bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of antidepressants and related drugs on the quantitatively analyzed EEGs of beagles
Authors: Frankenheim Jerry
Published: January 2005

Power spectral analysis was applied to beagles' EEGs to determine if clinically effective antidepressants produce changes different from those produced by related drugs. Bipolar EEGs were recorded from screws chronically implanted in the skull 5 mm anterior and 10 mm posterior to bregma, 4 mm left of midline. The normalized spectral estimates obtained after intravenous drug injection (minus the temporally corresponding spectral estimates after saline) were averaged across dogs. Drug effects were related to dose and time. Reliable effects of imipramine, amitriptyline, desipramine, and mianserin were an increase in the percent of power in the 4.5–7.5 Hz (theta) band, an increased percent of power in the alpha band at low doses, a decreased percent of power above 22 Hz (beta‐2), and an increased total spectral absolute power, at doses that produced no symptoms. Chlorpromazine's EEG effects were similar to the antidepressants'. Atropine increased percent theta and decreased percent beta‐1 and beta‐2, but was distinguished from the above drugs since it also increased percent delta and produced symptoms at the lowest effective dose. The other drugs either had no effect on percent theta (physostigmine) or decreased it (chlordiazepoxide, dextroamphetamine, and cocaine); cocaine increased only percent delta. Chlordiazepoxide, dextroamphetamine, and physostigmine increased percent beta‐1 and/or beta‐2, and they either decreased total power (dextroamphetamine) or produced no change in this parameter, and thus were distinguished from antidepressants. The results support the conclusion that antidepressants have distinct acute effects on brain electrical activity, and suggest that novel antidepressants can be detected by EEG spectral analysis in dogs.
A sequential model of pharmacologic assays for evaluating myocardial depressant effects of potential cardiovascular drugs
Authors: Kitzen Jan M. , Schwenkler Mary A. , Moeller Janice E. , Novick William J.
Published: January 2005

A model of sequentially arranged pharmacologic assays was developed to evaluate myocardial‐depressant properties of various drugs. The sequence of assays consisted of the following: hemodynamics in normal dogs, hemodynamics in ganglion‐blocked dogs, isolated‐stimulated guinea pig left atria, spontaneously beating guinea pig atria, and an optional follow‐up experiment consisting of hemodynamics in ganglion‐blocked dogs with cardiac pacing. Four reference compounds (clonidine, verapamil, hydralazine, and mixidine) plus a test compound (P79‐4058) were subjected to the test model with the goal of being able to discriminate between various types of myocardial depression. Results from this study indicate that the model was able to separate out three classes of actions: drugs with no depressant activity (hydralazine), drugs that cause myocardial depression indirectly via the nervous system (clonidine), and a third group that elicit myocardial depression directly (verapamil and P79‐4058). Mixidine produced variable results in this model. The proposed model appeared to be adequate in that enough information can be obtained so that new pharmacologic compounds may be evaluated and decisions as to further development can be made.
Effects of N‐substituted analogs of (−)‐α‐acetylmethadol and (−)‐α‐methadol on schedule‐controlled behavior
Authors: McMillan D. E. , Lattin D. L. , Hardwick W. C. , Greene D. L. , Raible P. K. , Richardson J. B.
Published: January 2005

The behavior of the pigeon maintained under a variable‐interval schedule of food presentation was used to compare the activity of four novel N‐substituted acetylmethadol and methadol analogs with that of methadone and (‐)‐α‐acetylmethadol (LAAM). All of the acetylmethadol and methadol analogs had narcotic agonist activity, as defined by the reversibility of their behavioral effects by naloxone. The effect of the N‐substituted analogs on variable‐interval responding was similar to that of methadone and LAAM, but all these compounds had a slower onset of action than methadone and a shorter duration of action than LAAM. None of the N‐substituted analogs showed narcotic antagonist activity when tested against methadone.
The effects of cibenzoline, an imidazoline derivative with antiarrhythmic properties, on systemic hemodynamics and regional myocardial performance
Authors: Verdouw Pieter D. , Hartog Johannes M. , Scheffer Michael G. , Van Bremen Robert H. , Dufour Alain
Published: January 2005

