrates of drug action. This information should greatly facilitate further investigations of the link between behavior and physiological processes as well as provide rational bases for development.
Novel long‐acting benzodiazepine receptor ligands Ro 41‐7812 and Ro 42‐8773: Neurological and behavioral profile
Authors: Moreau Jean‐Luc , Jenck François , Bonetti Erico P. , Martin James R. , Haefely Willy E. 
Published: January 2005

AbstractThe pharmacological profiles of two novel benzodiazepine receptor ligands, Ro 41‐7812 and Ro 42‐8773, were assessed in various tests in mice, rats, and monkeys. Both compounds were orally active, exhibiting clear anticonvulsant activity within a dose range devoid of sedation or motor impairment, as well as effects in an operant conflict test and in a palatable food consumption paradigm. Furthermore, these two compounds attenuated, with a long duration of action, the sedation and motor impairment induced by classical benzodiazepine receptor full agonists but failed to exhibit proconvulsant activity even at high doses. Thus, despite a predominantly antagonist pharmacological profile, these two benzodiazepine receptor ligands appear to exhibit relatively clear anticonvulsant effects and might prove to be of value in the treatment of epilepsies.
Comparative hemodynamic and renal effects of the low Km cGMP phosphodiesterase inhibitors cicletanine and zaprinast in anesthetized dogs
Authors: Lee King C. , Canniff Paul C. , Hamel Douglas W. , Pagani Edward D. , Gorcyzca William P. , Ezrin Alan M. , Silver Paul J. 
Published: January 2005

AbstractCicletanine, a vasorelaxant/natriuretic agent, inhibits low Km cGMP/phosphodiesterase (PDE) (IC50 = 300 μ). The objectives of this study were to compare the cardiovascular and renal effects of cicletanine with another cGMP‐PDE inhibitor, zaprinast (IC50 = 0.3 μ), at intravenous dosages of 0.3–3 mg/kg, and to examine the influence of β‐adreno‐receptor blockade (nadolol, 1 mg/kg, i.v.) upon the responses to cicletanine in anesthetized dogs. Cicletanine (3 mg/kg) and zaprinast (0.3−3 mg/kg) decreased mean arterial pressure (−21.2±3.9 mm Hg [mean±SEM, max. change] at 3 mg/kg and −64.7 ± 4.8 mm Hg at 0.3 mg/kg, respectively). The response curve of zaprinast was negatively related to the dosages. Cardiac output was increased or tended to increase by approximately 0.3 liter/min by both cicletanine and zaprinast at 3 mg/kg. Renal, but not femoral, blood flow was increased by both cicletanine and zaprinast (18.8±3.7 ml/min at 3 mg/kg and 17.0±4.6 ml/min at 1 mg/kg, respectively). These agents did not have major effects upon heart rate, left ventricular end diastolic pressure, and maximum rates of rise and decline in left ventricular pressure. These agents also did not affect pulmonary systolic, mean and diastolic arterial pressures, nor arterial blood pO2, pCO2, and pH. Both cicletanine and zaprinast increased or tended to increase urinary output (0.66±0.05 and 0.43±0.22 ml/min, respectively, both at 3 mg /kg) and urinary Na+ excretion (150.4±19.7 and 67.0±30.9 μEq/min, respectively, both at 3 mg/kg). Neither agents affected urinary K+ excretion. None of the responses to cicletanine were altered by β‐, suggesting that β‐ adrenoreceptors were not in volved in mediating the affects of cicletanine. In conclusion, the cGMP‐PDE inhibitors cicletanine and zaprinast vasodilate, increase renal blood flow, and induce diuresis and natrluresis in anesthetized dogs. However, the differences in the natriuretic and vasodilator effects of these agents cannot be explained by the difference in their potencies in PDE inhibition, suggesting that their effects in these dogs may involve additional mechanisms of action.
Prenatal ganglioside GM1 treatment protects ethanol‐induced sleep time in rats exposed to ethanol in utero during gestation days 7 and 8
Authors: Hungund Basalingappa L. , Gokhale Vinayak S. , Cooper Thomas B. , Mahadik Sahebarao P. 
Published: January 2005

