bluuebunny/crossref_metadata_2025 huggingface dataset:
MK‐801 produces antianxiety effect in elevated plus‐maze in mice
Authors: Sharma Avadhesh C. , Kulkarni S. K.
Published: January 2005

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

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

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

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

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

The 1‐(2‐hydroxy‐1‐phenylethyl)‐imidazole derivative Hoe 249 has a profile which suggests the compound is a promising candidate for clinical evaluation as an antidepressant drug. In pharmacological tests commonly considered predictive of antidepressant activity, e.g., reserpine‐ and tetrabenazine‐antagonism, reversal of oxotremorine‐ and apomorphine‐induced hypothermia, and potentiation of yohimbine toxicity, Hoe 249 is equipotent to nomifensine, but does not meet excitation and stereotypic behavior in a comparable dose range. Hoe 249 shows weak anticonvulsant activity against pentylenetetrazole‐induced seizures and it causes a slight dose‐dependent prolongation of hexobarbital narcosis. Biochemical studies characterize Hoe 249 as an inhibitor of synaptosomal dopamine and norepinephrine uptake, whereas serotonin uptake is not influenced. © 1992 Wiley‐Liss, Inc.
Hepatoprotective effect of an active constituent isolated from the leaves of Ricinus communis Linn
Authors: Shukla Binduja , Visen P. K. S. , Patnaik G. K. , Kapoor N. K. , Dhawan B. N.
Published: January 2005

Dose (1.5–12 mg/kg p.o. × 7) dependent choleretic, anticholestatic, and hepatoprotective activity in rat was observed with N‐demethyl ricinine isolated from the leaves of Ricinus communis Linn. The anticholestatic and hepatoprotective activity was seen against paracetamol‐induced hepatic damage. The choleretic and anticholestatic activity was evidenced by an increase in the volume of bile and its contents. The hepatoprotective effect was evaluated by an increase in the percent viability of hepatocytes (ex vivo) and by the reversal of altered enzymatic levels (glutamic oxaloacetic transaminase [GOT], glutamic pyruvic transaminase [GPT], and alkaline phosphatase) towards normal. The compound showed more potent activity than silymarin, a known hepatoprotective agent.
The development of a highly selective 5‐HT1 receptor agonist, sumatriptan, for the treatment of migraine
Authors: Feniuk Wasyl , Humphrey Patrick P. A.
Published: January 2005

Sumatriptan is a highly selective 5‐HT1 receptor agonist and an effective treatment for migraine. It causes constriction of cranial blood vessels. In anaesthetised animals, it selectively constricts parts of the carotid vasculature and has been shown to inhibit plasma protein extravasation from blood vessels of the dura mater induced by antidromic stimulation of the trigeminal nerve. This effect may result from a localised vasoconstriction of the meningeal vessels and/or a direct inhibitory effect on adventitial nerve endings. Sumatriptan penetrates the blood brain barrier poorly. These findings are consistent with the view that the locus of action of sumatriptan is at the level of the wall of cranial blood vessels that are distended and edematous during a migraine headache. © 1992 Wiley‐Liss, Inc.
Concepts for the design of 5‐HT1A serotonin agonists and antagonists
Authors: Glennon Richard A.
Published: January 2005

The accessibility and use of a standard 5‐HT1A agonist radioligand ([3H]8‐hydroxy‐2‐(dipropylaminotetralin) has resulted in the availability of a large amount of binding data on various serotonergic agents. This, in turn, has permitted the formulation of structure—affinity relationships (SAFIR). By contrast, much less information is available concerning the agonist and antagonist activity of these agents. This is primarily due to a lack of standard evaluation procedures, controversy regarding the presynaptic versus postsynaptic nature of certain models, and the recent realization that many 5‐HT1A agents are partial agonists. Thus, it has been difficult to formulate structure—activity relationships (SAR) for these agents. The present review examines the various classes of 5‐HT1A serotonergic agents and the available data on their 5‐HT1A agonist and antagonist activity with the aim of formulating SAR. These SAR should provide useful information for the subsequent design of 5‐HT1A‐selective agonists and antagonists. © 1992 Wiley‐Liss, Inc.
Effects of new clonidine derivatives on rabbit intraocular pressure
Authors: Li Byron H. P. , Chiou George C. Y.
Published: January 2005