The effects of increasing doses of cibenzoline (‐2(2,2‐diphenylcyclopropyl)‐2‐imidazoline, Cipralan), a new compound with antiarrhythmic properties, on systemic hemodynamics and regional myocardial performance were studied in anesthetized pigs. Doses of 0.5–2.0 mg kg−1 i.v. produced a 10–15% prolongation of the PP' interval, and a dose‐dependent increase (up to 60%) in QRS width, with only minor changes in PQ and ST length. Stroke volume decreased dose dependently (20–35%) immediately after drug administration, due to a decrease in myocardial contractility and an increase in systemic vascular resistance. Renal blood flow was unchanged, despite the decrease in cardiac output. Coronary blood flow decreased, while myocardial O2 extraction was unchanged. Hence myocardial O2 consumption decreased parallel to the decrease in flow, a consequence of the lowered myocardial O2 demand. Studies with radioactively labeled microspheres revealed that the decrease in myocardial blood flow was equally distributed over the transmural layers.
Comparative action of flunarizine, phenytoin, carbamazepine and two calcium‐entry blockers on spontaneous epileptiforrn bursts in the low calcium‐hippocampal slice preparation
Authors: Ashton David , Reid Kenneth , Willems Roland , Marrannes Roger , Wauquier Albert
Published: January 2005

Exposure of hippocampal slices to a medium containing a low Ca2+‐concentration and an increased concentration of Mg2+ and K+ resulted in the blockade of synaptic transmission and the development of spontaneous synchronized epileptiform bursts (SSEB) in area CA1. The SSEBs were measured extracellularly as a negative potential shift with superimposed population spikes. Flunarizine is a “Ca2+‐entry blocker” with antiepileptic actions in humans. We compared flunarizine with two reference antiepileptics (phenytoin and carbamazepine) and two other “Ca2+‐entry blockers” (verapamil and nimodipine) for their ability to reduce SSEBs. Flunarizine, which is insoluble in ACSF bathing medium, was applied in a nanodrop directly onto the CA1 region of the slice. All other drugs were applied in the bathing medium. Flunarizine (1 picomol), phenytoin (2 × 10−5 M), and carbamazepine (5 × 10−6, 5 × 10−5 M) reduced the SSEBs. Nimodipine (1 × 10−5 M) and verapamil (2 × 10−5M) were ineffective. Increases in extracellular K+ occurred synchronously with, and decreases in extracellular Ca2+ followed, negative potential deflections during SSEBs. As the amplitude of potential shifts decreased after flunarizine so did the ion‐shifts. Since changes in Ca2+ and K+ did not occur before changes in potential, modulation of Ca2+ or K+ channels in striatum pyrarnidale is unlikely to explain flunarizine's ability to reduce synchronized bursts. Further, the ability to block Ca2+ channels in the periphery appears to be unrelated to the ability to block SSEBs in this model. It is suggested that reduction of Na+ currents during depolarization may be the basis of the similar effects of phenytoin, carbamazepine and flunarizine in this model.
Triazolo antidepressants do not inhibit monoamine oxidase
Authors: Hyslop Deborah K. , Allen Lloyd E. , Taylor Duncan P.
Published: January 2005

The nontricyclic antidepressant trazodone and the related triazolo antidepressants nefazodone and etoperidone are monoamine uptake inhibitors. We quantified the interaction of these compounds with monoamine oxidases in vitro and in vivo. All three compounds were devoid of activity in these studies. This suggests that the clinical use of trazodone, nefazodone, or etoperidone will not be associated with deleterious dietary interactions seen with monoamine oxidase inhibitor antidepressants.
Ocular hypotensive effects of lofexidine, an alpha2‐adrenoreceptor agonist
Authors: Elko Edward E. , Tran Tung , Lal Harbans , Yorio Thomas
Published: January 2005

The 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

[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

The 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

Behavioral 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

The 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

Cicletanine, 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

Pregnant 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

We 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

CP‐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

The 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

The 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

The 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

The 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.
Hypotensive responses to the putative adenosine A3 receptor agonist N6‐2‐(4‐aminophenyl)‐ethyladenosine in the rat
Authors: Carruthers Alan M. , Fozard John R.
Published: January 2005

The hypotensive response to the putative adenosine A3 receptor agonist, N6‐2‐(4‐aminophenyl)ethyladenosine (APNEA), has been further investigated. In pithed rats with blood pressures maintained at normal values with angiotensin II, the hypotensive response to APNEA was resistant to blockade by 1,3‐dipropyl‐8‐cyclopentylxanthine (DPCPX) at a dose of 0.5 mg kg (1.7 μmol kg) iv, which abolished the bradycardia to APNEA and that to the prototype A1 receptor agonist, N6‐cyclopentyladenosine (CPA). The xanthine‐resistant hypotensive responses to APNEA were broadly similar in pithed animals whose blood pressures were maintained by phenylephrine, clonidine, or the inhibitor of nitric oxide (NO) synthase, NG‐nitro‐L‐arginine methyl ester (L‐NAME). The blocker of ATP‐dependent potassium (KATP) channels, glibenclamide, did not affect the hypotensive response to APNEA in animals infused with angiotensin II. Thus, the xanthine‐resistant hypotensive response to APNEA is not an effect dependent on a particular agonist‐receptor interaction. Neither the release of NO, newly synthesized from L‐arginine, nor activation of glibenclamide‐sensitive KATP channels can explain the putative A3 receptor‐mediated hypotensive response to APNEA. © 1993 wiley‐Liss, Inc.
Acadesine attenuates ischemic cardiac dysfunction in the isolated blood‐perfused rabbit heart
Authors: Young Mark A. , Mazur Curt , Mullane Kevin
Published: January 2005

