bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of p‐chloroamphetamine on morphine withdrawal syndrome
Authors: Lal Harbans , Reddy Chejerla
Published: January 2005

Adult male rats were injected four times a day with increasing doses of morphine sulfate until a dose of 405 mg/kg/day was tolerated. After 5 days of maintenance at that dose, withdrawal signs were observed at 24, 48, and 72 hr of withdrawal. Given 4 or 18 hr after last morphine injection, a single administration (3–12 mg/kg) of p‐chloroamphetamine (PCA) blocked withdrawal “wet shakes” and ptosis during the following withdrawal period. Dose‐dependent reduction in withdrawal hypothermia was observed only at 24 hr of withdrawal. Writhing was blocked only at higher doses. Morphine‐withdrawal aggression measured at 72 hr of withdrawal and loss in body weight were not blocked by any delayed action of PCA. However, withdrawal aggression was blocked by PCA when given 1 hr before measurement at a dose of 3 mg/kg. Mice that were made morphine dependent by repeated injections of morphine given in large doses, exhibited withdrawal jumping either after cessation of morphine injections, or on injection of naloxone. PCA (3–12 mg/kg) given 2 hr before naloxone blocked this jumping in a dose‐dependent manner. It also blocked withdrawal jumping in morphine‐deprived mice when injected 2 hr, but not 14 or 17 hr before measurement. Jumping induced by α‐naphthyloxyacetic acid (α‐NOAA) was not blocked. The effect of PCA on different signs of morphine withdrawal is time dependent and may be related to its similarly time‐dependent effect on brain serotonin and dopamine.
Cholinergic agents: Deficits in rat hippocampal choline acetyltransferase activity and spatial working memory induced by intracerebroventricular administration of stoichiometrically prepared 1‐ethyl‐1‐(2‐hydroxyethyl) aziridinium ion (AF64A)
Authors: Moos Walter H. , Davis Robert E. , Kinsora Jack J. , Schwarz Roy D. , Smith Melvin E. , Spencer Carolyn J.
Published: January 2005

A simplified procedure for preparing the cholinergic neurotoxin 1‐ethyl‐1‐(2‐hydroxyethyl) aziridinium ion (AF64A) is reported that employs stoichiometric base. When injected intracerebroventricularly into rats, stoichiometrically prepared AF64A causes impairments in spatial working memory in a water‐maze task. The behavioral changes are paralleled by deficits in hippocampal choline acetyltransferase activity, a neurochemical marker of the resulting cholinergic dysfunction.
Absence of anxiolytic effects of calcium channel antagonists
Authors: de Angelis L.
Published: January 2005

The potential anxiolytic effects of some calcium channel antagonists (nifedipine, nicardipine, and ±verapamil) were investigated in the elevated plus‐maze test in mice. The acute effects of the above‐mentioned drugs were compared with those of phenobarbitone and ±propanolol. Results showed that control mice spent less time in the open than in the closed arms, reflecting increased anxiety. Both phenobarbitone (20 mg/kg i.p.) and ±propanolol (5 mg/kg i.p.) increased the percentage of entries into open arms as well as the time spent on the open arms. Nifedipine (2 and 4 mg/kg i.p.), nicardipine (0.5 and 1.0 mg/kg i.p.), and ±verapamil (5 and 10 mg/kg i.p.) failed to alter significantly the behavior of mice. In summary, although there have been some reports based on other tests that calcium antagonists may have potential anxiolytic properties, this conclusion has not been supported by our results from the elevated plus‐maze test.
Cerebral metabolic effects of CI‐943 (8‐Ethyl‐7,8‐dihydro‐1,3,5‐trimethyl‐1Himidazo[1,2,‐c]pyrazolo[3,4‐e]‐pyrimidine), a potential antipsychotic drug
Authors: Kimes Alane S. , Raymon Lionel P. , Meltzer Leonard T. , Heffner Thomas , London Edythe D.
Published: January 2005

CI‐943 is a novel drug candidate that has antipsychotic‐like activity in a variety of behavioral tests in rodents and primates, but has no affinity for brain dopamine (DA) receptors. In order to obtain information on the neuroanatomical substrates for its behavioral actions, we used the autoradiographic 2‐deoxy‐D‐[1‐14C]‐glucose method to map and quantify the distribution of CI‐943 effects on the regional cerebral metabolic rate(s) for glucose (rCMRglc) in the rat. The effects of CI‐943 (40 mg/kg) were assessed at 10 and at 60 min after the drug was administered intraperitoneally. In the globus pallidus and the substantia nigra pars reticulata, rCMRglc were increased at 60 min following treatment, and in the lateral habenula, rCMRglc was increased at 10 and 60 min after treatment. In contrast, the predominant effect of CI‐943 in other areas (e.g., most cortical, several thalamic, basal ganglia, limbic, and midbrain areas) was to reduce rCMRglc. The metabolic pattern produced by CI‐943 was unique and consistent with previous findings that CI‐943 resembles other antipsychotic drugs in behavioral tests but differs from those agents in tests prodictive of extrapyramidal dysfunction.
Comparison of the in vivo pharmacological profiles of sabeluzole and its enantiomers
Authors: Werbrouck Leen , Megens Anton A. H. P. , Stokbroekx Raymond A. , Niemegeers Carlos J. E.
Published: January 2005

Sabeluzole, a compound with pronounced cognitive enhancing, antihypoxic, and anticonvulsant properties, is the racemic mixture of the enantiomers R 84 439 (R‐configuration) and R 84 440 (S‐configuration). Sabeluzole and its separate enantiomers were compared in tests evaluating cognitive enhancing, antihypoxic, anticonvulsant, and secondary activity. Only small differences in potency were observed over species (mice, guinea pigs, and rats), routes of administration (i.p., s.c., and p.o.), and time intervals (ranging from 0.5 to 16 hr). R 84 440 was generally slightly more potent (up to 2.6 times) but also slightly shorter acting than R 84 439 (5 vs. 7 hr after s.c. administration in rats). The present data confirm and further extend the pharmacological profile of sabeluzole and indicate that both enantiomers contribute to its biological activity. Selection of one of the enantiomers instead of racemic sabeluzole provides no practical advantage in terms of potency, onset and duration of action, oral absorption, or therapeutic index.
Stereoselective antihypertensive effects of the calcium channel blocker RO 23‐6152 in two models of renin‐dependent hypertension
Authors: Dundore Ronald L. , Cox Bryan F. , Klevans Larry R. , Brody Michael J.
Published: January 2005