Effects of 25 topically applied clonidine derivatives on rabbit IOP recovery model using intravenous hypertonic saline were studied. Among them, 12 compounds were dissolved in aqueous medium, 11 compounds in polyethylene glycol (PEG 200) and 2 compounds in dimethyl sulfoxide (DMSO). Four compounds showed marked delay in IOP recovery and were more active than S‐timolol and clonidine. Five compounds were about equiactive to S‐timolol and more active than clonidine in suppression of IOP recovery and prolongation of the duration of drug action. There were three compounds that were less active than S‐timolol yet they were still as active or were active than clonidine. Thirteen out of 25 compounds were inactive in suppressing IOP recovery curves. Most of these active compounds (9 out of 12) suppressed IOP recovery in the same magnitude for both treated and non‐treated contralateral eyes, indicating that these effects were manifested though central actions. Three out of 12 compounds showed more effect with treated eyes than with nontreated contralateral eyes, indicating that the local effects were predomiant.
ACE inhibitor lacks acute effect on cognition or brain blood flow in alzheimer's disease
Authors: Weiner Myron F. , Bonte Frederick J. , Tintner Ron , Ford Neville , Svetlik Doris , Riall Teresa
Published: January 2005

The effects of the acute administration of the ACE inhibitor ceronapril were studied in 12 Alzheimer's disease (AD) patients and 2 age‐matched controls. A 4‐week open trial was performed with daily doses of 40–80 mg/day. Testing was performed at baseline and at 4 weeks using the Mini‐mental State Exam and the cognitive portion of the Alzheimer's Disease Assessment Scale as cognitive measures, and regional cerebral blood flow (rCBF) as determined by Xe 133 single‐photon emission computerized tomography as an indirect measure of brain metabolism. There was no effect on cognition and blood flow increased significantly only in the left temporal region. It was concluded that the acute administration of the ACE inhibitor ceronapril had no significant acute effect on cognitive function of rCBF in AD. © 1992 Wiley‐Liss, Inc.
Milacemide: Safety assessment in senile dementia of the Alzheimer type
Authors: Dysken Maurice W. , Fakouhi T. Daniel , Skare Stacy S. , Mendels Joseph , LeWitt Peter , Hendrie Hugh C. , Venable Thomas C. , Hantsbarger Gary L. , Herting Robert L.
Published: January 2005

Milacemide, both an MAO‐B inhibitor and a prodrug for glycine, has demonstrated cognitive enhancing effects in animal models, in cognitively intact young and elderly, and has been suggested as a potential treatment for senile dementia of the Alzheimer type (SDAT). This multicenter open‐label trial evaluated the safety and potential efficacy of long‐term milacemide treatment in 209 SDAT outpatients (50–87 years of age). Milacemide treatment was intiated at 400 mg/day and was titrated up to a maximum dose of 1,600 mg/day. Laboratory screening tests, adverse effects reports, the Clinical Global Impression Scale, and the Patient Global Improvement Rating Scale were collected to assess patients' physical and cognitive functioning. Only 8 of 209 patients completed 1 year of treatment and the remaining patients were withdrawn due to adverse effects (73), protocol violations (89), treatment failure (34), and failure to follow‐up (5). Liver function tests became elevated in 145 patients and required study withdrawal of 67 of these patients. There was no evidence of cognitive enhancement or reduction in disease progression. It does not appear that milacemide is a viable treatment for SDAT patients. © 1992 Wiley‐Liss, Inc.
Clinical evaluation of bidisomide, a new class I antiarrhythmic: Initial intravenous dose‐finding study
Authors: Li Moreno Fidela , Summers Kaye L. , Menlove Ronald L. , Claypool William D. , Cox James R. , Garthwaite Susan M. , Karagounis Labros , Anderson Jeffrey L.
Published: January 2005