Acadesine (AICA‐riboside) is a nucleoside analog with cardioprotective properties. Most previous studies demonstrating cardioprotection with acadesine have been conducted in buffer‐perfused hearts, and no study has investigated the dose‐response relationship to acadesine in a blood‐perfused model. The objective of this study was to investigate the dose‐related cardioprotective effects of acadesine in donor‐perfused, isolated rabbit hearts subjected to 12 × 3 min episodes of global ischemia with intervening periods of reperfusion of 5 min duration. Five groups of hearts were studied: saline control and four treatment groups of acadesine, 0.1, 0.2, 0.5, 2.0 gm/kg/min (0.4, 0.8, 2.0, 8.0 μmol/kg/min) constant intravenous infusion to the support animal. Left ventricular (LV) pressure and coronary blood flow (CBF) in the isolated hearts were measured. In control hearts, baseline LV developed pressure averaged 129 ± 7 mmHg and declined to 43 ± 3% of baseline after 12 periods of ischemia and reperfusion. Acadesine significantly improved recovery of function at the lower doses tested, i.e., hearts treated with 0.1, 0.2, and 0.5 mg/kg/min (0.4, 0.8, 2.0 μmol/kg/min) recovered 61 ± 5%, 67 ± 7%, and 65 ± 7% of LV pressure, respectively (P < 0.05 vs. saline). This protective effect was not observed with the highest dose of acadesine, 2.0 mg/kg/min (8.0 μmol/kg/min) (52 ± 6%). The greatest recovery of function corresponded to plasma acadesine concentrations of 27 ± 6.0 μM, but the beneficial effect was lost when plasma concentrations reached 205 ± 28 μM. These results suggest that repetitive episodes of ischemia and reperfusion induced stunning in isolated blood‐perfused rabbit hearts, and that the severity of this dysfunction is attenuated by treatment with acadesine. © 1994 Wiley‐Liss, Inc.
Safety pharmacology of the respiratory system: Techniques and study design
Authors: Murphy Dennis J.
Published: January 2005

The known effects of drugs from a variety of pharmacologic/therapeutic classes on the respiratory system and worldwide regulatory requirements support the need for conducting respiratory evaluations in safety pharmacology. The objective of these studies is to evaluate the potential for drugs to cause secondary pharmacologic or toxicologic effects that influence respiratory function. Changes in respiratory function can result either from alterations in the pumping apparatus that controls the pattern of pulmonary ventilation or from changes in the mechanical properties of the lung that determine the transpulmonary pressures (work) required for lung inflation and deflation. Defects in the pumping apparatus are classified as hypo‐ or hyperventilation syndromes and are evaluated by examining ventilatory parameters in a conscious animal model. The ventilatory parameters include respiratory rate, tidal volume, minute volume, peak (or mean) inspiratory flow, peak (or mean) expiratory flow, and fractional inspiratory time. Defects in mechanical properties of the lung are classified as obstructive or restrictive disorders and can be evaluated in animal models by performing flow‐volume and pressure‐volume maneuvers, respectively. The parameters used to detect airway obstruction include peak expiratory flow, forced expiratory flow at 25 and 75% of forced vital capacity, and a timed forced expiratory volume, while the parameters used to detect lung restriction include total lung capacity, inspiratory capacity, functional residual capacity, and compliance. Measurement of dynamic lung resistance and compliance, obtained continuously during tidal breathing, is an alternative method for evaluating obstructive and restrictive disorders, respectively, and is used when the response to drug treatment is expected to be immediate (within minutes post‐dose). The species used in the safety pharmacology studies conducted in our laboratory are the same as those used in toxicology studies since pharmacokinetic and toxicologic/pathologic data are available in these species. These data can be used to help select test measurement intervals and doses and to aid in the interpretation of functional change. The techniques and procedures for measuring respiratory function parameters are well established in guinea pigs, rats, and dogs.
CL 284,846, a novel sedative‐hypnotic: Evaluation of its metabolites for pharmacological activity in vitro and in vivo
Authors: Vanover Kimberly E. , Mangano Richard M. , Barrett James E.
Published: January 2005