To compare antihypertensive effects, captopril, (+) diltiazem, the (+) and (−) enantiomers, and the racemic mixture of RO 23‐6152, 0.1–10 mg/kg, were administered intravenously to rats made hypertensive by occlusion of the abdominal aorta or by constriction of a renal artery. All drugs, with the exception of (−) RO 23‐6152, significantly decreased mean arterial pressure (MAP) and increased heart rate (HR). The (−) enantiomer of RO 23‐6152, 3 and 10 mg/kg, significantly increased MAP and decreased HR. Within the dosage range investigated (0.1–10 mg/kg), captopril, (+) diltiazem, and (+) RO 23‐6152 produced similar decreases in MAP. However, the racemate of RO 23‐6152 was significantly less effective in reducing MAP than (+) RO 23‐6152. We conclude that, with regard to antihypertensive activity, (+) RO 23‐6152 is as effective as captopril and (+) diltiazem. Furthermore, the antihypertensive effects of RO 23‐6152 are stereoselective.
Onset and recovery kinetics of V̇max reduction by class I antiarrhythmic agents: Relation to frequency dependence
Authors: Lee Martin Cynthia , Chinn Kevin
Published: January 2005

The onset and recovery kinetics of rate‐dependent n̈max reduction in guinea pig papillary muscles were measured for a new class I antiarrhythmic agent, bidisomide (SC‐40230), and compared to standard agents lidocaine, flecainide, and disopyramide. Frequency‐independent reduction of n̈max was found to be associated with long recovery time rather than onset kinetics or other factors, such as molecular weight. Bidisomide and flecainide had the slowest onset rates (τ=4 and 6 sec at 3.3 Hz, respectively) while lidocaine and disopyramide had much faster onset rates (τ=0.2 and 0.5 sec at 3.3 Hz, respectively). Recovery time constants were obtained by using the first n̈max value following a variable recovery time period after a stimulus train used to produce drug blockade. Flecainide and lidocaine had recovery time constants on the order of seconds (19 and 1 sec, respectively). Disopyramide, unlike previously reported, and bidisomide had very slow recovery time constants, on the order of minutes (2.4 and 8.8 min, respectively). The onset of n̈max reduction caused by bidisomide was most similar to flecainide, but the recovery time was most similar to disopyramide. The n̈max reduction caused by bidisomide and disopyramide was frequency‐independent (between 1 and 3.3 Hz), while that caused by flecainide and lidocaine was frequency‐dependent. Both bidisomide and disopyramide are frequency‐independent, which may be due to their long time constants for recovery from block.
Effects of HA‐966 on conflict, social interaction, and plus maze behaviors
Authors: Corbett Roy , Dunn Robert W.
Published: January 2005

Antagonists at the N‐methyl‐D‐aspartate (NMDA) receptor share a number of properties, including anticonvulsant and anxiolytic‐like behaviors. In the Cook and Davidson conditioned conflict paradigm, the NMDA receptor complex antagonists HA‐966 (1 and 3 mg/kg), CPP (10 mg/kg), MK‐801 (0.03 mg/kg), and the benzodiazepine, diazepam (3 and 10 mg/kg) significantly disinhibited conflict responding. Likewise, in the social interaction test and elevated plus maze assay, two non‐conditioned paradigms predictive of anxiolytic activity, the NMDA antagonists HA‐966, CPP, and MK‐801, as well as diazepam, all significantly increased both social interaction time and open arm exploration time, respectively. In general, antagonism of the NMDA receptor complex results in anxiolytic behavior in rodents. Moreover, selective antagonism at the strychnine‐insensitive glycine modulatory site (HA‐966) may represent a new and novel class of compounds with potential therapeutic efficacy in anxiety.
Effects of buspirone and other anxiolytics on punished key‐pecking in the pigeon
Authors: Nanry Kevin P. , Howard James L. , Pollard Gerald T.
Published: January 2005

Pigeons were trained to peck a key on a multiple schedule of reinforcement in which 30 responses in the presence of a white cue light produced 3 sec of access to food, and 30 responses in the presence of a red cue light produced 3 sec of access to food and an electric shock, which suppressed responding. Intramuscular injection of the sedative‐hypnotic anxiolytics chlordiazepoxide (0.3–10 mg/kg), alprazolam (0.1–3.0 mg/kg), and zopiclone (10–100 mg/kg) substantially increased punished responding. The nonsedative anxiolytics buspirone (0.1–3.0 mg/kg) and ipsapirone (1.0 and 3.0 mg/kg) increased punished responding as much as did the sedative‐hypnotics. Buspirone had similar effects in benzodiazepine‐naive and benzodiazepine‐experienced pigeons. Chlorpromazine (tested at 1–30 mg/kg) and imipramine (tested at 1–30 mg/kg) only decreased unpunished responding at high doses. These results show that (1) the antipunishment effects of buspirone and ipsapirone in the pigeon are replicable in another laboratory, (2) buspirone's effect occurs in benzodiazepine‐experienced pigeons, and (3) alprazolam and zopiclone have antipunishment effects in the pigeon.
Electrocardiographic effects of zatosetron and ondansetron, two 5HT3 receptor antagonists, in anesthetized dogs
Authors: Williams Patricia D. , Cohen Marlene L. , Turk John A.
Published: January 2005