AbstractPregnant rats were treated with ethanol intragastrically (5.8 g/kg in two divided doses) spaced 4 hr apart on gestation days (GD) 7 and 8. Ganglioside GM1 was injected (10 mg/kg, IM) 24 hr and 1 hr prior to ethanol on GD7 and 1 hr prior on GD8. The controls received saline only. Maternal blood alcohol reached peak levels of 4.3 mg/ml within 2 hr in both groups. There were no significant differences between the groups gain body weight, gestation time, or the litter size. There were also no significant differences in birth weight and the brain weight of the pups. At the age of 45 days, equal number of male offspring from each group were tested for hypnotic effect (sleep time) of ethanol challenge dose (3.5 g/kg). Animals that received ethanol alone in utero had a shorter sleep time compared to no ethanol controls (81 ± 19 and 130 ± 28 min respectively, P<.01). Ganglioside GM1 treated animals had sleep time similar to that of controls (131 ± 21 min). There were no significant differences in wakeup blood alcohol the groups. These results indicate that pretreatment with GM1 ganglioside of maternal rats antagonized decrease in sleep time in offspring induced by prenatal ethanol exposure.
Effect of a novel calcium antagonist AE0047 on several models of cerebral ischemia
Authors: Yamanaga Katsumi , Ohtaki Yutaka , Uchida Takeshi , Watanabe Masahiro 
Published: January 2005

AbstractWe examined the cerebral protective effects of AE0047 employing cerebral ischemia models. In the bilateral carotid arterial occlusion model (BCAO) employing spontaneously hypertensive rats (SHRs), oral administration of AE0047 (0.1–0.3 mg/kg) or nicardipine (3 mg/kg) improved the neurological symptoms by 2 hr after the BCAO procedure and energy metabolite changes 30 min after the BCAO procedure. AE0047 was significantly effective in these 2 models at one‐tenth the dosage of nicardipine. Dihydroergotoxine completely protected in an adrenaline‐induced lethality model. AE0047 also showed a protective action in this model and is considered to have an α‐adrenergic blocking action similar to dihydroergotoxine. In the KCN‐induced abnormal behavior (the coma and the disappearance of searching behavior) and death models, protective effects were observed in the AE0047 group, but not in the nicardipine group. Protective action was marked even 2–4 hr after AE0047 administration. Dihydroergotoxine also shortened the duration of coma and prolonged the survival time, but had no effect on mortality. From these results, it is suggested that the α‐adrenergic blocking action of AE0047 participates in the antihypertensive action. The protective effects of AE0047 were most striking at 2 and 4 hr after AE0047 administration. © 1992 Wiley‐Liss, Inc.
Biochemical and behavioral studies of the 5‐HT1B receptor agonist, CP‐94,253
Authors: Koe B. Kenneth , Nielsen Jann A. , Macor John E. , Heym James 
Published: January 2005

AbstractCP‐94,253, 3‐(1,2,5,6‐tetrahydro‐4‐pyridyl)‐5‐propoxypyrrolo[3,2‐b]pyridine, a new serotonergic ligand, was found to exhibit significantly greater binding affinity at 5‐HT1B receptors than at 5‐HT1A or 5‐HT1C receptors. Saturation studies showed CP‐94,253 to be a competitive inhibitor of [125l]iodocyanopindolol binding to 5‐HT1B sites. Its competition curve with this radioligand was shifted to the right (decreased affinity) in the presence of Gpp(NH)p, indicating an agonist function for CP‐94,253. Oral administration of CP‐94,253 to rats caused inhibition of food intake, decrease in body weight gain, and hyperlocomotion, effects apparently elicited via activation of 5‐HT1B receptors. © 1992 Wiley‐Liss, Inc.
Characterization of the unusual antinociceptive profile of tramadol in mice
Authors: Mattia Antonia , Vanderah Todd , Raffa Robert B. , Vaught Jeffry L. , Tallarida Ronald J. , Porreca Frank 
Published: January 2005