To assess effectiveness and tolerability of intravenous bidisomide, 16 patients (aged 57 ± 15 years) with ≥ 100 premature ventricular complexes (PVCs)/hr received a 10‐min infusion of bidisomide at 0.4 (n = 4), 0.75 (n = 4), 1.0 (n = 4), or 1.35 (n = 4) mg/kg body weight. Mean PVCs and repetitive beats per 3 and 15 min (± SD) from 2 hr pre‐ and 2 hr postdosing were determined and averaged after logarithmic transformation. Results: Group response assessed from 3‐min rhythm strips showed PVC reduction to be apparent at 15 min (48.2%, P = 0.06), significant at 30 min (57.2%, P = 0.02), maximal at 45 min (59.3%, P = 0.005), and declining at 60 min (48.8%, P = 0.06). Individual PVC reduction (> 70%) was observed in 0/4 (0%) at 0.4 mg/kg, 3/4 (75%) at 0.75 mg/kg, 3/4 (75%) at 1.0 mg/kg, and 3/4 (75%) at 1.35 mg/kg. Comparison of the log (PVCs per 3 min) showed a significant difference between lowest dose (0.4 mg/kg) and the higher doses (0.75 to 1.35 mg/kg) (P = 0.04). Individual reduction assessed on a 48‐hr Holter monitor was observed in 0/4 (0%) at 0.4 mg/kg, 2/4 (50%) at 0.75 mg/kg, 1/4 (25%) at 1.0 mg/kg, and 3/4 (75%) at 1.35 mg/kg. Comparison of the log (PVCs per 15 min) at various time points also showed a significant difference between the lowest dose (0.4 mg/kg) and the higher doses (P = 0.05). Analysis of log (PVCs/hr) in the succeeding 3 to 48 hr postdosing did not show a significant difference in PVC frequency compared to baseline. PR and QRS intervals increased significantly at 15 min ( + 5.4% for PR, + 6.8% for QRS, P < 0.05), and at 30 min ( + 5.3% for PR, + 4.8% for QRS, P < 0.05), returning to baseline by 90 min. RR and QT intervals did not change. Vital signs were stable and no evidence of any adverse hemodynamic effect was noted. No significant side effects occurred. Peak plasma bidisomide levels showed a dose response (1.7 ± 0.7, 2.8 ± 1.3, 5.4 2 0.3, 5.7 ± 1.7 μg/ml, doses 1 to 4 respectively, P = 0.0007). Similar results were obtained when the area under the curve (AUC) values were analyzed. Thus, bidisomide was well tolerated and effective in reduction of PVCs in single IV doses ≥ 0.75 mg/kg, associated with small increases in PR and QRS intervals. © 1992 Wiley‐Liss, Inc.
A‐75169 HCI: Pharmacological profile and ocular pharmacology studies of a new α‐2 antagonist
Authors: Giardina William J. , Buckner Steven A. , Hancock Arthur A. , Lee Jang‐Yun , Wismer Carol T. , DeBernardis John F.
Published: January 2005

A‐75169 HCI (1,2,3,4‐tetrahydro‐6‐hydroxy‐1‐[N‐methylamino)‐methyl‐N‐phenethyl]‐naphthalene HCI, a racemate, is derived from a series of compounds that combine selective α‐2 receptor antagonism and amine uptake inhibition in a single molecule. A‐75169 HCI showed high affinity (pK1 = 8.79) for cerebral cortex‐derived α‐2 adrenoceptors assayed with [3H] rauwolscine. The R‐enantiomer showed a tenfold greater affinity (pk1 = 9.09) for these receptors than the S‐enantiomer (pK1 = 8.10). A‐75169 HCI and both enantiomers had potent antagonistic effects at postsynaptic α‐2 adrenoceptors (pA2 values 7.31–7.49, dog saphenous vein). The racemate and the R‐enantiomer were moderately potent as antagonists for presynaptic α‐2 adrenoceptors (pA2 values 7.06 and 7.09, respectively, rat vas deferens), and they were more potent inhibitors (ID50 = 1.50 mg/kg, i.v., and 0.60 mg/kg, i.v., respectively) of clonidine‐induced mydriasis, an α‐2 mediated effect, than the S‐enantiomer. The S‐enantiomer was a more potent inhibitor of norepinephrine synaptosomal uptake than the R‐enantiomer (pIC50 = 6.00 and 5.79, respectively). When applied topically to the eyes of rabbits (3.0% solution) and monkeys (0.3% solution), the racemate significantly reduced intraocular pressure (IOP). The topical administration of A‐75169 HCI (0.5% solution) to dog cornea did not affect blood pressure or heart rate. A‐75169 HCI, a selective α‐2 antagonist possessing amine uptake blocking properties, is a potentially novel antiglaucoma compound. © 1993 Wiley‐Liss, Inc.
Pharmacological properties of dolasetron, a potent and selective antagonist at 5‐HT3 receptors
Authors: Miller Robert C. , Galvan Martin , Gittos Maurice W. , van Giersbergen Paul L. M. , Moser Paul C. , Fozard John R.
Published: January 2005