The pharmacology of 5‐hydroxytryptamine3 (5HT3)‐antagonists is an area under active investigation, and several agents of this class are currently under development for multiple therapeutic indications. Recently, two 5HT3 receptor antagonists of a tropane derived series, ICS 205 930 and zatosetron, have been shown to alter electrocardiographic properties of heart muscle. A prototypical, but structurally distinct (imidazole) 5HT3‐antagonist, ondansetron, was examined for its comparative cardiovascular activity in anesthetized dogs at intravenous doses of 0.66–5.25 mg/kg. Similar to zatosetron, a significant, dose‐dependent prolongation of the duration of the action potential of the electrocardiogram (Q‐Tc interval) occurred following ondansetron exposure, with a maximum increase of 28%. Other cardiovascular parameters (heart rate, mean arterial pressure, pulmonary pressure, cardiac output, peripheral vascular resistance, stroke volume and work index) were essentially unchanged by ondansetron treatment. At equivalent 5HT3 blocking doses, both ondansetron and zatosetron prolonged the Q‐Tc interval in anesthetized dogs similarly. However, for both compounds, the doses required to increase Q‐Tc interval were higher than the doses required to demonstrate 5HT3 receptor blockade. The fact that ondansetron, an imidazole, exhibited electrophysiological effects on cardiac muscle like the 5HT3 receptor antagonists derived from tropane suggests that the electrocardiographic effects are related to some property shared by 5HT3 receptor antagonists rather than a property of the tropane structure.
Centchroman: Binding with plasma proteins of rat, rabbit, guinea pig, and rhesus monkey
Authors: Ratna Sanjeev , Chandra Gyan , Ray Suprabhat , Roy S. K.
Published: January 2005

Incubation of plasma samples rat, rabbit, guinea pig, and rhesus monkey showed a nonsaturable low affinity binding with 14C‐centchroman. The Scatchard analysis of binding data revealed a low affinity and high capacity binding of centchroman with plasma protein. It was observed that 14C‐centchroman did not compete with 3H‐cortisol, 3H‐estradiol, non‐steroidal estrogenic/antiestrogenic agents, or with the binding sites of other steroidal sex hormones used with plasma samples of different animals. The characterization of centchroman bound complex with polyacrylamide gel electrophoresis showed that centchroman binds with plasma albumin at af of 0.68.
Vascular and platelet pharmacology of 2‐camphanone, a new drug for the treatment of hemorrhoids
Authors: Wang Mintao , Xie Jianming , Greenberg Stanley S. , Longnecker Gesina
Published: January 2005

2‐Camphanone (Alphanon ®) is under clinical evaluation for the treatment of hemorrhoids. This study examined the effect of 2‐camphanone on three parameters affecting hemorrhoidal distention: portal venous blood flow, vascular smooth muscle tone, and aggregation of human platelets. Mongrel dogs (10–18 kg) of either sex were anesthetized with pentobarbital sodium (35 mg/kg, i.v.) and instrumented for doppler measurment of portal vein and and fermoral artery blood flow velocity using a closed‐chest, spontaneusly breathing preparation. Intravenous. (i.v.) administration of 2‐camphanone (0.01, 0.03, 0.1, 0.3, and 0.6 mg/kg) or transdermal administration of 6 mg of 2‐camphanone selectively increased portal venous blood flow velocity by 13–31% above pre‐drug control values. 2‐Camphanone (0.1 to 100 μM) produced endothelium‐dependent relaxation of canine portal‐mesenteric (MV) and portal veins (PV), but not mesenteric arteries (MA), pre‐contracted with an EC50 concentration of norepinephrine (NE). 2‐Camphanone also inhibited acetylcholine‐induced contraction of MV but did not affect the contraction of the MV to NE, nerve stimulation, or KCl. The inhibitory effect of 2‐camphanone was not stereo‐sepcific but resided in both the (+) and (−)isomers. 2‐camphanone (up to 1 mM) did not affect platelet aggregation produced by ADP, collagen, or arachidonic acid, but inhibited epinephrine‐induced aggregation. The results show that 2‐camphanone increases portal venous blood flow velocity. 2‐Camphanone is effective by the i.v. and transdermal routes of administration. The effect may be mediated by substances released from the venous endothelium. Speculatively, this may reflect a free radical scavenging or anti‐oxidant effect of 2‐camphanone. This may be aided, in part, by camphanone‐induced inhibition of epinephrine‐mediated release of plateletderived venous stimulants during the stressful hemorrhoidal episodes.
Novel effects of memantine in antagonizing acute aldicarb toxicity: Mechanistic and applied considerations
Authors: Gupta Ramesh C. , Kadel Wade L.
Published: January 2005

Administration of a single sublethal dose of aldicarb (0.4 mg/kg, i.p.) to male Sprague‐Dawley rats produced the onset of hypercholinergic signs within 3–5 min. With increasing intensity the most severe signs, predominantly involving the peripheral nervous system (muscle fasciculations and convulsions), were evident within 15–30 min and lasted for about 90 min. Rats dosed with 0.1 mg/kg, i.p. did not develop intoxication while those dosed with 0.2 mg/kg, i.p. exhibited signs of moderate toxicity. A dosage of 0.6 mg/kg was found to be the minimal lethal dose (MLD). The inhibition of acetylcholinesterase (AChE) and carboxylesterase (CarbE) was dose‐depedent. Significant (P<0.01) inhibition in the activities of AChE and CarbE occured as early as within 15 min, and the maximal effect within 30 min. Time course of CarbE activity revealed marked inhibition in different neuronal and nonenuronal tissues, suggesting tremedous nonspecific binding of aldicarb. Prophylaxis with 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), provided compelte protection. Therapeutic administration of these two antidotes in combination also completely reversed the clinical signs of intoxication. It is suggested that memantine antagonized the aldicarb acute toxicity by protection/reactivation of activities of AChE and CarbE and reversible blockade of hyperneuromuscular transmission, in addition to muscarinic ACh receptor blockade by atropine.
Pharmacological characterization of the Raji lymphoblast platelet‐activating factor receptor
Authors: Travers Jeffrey B. , Li Qian , Fertel Richard H.
Published: January 2005