CL 284,846, N‐[3‐3‐cyanopyrazolo[1,5‐a]pyrimidin‐7‐yl(phenyl)]‐N‐ethylacetamide, is a novel non‐benzodiazepine sedative‐hypnotic with benzodiazepine‐like sedative effects, but with less apparent liability for accompanying undesired side effects. Three metabolites of the parent sedative‐hypnotic have been isolated and identified, a desethyl metabolite, CL 284,859, a desethyl‐5‐keto metabolite, CL 345,644, and a 5‐keto metabolite, CL 345,905. In experiments to determine the ability of these compounds to displace [3H]‐flunitrazepam from rat cortical benzodiazepine receptors, the IC50 values were 205 nM for CL 284,846 compared to 4.5 nM for diazepam as a positive control, and 11 μM for CL 284,859. The other two metabolite, CL 345,644 and CL 345,905, failed to displace [3H]‐flunitrazepam. In a second experiment designed to evaluate in vivo receptor‐mediated activity, CL 284,846 (3.0 mg/kg; 9.836 μmol/kg) was established as a discriminative stimulus (DS) in rats. While CL 284,846 (0.03ndash;3.0 mg/kg; 0.098–9.836 μmol/kg) showed a doserelated increase in drug‐appropriate responding and one dose of triazolam (0.3 mg/kg; 0.875 μmol/kg) substituted as a positive control, all three metabolites (3.0–100.0 mg/kg; 10.3–341.3 μmol/kg for CL 284,859; 6.0–201.2 μmol/kg for CL 345,644; 9.3–311.5 μmol/kg for CL 345,905) failed to substitute for the DS effects of CL 284,846. These results suggest that CL 284,859, CL 345,644, and CL 345,905, the metabolites of the sedative‐hypnotic CL 284,846, have no significant neuropharmacological effects at central benzodiazepine receptors and, thus, do not contribute to the activity of the parent compound. © 1994 Wiley‐Liss, Inc.
DIVERSOMERTM technology: Solid phase synthesis, automation, and integration for the generation of chemical diversity
Authors: Dewitt Sheila Hobbs , Schroeder Mel C. , Stankovic Charles J. , Strode John E. , Czarnik Anthony W.
Published: January 2005

The drug discovery process depends upon the synthesis and testing of thousands of compounds to bring a new drug through discovery, clinical testing, development, and FDA approval. Recent advances in high throughput screening have created the need for the accelerated synthesis of small organic molecules. By combining solid phase chemistry, organic synthesis, and automation with a unique apparatus capable of performing techniques common to organic synthesis, “libraries” of organic compounds (DIVERSOMERSTM) are efficiently generated. This was demonstrated by the multiple simultaneous synthesis of 40 hydantoins and 40 benzodiazepines, related to Dilantin® and Valium®, respectively. © 1994 Wiley‐Less, Inc.
D2 and 5‐HT2 modulation of psychostimulant‐induced facilitation of brain stimulation reward
Authors: Tsibulsky Vladimir , Dashevsky Boris , Frank Robert A.
Published: January 2005

Previous research in our laboratory demonstrated that mixed D2/5‐HT2 antagonists (i.e., MDL 28, 133A, and risperidone) attenuate both amphetamine and cocaine‐induced facilitation of brain stimulation reward. The relative contributions of dopaminergic and serotonergic antagonism to these effects was assessed in the present study. Factorial combinations of the D2 antagonist eticlopride and the 5‐HT2 antagonist MDL 100,907 were evaluated for their ability to reverse both cocaine and amphetamine‐induced facilitation of brain stimulation reward. Eticlopride significantly reduced the effects of both amphetamine and cocaine, while MDL 100,907 had no effect on self‐stimulation thresholds when administered alone, or in combination with eticlopride. Thus, no evidence for serotonergic regulation of the euphoric effects of psychostimulants was obtained. © 1995 Wiley‐Liss, Inc.
Profile of analgesic interaction between aspirin and d‐propoxyphene obtained by means of the surface of synergistic interaction
Authors: López‐Muñoz Francisco J.
Published: January 2005