In the rabbit isolated perfused hear, dolasetron (MDL 73,147) was found to be a potent (PA2 = 9.8) antagonist at 5‐hydroxytryptamine3 (5‐HT3) receptors present on sympathetic nerve terminals. In anesthetized rats, intravenous (iv), intraduodenal (id), or oral administration of dolasetron blocked the von Bezold‐Jarisch reflex elicited by iv injection of 5‐HT; the iv ED50 was approximately 3 μg/kg and following a dose of 140 μg/kg iv the reflex was abolished for >85 min. The compound displayed no significant affinity for 5‐HT1, 5‐HT2, or a variety of other radioligand binding sites at concentration of 10 μM. In conscious ferrets, dolasetron suppressed the vomiting induced by an iv injection of the anti‐cancer drug cisplatin (10 mg/kg). Intravenous doses (0.05–0.5 mg/kg) administered 30 min before and 45 min prior to cisplatin, were clearly anti‐emetic and single oral doses of 0.5 or 2 mg/kg, given 30 min prior to cisplatin were also effective. Minimal changes in the behaviour of mice were observed at doses up to 100 mg/kg given ip or subcutaneously (sc). It is concluded that dolasetron is a potent, selective, and reversible antagonist at neuronal 5‐HT3 receptors, which is well tolerated. The compound is effective at low doses in an animal model predictive of clinical efficacy in cytotoxic drug‐induced vomiting. © 1993 Wiley‐Liss, Inc.
3‐Nitropropionic acid, obtained from astragalus species, has vasodilator and antihypertensive properties
Authors: Castillo Carlos , Valencia Ignacio , Reyes Gerado , Hong Enrique
Published: January 2005

3‐Nitropropionic acid (NPA) elicited a dose‐dependent relaxation of precontracted rabbit aortic rings. Since the NPA effect was independent of the contractile agonist used, it did not appear to act by blocking a specific set of receptors. Aortic rings precontracted with KCl were less sensitive to relaxation by NPA suggesting that at least part of the mechanism of vasodilation is not related to an inhibition of calcium influx through the voltage‐dependent Ca+ + channel. The arterial relaxation induced by NPA is independent of endothelium and it is not mediated by muscarinic, β‐adrenergic, nor histaminergic (H1) receptors. On the other hand, methylene blue clearly inhibited the vasodilation induced by NPA suggesting that it is a consequence of guanylate cyclase stimulation. Finally, a mild but consistent decrease of both systolic and diastolic arterial blood pressure was observed after oral NPA administration during 4 weeks to renal hypertensive dogs. The data in the present study clearly demonstrate that NPA possesses vasodilator and antihypertensive properties. © 1993 Wiley‐Liss, Inc.
Physiological and pathological roles of purines: An update
Authors: Burnstock Geoffrey
Published: January 2005

In this review article, the early history of studies of purinergic neurotransmission and of purinoceptor subclassification is described. This is followed by a survey of current knowledge of the distribution of purinoceptors and of the physiological roles of purines in the nervous system, muscle, secretory, endocrine and immune cells, as well as in spermatocytes, osteoblasts, fibroblasts, and tumour cells. Recent studies of transduction mechanisms for different purinoceptor subtypes, as well as reports of the molecular properties of encoding genes for purinoceptors, are reviewed. The evolution of purinergic mechanisms and the long‐term ‘trophic’ actions of purines are discussed. Finally, the clinical potential of purines and related compounds for various cardiovascular and behavioural disorders. As well as for inflammation and cancer are considered. © 1993 Wiley‐Liss, Inc.
Storage, release, uptake, and inactivation of purines
Authors: Meghji Parviz
Published: January 2005

Adenine nucleotides are released into the interstitial space during platelet thrombus formation and neurotransmission. ATP has also been reported to be released from the heart and endothelial cells in some studies. Ecto ATPase, ADPase, and 5′‐nucleotidase activities capable of hydrolyzing ATP sequentially to adenosine are present in many cell types and may serve to terminate the actions of the nucleotides. The opposing effects of adenosine and ATP on the same cell types have suggested a modulatory role for adenosine of the actions of extracellular ATP and that the rates of hydrolysis of nucleotides might be regulated. Consistent with this it has been found that the balance between feedforward inhibition of 5′‐nucleotidase by ADP and/or ATP and preferential delivery of AMP from ADPase to 5′‐nucleotidase determines the rate of adenosine production and that this differs in different cell types. Alternatively, adenosine may be produced intracellularly as a result of an imbalance between energy demand and supply. There are at least two different cytosolic forms of 5′‐nucleotidase. Degradation of ATP during increased metabolic activity results in an increase in intracellular AMP concentration. Either cytosolic enzyme has a high KM (2–5 mM) and would thus respond to this increase with a proportional rise in the rate of adenosine production. The nucleoside transporter is essential to allow the diffusion of adenosine to extracellular receptor sites. In general, adenosine must be taken up via the nucleoside transporter before it is inactivated either by phosphorylation by adenosine kinase in the micromolar range or by deamination by adenosine deaminase at higher concentrations. © 1993 Wiley‐Liss, Inc.
Adenosine deaminase inhibitors: Structure‐activity relationships in 1‐deazaadenosine and erythro‐9‐(2‐hydroxy‐3‐nonyl)adenine analogues
Authors: Cristalli Gloria , Eleuteri Alessandra , Vittori Sauro , Volpini Rosaria , Camaioni Emidio , Lupidi Giulio
Published: January 2005