Previous studies in our laboratory have described the presence of high‐affinity plateletactivating factor (PAF) binding sites on the B lymphoblast cell line, Raji. In the present study, PAF receptor antagonists were used to examine the specificity of [3H]PAF binding and PAF‐induced intracellular calcium mobilization in this human lymphocyte cell line. In binding studies conducted at 4°C, PAF receptor antagonists competed with [3H]PAF for binding to Raji lymphocytes with the following rank order of potency: Ro 19‐3704 ∼ CV‐6209 > CV‐3988 > BN52021 > alprazolam. This order of potency is similar to those described for binding studies in platelets and neutrophils. The PAF receptor antagonists CV‐6209 and alprazolam inhibited the PAF‐induced calcium changes and PAF binding with similar potencies, indicating that the high‐affinity PAF binding sites are functional receptors coupled to calcium mobilization. The calcium channel antagonists verapamil, diltizem, and nimodipine inhibited Raji lymphoblast PAF binding with similar potencies, but had no effect on PAF‐induced intracellular calcium changes, suggesting the possibility that these compounds are not true competitive antagonists. These studies provide evidence that the Raji lymphoblast PAF receptor is pharmacologically similar to PAF receptors found on platelets and neutrophils, and thus could be of use as a model system to study the PAF receptor.
Stimulation of phosphoinositide hydrolysis by ibotenic acid in cerebellar neurons via two glutamate receptor subtypes
Authors: Raulli Robert , Wroblewski Jarda T.
Published: January 2005

In primary cultures of cerebellar granule cells, ibotenate produced a dose‐dependent biphasic stimulation of phosphoinositide (PI) hydrolysis. The high‐affinity component of ibotnate action (EC50 = 100 nM) was characteristic of the metabolotropic glutamate receptor activation. The action of ibotenate, like that of quisqualate, was inhibited by pretreatment of granule cells with pertussis toxin, confirming the participation of a guanosine triphosphate (GTP)‐binding protein in ibotenate signal transduction. In contrast, the low‐affinity component of ibotenate‐stimulated PI hydrolysis (EC50 = 100 μM) exhibited the pharmacology of the N‐methyl‐D‐aspartate (NMDA) receptor. This action was inhibited by NMDA receptor antagonists 3‐(2‐carboxy‐piperazin‐4‐yl)propyl‐1‐phosphonic acid (CPP) and (+)5‐methyl‐10, 11‐dihydro‐5H‐dibenzocyclohepten‐5, 10‐imine maleate (MK‐801) and was potentiated by glycine. Moreover it was inhibited by 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX), acting as an antagonist at the positive modulatory site of the NMDA receptor. The low‐affinity component of ibotenate‐induced Pl hydrolysis correlated well with the ability of ibotenate to induced 45Ca2+ influx, confirming the action of ibotenate at the ionotropic NMDA receptor. Thus, in cerebellar granule cells, ibotenate appears to stimulate Pl hydrolysis by acting at two distinct glutamate receptor subtypes.
A comparison of the potency and specificity of the direct muscle relaxant activity of azumolene and dantrolene
Authors: Dhillon Daljit S. , Pong Schwe F. , Moorehead Thomas J.
Published: January 2005

Dantrolene is a unique directly acting skeletal muscle relaxant that is clinically useful in the treatment of chronic muscle spasticity and malignant hyperthermia. Azumolene is a new dantrolene‐like drug that has better aqueous solubility and that may also be of use in the treatment of acute muscle spasm. Potency of both compounds was determined in the anesthetized, curarized rat gastrocnemius (using different routes of administration) and the isolated chick biventer muscle preparations. The specificity of effects in vitro was evaluated by comparing effects in the chick biventer with those seen in the rat aortic strip. Route of administration governed potency for both drugs, with rank order i.v., i.p., and i.d. being the least potent. In vivo, dantrolene was approximately twice as potent as azumolene when administered by any of the routes tested. However, both drugs are equipotent in vitro. Reasons for the discrepancy between in vivo and in vitro potencies are discussed. The muscle relaxant effects of both azumolene and dantrolene are specific for skeletal muscle, being 10‐fold more potent in skeletal than in arterial smooth muscle. The reasons for this specificity are probably due to basic differences in the physiology of smooth and skeletal muscle. We conclude that the new agent, azumolene, is a specific, potent skeletal muscle relaxant with properties qualitatively similar to those of dantrolene.
Additive and superadditive vasodilating combinations of diltiazem and glyceryl trinitrate in isolated rabbit aorta
Authors: Freeman Keith A. , Bove Alfred A. , Tallarida Ronald J.
Published: January 2005

The combined use of two drugs with overtly similar action is a common therapeutic strategy. Combinations in doses that produce synergism are frequently sought. In this study, we examined the vasodilating action of diltiazem (DIL) and glyceryl trinitrate (GTN), tested in several fixed‐ratio combinations on an isolated preparation of the rabbit aorta. This pair of drugs, widely used clinically, exhibited significant superadditivity (synergism) in certain fixed‐ratio combinations tested, i.e., 30:1 and 100:1 of DIL:GTN (based on weight), and only simple additivity in other dose ratios, 1:15, 1:1, and 15:1. A demonstration of synergism requires that the total dose of the mixture needed to produce a level of effect be significantly less than the theoretically additive dose calculated; hence, statistical confidence limits of the additive value are needed. Testing of this nature has been limited for statistical reasons to drug combinations that produce parallel regressions of effect on log (dose). In this paper we illustrate the application of new statistical methodology that permits testing of drug combinations that produce nonparallel assays and report our experimental findings, which show that only certain fixed‐ratio combinations of DIL and GTN are superadditive (synergistic) in this test. Although vasodilation alone does not imply antianginal action, these findings may serve as a guide for further clinical testing.
Effects of the antidepressant compound nefazodone on central monoaminergic neuronal discharge in rats
Authors: Vandermaelen Cam P. , Braselton John P.
Published: January 2005