AbstractThe present study characterized the antinociceptive effects of tramadol with emphasis on the site of action, the possible development of antinociceptive tolerance, and possible cross‐tolerance to morphine. Both tramadol and morphine produced antinociception as assessed in male, ICR mice using the warm water (55°C) tail‐flick test. Intrathecal (i.t.) tramadol produced an antinociceptive response, but with a shallow dose‐response curve (DRC), but i.c.v. tramadol was ineffective up to toxic doses (> 380 nmol). Simultaneous co‐administration of tramadol by the i.c.v. and i.t. routes in a 1:1 fixed dose‐ratio resulted in a synergistic interaction. Construction of a naloxone dose‐response curve against an A90 dose of agonist yielded an AD50 (and 95% C.L.) of 0.19 (0.14–0.33) and 0.55 (0.38–0.74) μmol/kg against morphine and tramadol, respectively; both agonists were completely antagonized by naloxone. In mice pretreated twice daily (8:00 a.m. and 5:00 p.m.) with s.c. morphine the DRC for morphine was displaced 16‐fold to the right, indicating significant development of antinociceptive tolerance. The same pretreatment resulted in only a 3‐fold right‐ward shift in the tramadol DRC. Chronic twice‐daily (8:00 a.m. and 5:00 p.m.) pretreatment with tramadol resulted in only an approximate 3‐ and 4‐fold rightward displacement in the tramadol and morphine DRCs, respectively. These results suggest that tramadol has an unusual antinociceptive mechanism which may reflect a primary site of action at spinal sites with a synergistic spinal/supraspinal interaction. Further, the lack of complete cross‐tolerance between tramadol and morphine supports the suggestion of a non‐opioid mechanism for this compound, whereas the complete antagonism by naloxone apparently reflects the opioid component of its mechanism in this test. Finally, the minimal development of tolerance to tramadol antinociception reinforces the view of a favorable tolerance‐dependence profile for this compound. © 1993 Wiley‐Liss, Inc.
Purinergic receptors in the nucleus tractus solitarius mediate distinct cardiorespiratory response patterns
Authors: Barraco Robin , Ergene Erhan , El‐Ridi Mamdouh 
Published: January 2005

AbstractThe purpose of the study was to examine the role of brainstem purinergic receptors in mechanisms of cardiorespiratory control mediated by the nucleus tractus solitarius (NTS), the major integrative site in the brainstem involved in the regulation of cardiorespiratory function and the reflex coordination of cardiorespiratory response patterns. Microinjections of selective agonists for purinergic receptor subtypes were made into the caudal NTS of anesthetized, spontaneous breathing rats. CGS 21680, a selective agonist for adenosine A2a receptors, elicited pronounced, dose‐related decreases in blood pressure, whereas cyclopentyladenosine (CPA), a selective agonist at adenosine A1 receptors, elicited dose‐related increases in blood pressure. These depressor and pressor response patterns were completely and selectively blocked, respectively, by pretreatment with CGS 15943a, a selective A2a receptor antagonist, and by 1,3‐dipropyl‐8‐cyclopentylxanthine (DPCPX) a selective A1 receptor antagonist. 5′‐N‐ethylcarboxamidoadenosine (NECA), an analog exhibiting mixed agonist actions at adenosine receptor subtypes, elicited both depressor and pressor responses depending on the dosage. Additionally, in contrast to the findings with CGS 21680 and CPA, only NECA elicited very pronounced, dose‐related decreases in respiratory rate at dosages which did not affect blood pressure. Related lines of evidence suggested that NECA‐induced depression of respiration was mediated via A2b receptors. Microinjections of α,β‐MeATP, a selective agonist for P2x receptors, elicited apnea, and these effects were blocked by suramin, a selective antagonist at P2x receptors, but not by DMPX, a methylxanthine exhibiting mixed antagonist properties at P1 adenosine receptors. Moreover, similar microinjections of 2‐MeSATP, a selective agonist at P2x receptors, were ineffective in eliciting cardiorespiratory response patterns and it is likely that brainstem purinergic receptors may therefore play a crucial role under both physiologic and pathophysiologic conditions. © 1993 Wiley‐Liss, Inc.
Purinergic drugs: Opportunities in the 1990s
Authors: Williams Michael 
Published: January 2005