Adenosine deaminase (ADA) is the enzyme which catalyzes the irreversible deamination of adenosine and deoxyadenosine to inosine and deoxyinosine, respectively. It is widely distributed in vertebrate tissues and is thought to be essential for proper functioning of mammalian cells. ADA inhibitors may have several clinical applications (i.e., in the chemotherapy of lymphoproliferative disorders, in the immunosuppresive therapy, in adenosine level modulation). Modification of the purine moiety of adenosine led to ADA inhibitors. In particular, 1‐deazaadenosine (1, Ki = 0.66 μM) and its 2′‐deoxy derivative (21, Ki = 0.19 μM) are the most potent in the series. Substitutions on the N6amino group did not produce a decrease in activity only when small groups, as hydroxyl or methyl, were introduced. The presence of a chlorine atom in position 2 produced a decrease in ADA inhibitory activity. All these findings are in agreement with a direct interaction of the 1‐deazapurine moiety with the catalytic site of ADA. Erythro‐9‐(2‐hydroxy‐3‐nonyl)adenine (12, EHNA) and 3‐deazaEHNA (14) are potent ADA inhibitors with Ki in the nanomolar range. Opening the pyrimidine ring of EHNA led to a series of erythro‐1‐(2‐hydroxy‐3‐nonyl)imidazole derivatives which are still ADA inhibitors. In order to introduce additional simplification and to investigate the role of nitrogen atoms in the azole structure, a series of di‐, tri‐, and tetrazoles bearing the 2‐hydroxy‐3‐nonyl chain have been synthesized and tested. The results indicated that the presence of N‐3 in the azole ring is critical for the inhibitory activity and that the introduction of additional nitrogens led to compounds whose potency range accounts for a direct interaction with an inhibitory site of ADA. © 1993 Wiley‐Liss, Inc.
Multiple effects of extracellular ATP in cardiac tissues
Authors: Vassort Guy , Scamps Frédérique , Pucéat Michel , Clément‐Chomienne Odile , Alvarez Julio
Published: January 2005

Before its degradation to adenosine, extracellular ATP released by nerves, or by cardiac cells during ischemia, induces a positive inotropy related to stimulation of the calcium conductance by P2‐purinoceptors. This stimulation is additive with the β‐adrenergic one and seems to occur via the activation of an isoform of a Gs‐protein sensitive to cholera toxin, although with no increase in cAMP. No Phosphorylation of the CA Channel is required since the P2‐purinergic stimulation is rapidly reversible even in the presence of the poorly hydrolysable compounds ATPγS or GTPγS intracellularly. Transiently, ATP may also depolarize the cells and trigger arrhythmias by binding to a new P3‐purinoceptor type which requires Mg ions. Such a receptor induced a tyrosine phosphorylation of CI/HCO3 Exchanger, a band 3‐like protein which under such activation induces a large, transient acidosis. © 1993 Wiley‐Liss, Inc.
Adenosine and cerebral microcirculation
Authors: Kuschinsky Wolfgang
Published: January 2005

Adenosine participates in the coupling of function to blood flow in the brain. With regard to the 2 mechanisms of coupling, the feedforward and feedback mechanisms, adenosine plays an important role in feedback regulation. Whereas the feedforward mechanism is based on the fast release of K+ form the cell, which induces an immediate vasodilatory response of cerebral vessels, feedback regulation appears to yield a long‐term adjustment of blood flow to the metabolic demands of the brain tissue. This holds for physiological conditions and even more for pathophysiological conditions, such as hypoxia and ischemia. © 1993 Wiley‐Liss, Inc.
Adenosine A2a receptor expression in striatal neurons: Implications for basal ganglia pathophysiology
Authors: Schiffmann Serge N. , Halleux Pascale , Menu Roberte , Vanderhaeghen Jean‐Jacques
Published: January 2005