The effects of i.v. administration of the antidepressant compound nefazodone were assessed on the firing rates of spontaneously active noradrenergic neurons in the locus coeruleus (LC), serotonergic neurons in the dorsal raphe (DR), and dopaminergic neurons in the substantia nigra (SN) of chloral hydrate anesthetized male albino adult rats, utilizing extracellular single‐unit recording methods. Nefazodone, tested in doses of 0.1–10.0 mg/kg, had variable effects on LC neurons, but the predominant effect was a mild excitation of firing (ED25 = 1.953 mg/kg). This may in part be caused by the 5‐HT2 antagonist properties of the compound, since ritanserin also produced a mild excitation of LC neurons. By comparison, desipramine very reliably inhibited LC neurons (ED50 = 0.333 mg/kg, i.v.). For DR neurons, i.v. nefazodone (0.1–3.2 mg/kg) produced variable effects, with inhibition being the most common (63% of cases tested). The ED25 for inhibition was 1.230 mg/kg, and in no case was inhibition of 50% or greater observed. By comparison, clomipramine very reliably inhibited DR neurons (ED50 = 0.501 mg/kg, i.v.). For SN neurons, the effects of i.v. nefazodone were also variable, with no consistent effects observed. These results indicate that acute nefazodone produces relatively weak effects on monoaminergic neuronal impulse flow in anesthetized rats, and suggest that major modifications of monoaminergic neuronal impulse flow probably do not play an important role in any neuroadaptive changes that may contribute to the clinical antidepressant actions of nefazodone.
Comparative effects of valproate, anxiolytic, or anxiogenic drugs on the light/dark aversion test
Authors: De Angelis Luisa
Published: January 2005

The potential anxiolytic‐like effects of 200, 300, and 400 mg/kg i.p. of sodium valproate were evaluated in the light/dark aversion test in mice. For comparison, we included the reference anxiolytic drug, diazepam (2.5, 5.0, 10 mg/kg i.p.) as well as putative anxiolytics, i.e., clonidine (0.015, 0.030, 0.060 mg/kg i.p.), verapamil (5, 10, 20 mg/kg i.p.), or anxiogenic drugs, pentylenetetrazol (5, 10, 15 mg/kg i.p.).

Results showed that control mice preferred the dark compartment where they spent approximately 70% of their time. After administration of 5 and 10 mg/kg i.p. of diazepam or 400 mg/kg i.p. of valproate, the increase in exploratory behavior in the lit area was associated with an increase both in the number of transitions and in the time spent in the lit area. Pretreatment with 0.030 and 0.060 mg/kg i.p. clonidine caused an increase in the time spent in the lit area. Verapamil had no significant effect on both measures of this test. Pentylenetetrazol, in doses which did not cause convulsions, was anxiogenic.

In conclusion, these results in the light/dark aversion test are consistent with clinical data showing that valproate, a GABA‐agonist, and clonidine, an α2 adrenoceptor agonist, possess anxiolytic properties. © 1992 Wiley‐Liss, Inc.
S 14506: A novel, potent, high‐efficacy 5‐HT1A agonist and potential anxiolytic agent
Authors: Colpaert Francis C. , Koek Wouter , Lehmann John , Rivet Jean‐Michel , Lejeune Françoise , Canton Hervé , Bervoets Karin , Millan Mark J. , Laubie Michel , Lavielle Gilbert
Published: January 2005

The studies characterized the newly discovered 7‐methoxy naphtylpiperazine S 14506 and examined the possible relationship between the apparent in vivo efficacy of 5‐HT1A ligands and the magnitude of their anxiolytic potential. In vitro radioligand binding studies indicated S 14506 to bind with high affinity and in an apparently competitive manner to 5‐HT1A sites, while having much less affinity for other 5‐HT binding sites. S 14506 demonstrated exceptional anxiolytic potential in the pigeon conflict procedure; the magnitude of its effects exceeded that of the other 5‐HT1A ligands 8‐hydroxy‐2‐(n‐propylamino) tetralin (8‐OH‐DPAT), (+)‐flesinoxan, buspirone, and BMY 7378. The anticonflict action of S 14506 was antagonized by the 5‐HT1A antagonist (–)‐alprenolol. Like the prototypical 5‐HT1A agonist 8‐OH‐DPAT, S 14506 induced forepaw treading, hypothermia and spontaneous tail flicks, antagonized morphine‐induced analgesia, and produced stimulus generalization in rats discriminating 8‐OH‐DPAT from saline. The apparent in vivo efficacy of the 5‐HT1A ligands in stimulating corticosterone release varied as follows: S 14506 > 8‐OH‐DPAT > (+)‐flesinoxan > buspirone > BMY 7378. This rank order corresponded with the rank order of magnitude of the anxiolytic action which the same compounds produced in the pigeon conflict procedure. The rank order of in vivo potency of these compounds in producing 5‐HT1A agonist actions in rodents. (i.e., S 14506) > 8‐OH‐DPAT > (+)‐flesinoxan > bus‐pirone > BMY 7378) also corresponded with their rank order of potency in producing anticonflict effects. The data characterize S 14506 as an extremely potent, orally active, high‐efficacy agonist at 5‐HTl1A receptors that demonstrates exceptional anxiolytic potential in the pigeon conflict procedure. The results provide strong evidence that the activation of central nervous system (CNS) 5‐HT1A receptors yields marked anticonflict effects and that the anxiolytic potential of 5‐HT1A ligands is proportional to their efficacy at 5‐HT1A re‐ceptors. © 1992 Wiley‐Liss, Inc.
Anti‐Inflammatory activity of 11β‐hydroxypregna‐1,4‐diene‐3,20‐dione
Authors: Rondinone Cristina M. , Schillaci Roxana , Roldán Alicia
Published: January 2005