AbstractThe premise that purinergic nucleosides and nucleotides subserve roles as autocrine agents, neurotransmitters, or neuromodulators has been well established over the past 20 years. Mechanistically, adenosine, the endogenous ligand for P1 type purinoceptors, acts to modulate the release of a variety of neurotransmitters as well as modulating the effects of such agents at the postsynaptic level. P2 receptor agonists, including ATP and ADP, appear to act more like traditional neurotransmitters undergoing quantal release and producing their effects directly through G‐protein linked receptors or ligand gated ion channels. There is, however, little direct evidence at this time for pathophysiologies directly attributable to purinoceptor malfunction.Nonetheless, the adenosine formed from ATP breakdown appears to play a protective role in hypoxic and ischemic situations. And adenosine A1 agonists as well as agents that act to potentiate the actions of endogenous adenosine (AICA riboside, adenosine uptake blockers, adenosine kinase inhibitors etc.) are being evaluated for use in stroke and reperfusion injury.A1 receptor agonists may also have potential as anticonvulsants and in the treatment of type II diabetes. A2a receptor ligands because of their unique co‐localization with D2 receptor containing neurons in the striatopalladial pathway of the basal ganglia may have potential use in the treatment of diseases involving dopaminergic malfunction for instance, Parkinsonism and schizophrenia.Agonists therapy may, however, be limited by the non‐specific actions of agonists at nontarget tissues and the tolerance typically associated with chronic agonist therapy. As a result, there is increased focus on indirect modulation of adenosine systems by either adenosine potentiators or allosteric modulators, the latter class including PD 81, 723 and the newly discovered peptide, adenoregulin.Approaches to adenosine antagonists and therapeutic agents have resulted in the identification of 8‐substituted xanthines including KFM 19 and MDL 102, 234 that are currently being evaluated as cognition enhancers with potential use in Alzheimer's disease.While chemistry in the area of P2 purinoceptor has been limited, ATP itself may have potential use in the treatment of cancer and shock. Continued progress in the understanding of the physiological role of the various classes of purinoceptor has the potential to lead to novel therapeutics in the 1990s. © 1993 Wiley‐Liss, Inc.
Analgesic effects of combinations containing opioid drugs with either aspirin or acetaminophen in the rat
Authors: López‐Muñoz Francisco J. , Castañeda‐Hernández Gilberto , Villalón Carlos M. , Terrón José A. , Salazar Luis A. 
Published: January 2005

AbstractThe analgesic effects of combinations of either aspirin or acetaminophen with morphine, d‐propoxyphene, and pentazocine were studied in the pain‐induced functional impairment in the rat model (PIFIR). Pain was induced by the intra‐articular injection of uric acid in the right hind limb inducing its dysfunction. Animals then received analgesic agents, and the recovery of functionality over time was assessed as an expression of analgesia. The combination of aspirin with either morphine or d‐propoxyphene resulted in analgesic effects similar to those expected on the basis of addition of the effects of the individual component drugs. However, the combination of aspirin with either morphine or d‐propoxyphene resulted in analgesic effects similar to those expected on the basis of addition of the effects of the individual component drugs. However, the combination of aspirin and pentazocine resulted in a potentiation (46%), the observed analgesia being significantly greater than the expected effect. Coadministration of acetaminophen and morphine resulted in an analgesic effect that was not different from that expected on the basis of addition, whereas acetaminophen with d‐propoxyphene resulted in a lower effect (21%). Moreover, the combination of acetaminophen and pentazocine resulted in a lower effect (21%). Moreover, the combination of acetaminophen and pentazocine resulted in an effect that was similar to that seen with either acetaminophen or pentazocine alone. The percent change in combination was 41% lower than the addition of the individual effects. It appears that, while certain combinations of opioids and nonsteroidal anti‐inflammatory drugs (NSAIDs) may be beneficial, other combinations may be detrimental. Therefore, great care should be taken in the choice of the components of analgesic drug mixtures. Preclinical pharmacological information about the efficacy of drug associations should be taken into consideration before testing in humans. © 1993 Wiley‐Liss, Inc.