Two dog adenosine receptors have been recently cloned. They were pharmacologically characterized as an A1 and the A2a receptor, respectively. The adenosine A2a receptor is exclusively expressed in medium‐sized neurons of the striatum as demonstrated by in situ hybridization. The relationships of this A2a receptor with three major components of the striatum, enkephalin, substance P, and choline acetyltransferase, were studied in the rat. This demonstrates that the adenosine A2a receptor is exclusively expressed by the enkephalinergic striatal neuronal subpopulation that also selectively expresses the dopamine D2 receptor. Conversely, The A2a receptor is never detected in the substance P containing neurons or in the cholinergic neurons. This observation most probably constitutes the anatomical substratum for the preciously described A2a‐D2 receptors interactions. It also indicates that A2a receptor is selectively express in the indirect pathway of the basal ganglia system which is hypoactive in hyperkinetic disorders such as Huntington's disease and hyperactive in hypokinetic disorders such as Parkinson's disease. The development of highly A2a selective ligands could be therefore useful in the therapy useful in the therapy of basal ganglia degenerative diseases. © 1993 Wiley‐Liss, Inc.
Electrophysiological analysis of exogenous and endogenous adenosine actions in the rat and human hippocampus in vitro
Authors: Haas Helmut L. , Gerber Urs , Greene Robert W. , Stevens David R.
Published: January 2005

Adenosine acts in at least three different ways at A1 receptors in order to reduce excitability and signal transfer. In the hippocampus, it causes in a steady state outward (potassium) current which is blocked by barium ions and not sensitive to voltage; (ii) an increase in the calcium and cyclic AMP‐dependent current 1AHP which is responsible for a long lasting afterhyperpolarization and the accommodation of action potential firing; (iii) a presynaptic reduction of excitatory but not inhibitory transmitter release. The mechanism of this effect is unclear. It is, in contrast to the former, not sensitive to pertussis toxin. When the adenosine elicited potassium currents at the postsynaptic site are blocked, slow inward currents, normally carried by calcium, are unaffected by adenosine. A2 receptor mediated actions have not been found in the hippocampus. While the precise analysis of these effects has been done largely on rats they were all found in human hippocampal slices as well. © 1993 Wiley‐Liss, Inc.
Analgesic profile of the sodium salt of pemedolac
Authors: Chau Thuy T. , Walter Thomas , Katz Alan , Weichman Barry M.
Published: January 2005

Pemedolac Na, 1‐ethyl‐1,3,4,9‐tetrahydro‐4‐(phenylmethyl)‐pyrano [3,4‐b] indole‐1‐acetic acid sodium salt, exhibited equipotent analgesic effects after oral, iv, and im administration, suggesting that it is well absorbed. In mouse writhing models, the ED50 values ranged from 0.3 mg (0.81 μmol)/kg (vs. acetylcholine) to 4.3 mg (11.6 μmol)/kg (vs. paraphenylbenzoquinone [PBQ]). In the rat Randall‐Selitto model, the ED50 o the compound was approximately 0.001 mg (2.7 nmol)/kg, with a flat dose response curve. The peak effects lasted for 7–9 h, 10–18 h, and 5 h following oral, im, and iv injections, respectively. Intracerebroventricular (i.c.v.) injections of pemedolac Na inhibited the PBQ‐induced writing in mice with an ED50 of 43.5 μg (0.12 μmol)/mouse, and this effect was not antagonized by naloxone. It was inactive in the hot plate and tail flick tests, demonstrating that pemedolac Na does not act via an opiate mechanism. These results indicate that pemedolac Na is a viable parenteral and oral analgesic, typified by high analgesic potency, a rapid onset and long duration of action, and an extremely wide safety index. © Wiley‐Liss, Inc.
Oxiracetam and aniracetam increase acetylcholine release from the rat hippocampus in vivo
Authors: Giovannini Maria Grazia , Rodinò Paola , Mutolo Donatella , Pepeu Gincarlo
Published: January 2005