This work demonstrates that in acute and chronic injectable treatments, as well as in topical application, ΔHOP is efficient as an anti‐inflammatory drug, equivalent to dexamethasone on carrageenan‐induced edema of rat paws and on croton oil‐induced ear inflammation. The difference between both steroids resides in the low potency of ΔHOP, since 60 times higher doses of ΔHOP are needed to achieve pharmacological effects similar to dexamethasone. However, even at these high doses ΔHOP, unlike glucocorticoids, did not decrease thymus nor adrenal weight although increasing liver glycogen deposition. © 1992 Wiley‐Liss, Inc.
Effect of fenoldopam prodrug, SK&F R‐105058, on renal function in rats
Authors: Sakamoto Takashi , Lokhandwala Mustafa F.
Published: January 2005

Recent development of and studies on fenoldopam prodrugs have shown their prolonged hemodynamic effects. This study was carried out in order to examine the effect of a fenoldopam prodrug on renal function in rats. In the present study we administered SK&F R‐105058, the 4′,7,8‐tris‐N‐ethyl carbamate ester of R‐fenoldopam, at a dose of 30 μg/kg/min intravenously to the anesthetized rats. This prodrug produced long‐lasting increases in water and sodium excretion after termination of the 30‐min drug infusion with minimum changes in hemodynamic parameters. The diuresis and natriuresis were attenuated in the presence of a selective DA1 receptor antagonist SCH 23390. Therefore, it is suggested that production of fenoldopam from its precursor drug SK&F R‐105058 caused these prolonged renal effects, which were mediated via the activation of DA1 receptors located on renal tubules. © 1992 Wiley‐Liss, Inc.
Memory impairments induced by peripherally administered cholecystokinin a‐type receptor antagonists in rats
Authors: Itoh Shinji , Takashima Akira , Maeda Yumino
Published: January 2005

Intraperitoneal injection of cholecystokinin (CCK) A‐type receptor antagonists, L‐364,718 and CR 1409, caused dose‐dependent memory impairments in passive and active avoidance responses and in Morris water pool test in rats. These antagonist effects were significant at a dose of 1 mg/kg, while with proglumide, 50–100 mg/kg were required to produce a similar memory deficit. The results suggest that loss of biologically active CCK octapeptide (CCK‐8), not only in the brain but also in the peripheral tissues, causes memory impairmets in rats. © 1992 Wiley‐Liss, Inc.
Antipsychotic profile and side‐effect liability of haloperidol, risperidone, and ocaperidone as predicted from their differential interaction with amphetamine in rats
Authors: Megens Anton A. H. P. , Niemegeers Carlos J. E. , Awouters Frans H. L.
Published: January 2005

Motor activity effects of haloperidol, risperidone, and ocaperidone were studied in rats challenged with amphetamine. At a low dose of amphetamine, the compounds were about equipotent in reducing amphetamine‐induced hyperactivity to normal values (lowest ED50s: 0.015–0.023 mg/kg). Haloperidol completely blocked motility at a slightly higher dose (0.14 mg/kg). In contrast, much higher doses of risperidone and ocaperidone were required for complete blockade of motility (ED50s: 2.0 and 1.7 mg/kg, respectively). With increasing dose of amphetamine, risperidone became considerably less potent than haloperidol in reducing hyperactivity; ocaperidone remained at least as potent as haloperidol in this respect. Moreover, risperidone lost, while ocaperidone maintained, its high margin towards complete blockade of motility. The compounds were also equipotent (lowest ED50s: 0.0075–0.0089 mg/kg) in reversing amphetamine‐induced behavioral withdrawal (stationary stereotypy) to more environment directed behavior (active exploration). However, this ‘disinhibitory’ effect was maintained over a much wider dose range with risperidone than with haloperidol and ocaperidone. The observed differences in interaction with amphetamine are presumably related to relative serotonin 5HT2/dopamine D2 antagonistic activity and suggest important differences in therapeutic profile and side‐effect liability of the compounds. The implications for distinct clinical applications of the compounds are discussed: risperidone might be the drug of choice for maintenance therapy of chronic schizophrenics, especially for patients with mild positive symptoms and type II patients with predominant negative symptoms and ocaperidone for therapeutic treatment of the pronounced positive symptoms in acute schizophrenia or during exacerbations of chronic schizophrenia. © 1992 Wiley‐Liss, Inc.
Diurnal variation in hepatic glutathione content as a function of age
Authors: Rikans Lora E. , Nokubo Munetaka , Kanai Setsuko , Kitani Kenichi
Published: January 2005

The purpose of this study was to investigate the influence of aging on the diurnal varitaion in glutathione (GSH) content of mouse liver. Young (7 months) and old (27 months) C57BL mice were housed under standarized conditions with lighting from 0800 to 2000 and free access to food and water. GSH was determined in acid extracts of liver homogenates by HPLC separation and fluorometric detection of the o‐phthaldialdehyde derivative. A diurnal rhythm in hepatic GSH concentration was evident in young and old mice of both sexes. Peak levels of GSH occurred at 1000 and were unaffected by age or gender; however, age and sex‐dependent differences were observed in the lowest concentration of GSH and in the amplitude of the GSH cycle. Hepatic GSH levels at 2200 and 0600 were 30–35% lower in old males than in young males and 25–40% lower in young females than in young males. The results may provide an explanation for the inconsistencies in previous findings about the influence of aging on hepatic GSH concentrations. © 1992 Wiley‐Liss, Inc.
Interleukin‐2 in liposomes: Increased intravenous potency and less pulmonary toxicity in the rat
Authors: Anderson Peter M. , Hasz Diane , Dickrell Lydia , Sencer Susan
Published: January 2005