The analgesic effects of aspirin [acetyl salicylic acid (ASA)] and d‐propoxyphene (PROP) administered either separately or in 24 different combinations were determined in the pain‐induced functional impairment in the rat (PIFIR) model. This allowed the detection of the profile of analgesic interaction of the combinations. Furthermore, we set out to determine the optimal degree of potentiation obtained with a specific combination of the above drugs by means of the surface of synergistic interaction of the combinations. This parameter was calculated from the total analgesic effect produced by the combination after having subtracted the analgesic effect produced by each drug alone. The ED50 for ASA and PROP were 210.4 ± 1.2 and 66.3 ± 1.2 mg/kg, respectively. Over the dose ranges used, the analgesic activities of either ASA or PROP tended to be smaller than those of their respective combinations. Furthermore, 10 combinations showed various degrees of potentiation (P < 0.01), while the others (14) exhibited additive analgesic effects. The combination of ASA (562.3 mg/kg, po) and PROP (31.6 mg/kg, sc) produced the maximum analgesic effect. However, 5 combinations of ASA with PROP (56.2–56.2, 100–56.2, 177.8–56.2,316.2–56.2, and 177.8–31.6 mg/kg) produced the highest potentiation effects. The surface of synergistic interaction clearly showed which combination of these analgesic drugs produced the highest degree of potentiation in the rat. This study shows that a specific ratio of combination of analgesic drugs can produce optimum potentiation of their analgesic effects. © 1995 Wiley‐Liss, Inc.
Clinical and regulatory perspectives on general/safety pharmacology tests: Results of a pharmaceutical industry survey
Authors: Murphy Dennis J. , Gossett Kent A. , Kerns William D.
Published: January 2005

General/safety pharmacology is an emerging discipline within the pharmaceutical industry in which unanticipated effects of new drug candidates on major organ function (i.e., secondary pharmacological effects) are critically assessed in a variety of animal models. A survey was conducted to obtain customer input on the role and strategies of this emerging discipline. Four surveys were distributed to each of 30 U.S. pharmaceutical companies. Two surveys went to individuals within the regulatory department, and two went to individuals within the clinical department of each company. All responses were returned anonymously to the survey authors. Sixty‐six responses from at least 19 different companies were obtained. The responses from the clinical and regulatory departments were essentially the same and led to the following conclusions: (1) Major organ functions are monitored routinely in clinical trials to assess potential adverse drug effects; (2) major organ function studies are considered an essential part of non‐clinical drug safety testing; (3) respiratory, gastrointestinal, autonomic, and endocrine evaluations are considered an important part of major organ function studies, whereas cardiovascular, renal and central nervous evaluations are considered essential; (4) non‐clinical testing of these major organ functions should be conducted early in drug development, preferably before initiation of clinical trials; and (5) organ function investigations involving mechanisms of secondary pharmacological effects or drug interaction are considered an important part of general/safety pharmacology testing. © 1995 Wiley‐Liss, Inc.
Effect of cutaneous stimulation on the development of misdirected wiping reflexes in skin‐grafted Discoglossus pictus
Authors: Baker Robert E. , Veltman Wim A. M. , Corner Michael A.
Published: January 2005

The frog, Discoglossus pictus, has been studied with respect to wiping reflex behavior developing after skin rotations performed at larval stages. Misdirected wiping reflexes were obtained only from belly skin‐grafts placed on the animals's back; back skin‐grafts on the belly failed to elicit any misdirected limb movements in this species. We found that misdirected reflexes occurred more readily in 3‐week and older animals if not subjected to any previous test experience, than in younger naive frogs. Frogs that had been exposed to daily cutaneous stimulation between 2 to 4 weeks after metamorphosis showed a delayed development of misdirected responses.
System organization of alimentary behavior in the newborn and the developing cat
Authors: Anokhin Peter K. , Shuleikina Kira V.
Published: January 2005

This review deals with the structural, behavioral, and EEG correlates of searching for food and food intake. Data were collected on freely behaving kittens of 1 to 60 days of age with chronically implanted electrodes. The 1st manifestations of hunger involve activation of limbicreticular structures and electroencephalographic (EEG) activity consisting of fast oscillations of 30–40–60 cps, correlated with general behavioral arousal as manifested by motor restlessness and vocal reactions. The more specific behavior form of hunger‐feeding motivation‐involves structures that include the motor and parietal cortex, amygdala, and medial hypothalamus; the EEG activity consists of high‐amplitude, slow waves of 3–6 or 6–8 cps; and the behavioral correlate is purposeful search for the mother's teat or food. Satiation is associated with activity of the synchronizing structures in the forebrain and lower brain stem, as well as in the relay nuclei that transmit the sensory flow from oral afferents; EEG activity consists of regular rhythms of 10–14 and 2–4 cps; and the behavioral correlate is the act of feeding.