The effect of two nootropic drugs, oxiracetam and aniracetam, on cholinergic neurotransmission in vivo was investigated in the rat by means of the transversal microdialysis techique. The basal release of acetylcholine (ACh) from the hippocampus and parietal cortex was 2.93 ± 0.17 and 3.10 ± 0.18 pmol/min (mean ± s.e.m.), respectively, and remained stable for at least 3 h, while the initial efflux of choline was 51.9 ± 2.6 and 42.8 ± 6.4 pmol/20 min (mean ± s.e.m.), respectively, and decreased by about 50% during the first 60 min of collection. Oxiracetam, tested at doses of 50, 100, and 300 mg/kg ip, elicted a 63% increase in ACh release from the hippocampus at the dose of 100 mg/kg only. This effect of oxiracetam was inhibited by perfusion with tetrodotoxin (TTX), 5 × 10−7 M. In oxiracetam‐treated rats the decrease in choline efflux was less pronounced than in controls (‐23% of the initial value) at the dose of 100 mg/kg. Aniracetam (100 mg/kg, orally) elicited a sustained increase of ACh release from the hippocampus (+ 58%, 120 min after the administration), without affecting choline efflux. Doses of 50 and 300 mg/kg, orally, of aniracetam were ineffective. Oxiracetam and aniracetam (50 and 100 mg/kg) neither modified the output of ACh or choline from the parietal cortex nor induced gross behavioral changes. These results indicate that oxiracetam and aniracetam could act on cognitive processes by stimulating the hippocampal cholinergic pathways. © Wiley‐Liss, Inc.
Problems and perspectives in the design of anti‐HIV‐1 agents
Authors: Mohan Prem
Published: January 2005

The human immunodeficiency virus (HIV) that produces the acquired immune deficiency syndrome (AIDS) continues to evade all strategies for potential therapeutic intervention. Global efforts in the search for potential anti‐HIV‐1 agents have mainly centered around the design of enzyme inhibitors and derivatives that inhibit viral binding or gene expression. Both nucleoside and non‐nucleoside reverse transcriptase inhibitors have demonstrated potent anti‐HIV‐1 activity. However, toxicity considerations and the emergence of resistant strains will require further structural manipulations to diminish these undesirable properties. Protease inhibitors also exhibit activities at nanomolar concentrations, but many of these agents may suffer from problems of absorption and biodegradation. These apparent shortcomings have been circumvented by the preparation of peptidomimetic molecules. Similarly, smaller CD4 mimetics have emerged as alternatives to the larger soluble CD4 derivatives as inhibitors of viral binding. Other viral binding inhibitors, the anionic molecules, suffer from an inherent inability to enter cells and potential anticoagulant activity. These properties may be remedied by rational analog design and synthesis. Oligonucleotides can be constructed to inhibit specific segments of selected regulatory genes of the virus. These agents have been critiqued on the basis of stability, cellular uptake, and assurance of hybridization. Once again, structure activity relationship studies have revealed that many of these apparent problems can be overcome. The more recently discovered agents belong to the unique classes oftatantagonists or viral uncoating inhibitors. © 1993 Wiley‐Liss, Inc. © 1993 Wiley‐Liss, Inc.
Psychomotor stimulants versus antidepressants in the learned helplessness model of depression
Authors: Geoffroy Marianne , Christensen Anne V.
Published: January 2005

Animal models of depression which use stress to induce abnormal behavior generally cannot discriminate antidepressants from drugs which are central stimulants and predominantly stimulate dopamine (DA) neurons. Thus these models lack pharmacological specificity. The present study shows that the Learned Helplessness (LH) model, applied to Wistar rats, becomes a more valid pharmacological model if registration of the animals' behavior during the interval between each trial of the LH shuttlebox test is added. The DA drugs amphetamine, methylphenidate, nomifensine, apomorphine, quinpirole (specific D2 agonist), SKF 81297 (specific D1 agonist), and the antidepressants imipramine, amitriptyline, and isocarboxazide were tested. The results show that the DA drugs had an acute effect and increased the number of shuttle box crossings in the intervals between the test trials. The antidepressants had no acute effect and did not increase the number of intertrial crossings in the therapeutic dose range. The LH model thus seems to be advantageous when discrimination between drugs with DA psychomotor stimulating properties and drugs with antidepressant properties is needed. © 1993 Wiley‐Liss, Inc.
Effect of desferrioxamine on the hepatotoxicity of adriamycin in normal mice
Authors: Al‐Bekairi Abdullah M. , Osman Abdel‐Moneim M. , Hafeez Mohamed A. , Al‐Gharably Naji M. , Al‐Shabanah Othman A. , Al‐Harbi Mohamed M.
Published: January 2005