Incorporation of interleukin‐2 (IL‐2) into multilamellar vesicles, IL‐2 liposomes, significantly modifies the biodistribution and prolongs the clearance of the cytokine. The rat was used to evaluate and characterize subacute toxicity and short‐term pathologic effects of intravenous (i.v.) IL‐2 liposomes. Once daily i.v. IL‐2 liposomes in doses of 0.3 × 106u/kg, 1.5 × 106u/kg, 4.0 × 106u/kg, and 20 × 106u/kg were given to rats for 15 days; control rats received i.v. empty liposomes or buffered saline. Hematologic parameters, serum chemistry, and gross pathologic and histopathologic findings were recorded. Only at the highest dose of IL‐2 liposomes were effects consistently severe enough to produce weight loss, decreased food consumption, hepatitis, anemia, and death. At this dose females were more susceptible to mortality than males; only 1 of 5 females survived compared to 4 of 5 males. Peripheral blood leukocyte increases after IL‐2 liposomes were mainly associated with lymphocytosis with only minor changes in neutrophils, monocytes, and eosinophils. The marrow had significant dose‐related hematopathologic findings limited to decreased percentages of lymphocytes and increased myeloid:erythroid (M:E) ratio in the 20 × 106u/kg group. No increases in marrow eosinophils or eosinophilic precursors were demonstrated. The major toxic effects of IL‐2 liposomes in rats were hepatic. Dose‐related elevations in liver enzyme serum chemistries (aspartate aminotransferase [AST], alanine aminotransferase [ALT], bilirubin, γ‐glutamyl transferase [GGT], and alkaline phosphatase) were seen. Occasional rats had evidence of bridging fibrosis in addition to centrilobular and periportal lymphocytic and eosinophilic infiltration of the liver. Pulmonary histopathology was characterized by peribronchial and perivascular lymphoid and eosinophilic infiltration with minimal or no septa1 involvement. In summary, the spectrum of pathologic and toxicologic changes in rats receiving once daily IL‐2 liposomes are similar to those previously reported in rats given the free cytokine twice daily, but occur at reduced doses with less lung pathology. Thus, compared to free cytokine i.v. IL‐2 liposomes in rats have increased potency and decreased pulmonary toxicity. © 1992 Wiley‐Liss, Inc.
Investigation of the sedative and congnitive effects of cyclobenzaprine compared with diphenhydramine and placebo using a computerized test battery
Authors: Lines Christopher , Dawson Catherine , Ambrose Judith , Panebianco Deborah , Cheng Kenneth , Traub Michael
Published: January 2005

Two studies were undertaken to investigate the sedative and congnitive effects of cyclobenzaprine (Flexeril®) in volunteers, using a computerized battery of congnitive tests and subjective rating scales. In Study 1 the effect of acute administration of two doses of cyclobenzaprine (2.5, 5 mg orally) were compared with a single dose of diphenhydramine (Benadryl; 50 mg orally) and placebo. On most tests diphenhydramine produced a significant impairment compared to placebo, whereas there were typically no significant differences between cyclobenzaprine and placebo. In Study 2 the effects of repeated dosing with cyclobenzaprine (5 mg three times daily for 10 doses) were compared to placebo. The test battery was administered after the fourth and tenth doses. There was a small but mainly nonsignificant trend for subjects receiving cyclobenzaprine to do worse at the first test session. No differences between treatments were apparent by the second test session. The battery of tests used here would appear to be useful for assessing sedation. © 1992 Wiley‐Liss, Inc.
Profile of cholinomimetic drugs in primates: Status of screens for potential Alzheimer therapies
Authors: Rupniak Nadia M. J.
Published: January 2005

Criticism of the validity of preclinical screens for cognitive enhancers and unsuccessful attempts at cholinotherapy for Alzheimer's disease cast doubt on the likely efficacy of such treatment. However, inadequacies of existing cholinergic drugs and inconclusive clinical trials leave unanswered the question of whether symptomatic relief from dementia can be achieved. Preclinical screens using primates may provide valuable information to support selection of appropriate compounds for clinical development. At present it is not possible to routinely screen cholinergic agents in a manner which provides convincing evidence for beneficial cognitive effects of known relevance for Alzheimer's disease. However, direct comparison of the in vivo effects of a range of cholinomimetic agents in primates has assisted selection of a novel cholinesterase inhibitor, eptastigmine (L‐689,487). In rhesus monkeys, the cholinesterase inhibitors physostigmine and eptastigmine, but not tacrine, were able to fully reverse scopolamine‐induced performance deficits in a visuospatial task. The duration of action of eptastigmine was considerably longer following oral administration (around 4.5 hr) than for physostigmine (approximately 30 min). In contrast, the directly acting, nonselective muscarinic agonists pilocarpine and RS86 were able to induce only partial reversal of the central effects of scopolamine, apparently due to dose‐limiting toxicity. Similarly, the selective M1/M3 direct agonists AF1026 and L‐689,660 caused only partial or no reversal of the scopolamine‐induced impairment. The superior in vivo profile of eptastig‐ mine should enable more definitive evaulation of cholinotherapy for Alzheimer's disease. © 1992 Wiley‐Liss, Inc.
In vivo and in vitro effects of the novel antiarrhythmic ipazilide on cardiac and vascular smooth muscle function
Authors: Ezrin Alan M. , Lee King C. , Harris Alex L. , Silver Paul J.
Published: January 2005

Ipazilide fumarate is a novel antiarrhythmic currently undergoing clinical evaluation. Since most antiarrhythmics have adverse cardiovascular side effects, we examined the potential effects of ipazilide on cardiac muscle and vascular hemodynamic function utilizing in vivo and in vitro models. The cardiovascular effects of ipazilide and selected reference antiarhythmics, disopyramide and sotalol, at relevant antiarrhythmic concentrations were compared. All agents decreased cardiac contractility, as evident by reductions in dP/dt and cardiac output in anesthetized dogs, and by decreases in contractile force in isolated guinea pig papillary muscles. In vivo, ipazilide was approximately 3–10 × less potent than disopyramide or sotalol while in vitro, ipazilide produced a greater decrease in contractility at a relatively high concentration (30 μM). All three agents increased cardiac preload as reflected by increases in left ventricular end diastolic pressure and right atrial pressure, with ipazilide 2–3 × less potent than disopyramide or sotalol. Differential effects on vascular function were also evident with the three agents. Disopyramide and sotalol significantly increased systemic vascular resistance, and either pulmonary vascular resistance (disopyramide) or left coronary arterial vascular resistance (sotalol); ipazilide did not significantly affect any of these parameters. In isolated rat arterial or canine coronary arterial smooth muscle, ipazilide produced concentration‐related vasorelaxation, with EC50 values ranging from 11–300 μM. Efficacy of ipazilide was higher in depolarized vascular tissue. In conclusion, since previous preclinical studies have indicated equal or greater antiarrhythmic activity of ipazilide relative to disopyramide or sotalol, the current data indicate the possibility for lessened in vivo hemodynamic effects of ipazilide at efficacious antiarrhythmic dosages. © 1992 Wiley‐Liss, Inc.
β2‐Adrenoceptors mediate inhibition of carbachol‐induced contraction and cAMP generation in isolated smooth muscle cells from rabbit gastric antrum
Authors: Moummi Chafiq , Magous Richard , Bali Jean‐Pierre
Published: January 2005

The regulation of inhibition of carbachol‐induced contraction by β‐adrenoceptors of rabbit gastric antrum has been investigated. A functional assay using isolated smooth muscle cells (ISMC) was used to study the effect of β‐adrenergic agonists and antagonists on carbacholcontracted ISMC and cAMP generation. The nonselective β‐adrenergic agonist isoproterenol caused concentration‐related inhibition of carbachol‐induced contraction associated with a significant increase in cellular cAMP. The EC50 for the effect of isoproterenol on cell inhibition of carbachol‐induced contraction was closely related to the EC50 for cAMP formation; the two curves were superimposable, indicating a positive correlation between the biological activity (inhibition of carbachol‐induced contraction) and the intracellular event (cAMP formation) caused by the activation of β‐adrenoceptors. The Kinetic studies demonstrate that maximum inhibition of carbachol‐induced contraction and a parallel elevation of intracellular cAMP content were reached at 30 sec of incubation with isoproterenol. The β2‐selective receptor agonist terbutaline induced inhibition of carbachol‐induced contraction of carbachol‐contracted ISMC and cAMP generation. However, the relatively β1‐selective receptor agonist norepinephrine had no significant effect. Propranolol, a nonselective β‐ adrenoceptor antagonist (β1 and β2) caused a significant inhibition of the carbacholβ2 induced contraction and rise in cAMP induced by isoproterenol and terbutaline, while the β1‐selective adrenergic receptorantagonist metoprolol, even at higher concentration, was inactive. These data demonstrate that there is a correlation between inhibition of carbachol‐induced contraction and cAMP generation upon activation of the β2‐adrenoreceptors in the ISMC of rabbit gastric antrum. © 1992 Wiley‐Liss, Inc.
Enhancement of systemic delivery of peptide drugs via ocular route with surfactants
Authors: Chiou George C. Y. , Shen Z. F. , Zheng Y. Q. , Chen Y. J.
Published: January 2005

The enhancement of systemic delivery of peptide drugs by absorption enhancers via ocular route was studied in the rabbits. The systemic absorption of α‐melanocyte stimulating hormone (α‐MSH) was enhanced by 0.5% polyoxyethylene 9‐lauryl ether (BL‐9) and 0.5% polyoxyethylene 20‐stearyl ether (Brij‐78) for 11 fold and 10 fold, respectively. The enhancement of systemic delivery of somatostatin, vasoactive intestinal peptide (VIP) and adrenocorticotropic hormone (ACTH) by BL‐9 (5.1 fold, 4.0 fold, and 5.3 fold, respectively) and Brij‐78 (6.4 fold, 5.2 fold, and 5.8 fold, respectively) was about half of those of α‐MSH. In all cases, the blood concentration of peptides reached the peak faster with BL‐9 (in 5–20 min after drug instillation) than with Brij‐78 (in 10–60 min after drug instillation). It is concluded that peptide drugs can be delivered systemically through the ocular route particularly when permeation enhancers are added to reduce the costs of the peptide drugs. © 1992 Wiley‐Liss, Inc.
Electropharmacology of bidisomide in the normal intact canine heart
Authors: Garthwaite Susan M. , Frederick Leo , Cook Chyung , Hatley Frida
Published: January 2005

Bidisomide (SC‐40230) is a class I antiarrhythmic agent. The effects of bidisomide on the electrophysiology of the intact heart were studied using an anesthetized dog model. Three cumulative intravenous doses of bidisomide were studied (n = 5)—1.5, 11.5, and 22.1 mg/kg—given as a loading dose followed by a maintenance infusion to produce three plasma concentration ranges—1.9‐–2.3, 17.2–21.2, and 22.7–24.1 μg/ml. A placebo group (n = 5) received the equivalent volume of saline. Heart rate, blood pressure, lead II electrocardiogram (ECG) intervals, as well as conduction, refractoriness, and nodal function were measured. Placebo had no effect on any parameter. With the exception of prolonging the atrial refractory period, bidisomide had no effect on any parameter at the lowest dose studied. Bidisomide caused a dose‐dependent and statistically significant increase in sinus node recovery time, atrial and ventricular conduction time, atrial effective refractory period, A‐H and H‐V intervals, P‐R and QRS intervals, Wenckebach point, and spontaneous cycle length. The effect of bidisomide on atrial refractory period and on A‐H interval was cyclelength dependent. Bidisomide increased or did not change ventricular refractory period in the five dogs studied. Blood pressure decreased less than 15% at plasma bidisomide concentrations up to 20 μg/ml. These experiments demonstrated that bidisomide affects conduction and/or refractoriness in all parts of the heart and has electrophysiologic effects consistent with ventricular and supraventricular antiarrhythmic activity. © 1992 Wiley‐Liss, Inc.