The effect of the iron chelator, desferrioxamine (DFO) upon the hepatotoxic effects associated with the use of adriamycin as a cytotoxic agent were evaluated in normal albino mice. Hepatocellular toxicity was assessed by measuring serum aspartate transaminase (SGOT), serum alanine transaminase (SGPT) and serum alkaline phosphatase (ALP) activity. In addition, glucose‐6‐phosphatase (G‐6‐PTase) activity, nucleic acids, calcium, magnesium, and iron levels in liver tissue were also measured. Adriamycin treatment (2 mg/kg i.p.), administered every other day for a total of 5 doses produced a 2.5‐fold increase in SGOT and SGPT, while ALP activity showed a 30% increase in comparison to normal, untreated controls. However, hepatic G‐6‐PTase activity showed a significant decrease after the adriamycin treatment regimen. The calcium and iron content of liver showed also a marked decrease, while magnesium levels were increased two‐fold after treatment with adriamycin. In the presence of the iron chelator, DFO (100 mg/kg i.p., administered every other day for 5 doses), adriamycin treatment did not result in any significant changes in SGOT, SGPT, ALP, or hepatic G‐6‐PTase activity. Histopathological examination of mouse liver showed diffuse ballooning degeneration of liver cells with perivascular cellular infiltration after adriamycin treatment. In the presence of DFO, only focal cellular degenerative and minimal fatty changes were observed. The observed hepatocellular damage is believed to be a result of the lipid peroxidation induced by adriamycin. The role of DFO in preventing lipid peroxidation has been discussed. This study provides evidence that DFO may be useful for prevention of the lipid peroxidation and hepatocellular damage induced by adriamycin. © 1993 Wiley‐Liss, Inc.
Site specific variations in rat adipose tisue transforming growth factor‐α: Effects of age
Authors: Crandall David L. , Cervoni Peter , Kral John G.
Published: January 2005

Transforming growth factor alpha (TGF‐α) was assayed in subcellular preparations obtained by sequential centrifugation of adipose tissue homogenates from epididymal and perirenal adipose tissue depots in young and aged rats. When expressed per unit wet weight, per mg protein or per fat cell, TGF‐α activity in young rats was greater in the epididymal than in the perirenal depot. In aged rats, absolute quantity of TGF‐α was significantly increased in the larger perirenal depot. This study demonstrates the presence of TGF‐α in adipose tissue homogenates, and implicates this cytokine in the growth of adipose tissue. © 1993 Wiley‐Liss, Inc.
MK‐329: A non‐peptide cholecystokinin a antagonist
Authors: Evans Ben E.
Published: January 2005

Peptide receptors represent important targets for a variety of potentially important disease modifying drugs. Over the past 20 years, considerable effort has been spent on modifying the natural ligands for peptide receptors, the peptides themselves, with limited success. Using a targeted screen, namely cholecystokinin (CCK)‐A receptor binding, the Merck group in 1984 discovered asperlicin, a potent non‐peptide cholecystokinin antagonist selective for peripheral tissues, that was isolated from Aspergillus alliaceaus. This compound was used as a lead to develop MK‐329, a CCK‐A receptor antagonist, the evolution of which is discussed within the context of the drug discovery process and receptor modeling strategies. © 1993 Wiley‐Liss, Inc.
Linopirdine (DuP 996) selectively enhances acetylcholine release induced by high potassium, but not electrical stimulation, in rat brain slices and guinea pig ileum
Authors: Smith Craig P. , Brougham Linda R. , Vargas Hugo M.
Published: January 2005

The enhancement of acetylcholine (ACh) release during electrical or potassium depolarization was compared in the presence of either linopirdine or 4‐aminopyridine (4‐AP) using two different functional assays. We measured ACh and choline (Ch) directly from striatal perfusates using high performance liquid chromatography and electrochemical detection or indirectly by measuring ACh‐mediated twitch height changes in the electrically stimulated guinea pig ileum. Potassium‐induced twitch responses were also measured in resting ileal segments. Linopirdine significantly enhanced ACh release in the presence of elevated potassium levels in rat striatal slices and guinea pig ileum, but had no effect during electrical stimulation in either model. In contrast, 4‐AP enhanced ACh release in both electrically stimulated striatal slices and ileal strips. In agreement with other studies, atropine enhanced ACh release during either electrical or potassium stimulation paradigms in the striatal slice. The in vitro observations in this report suggest that linopirdine has limited ability to augment the cholinergic neurotransmission evoked by electrical stimulation. © 1993 Wiley‐Liss, Inc.
Setting the record straight: The office of technology assessment report—pharmaceutical R&D costs, risks, and rewards
Authors: Sapienza Alice M.
Published: January 2005

The U.S. Office of Technology Assessment (OTA) report on pharmaceutical research and development (R&D)—costs, risks, rewards—has generated a range of often heated responses, both for and against the industry. The purpose of this commentary is to clarify two points of confusion that repeatedly appear about the report: First, it is not a new and definitive study of the cost of pharmaceutical R&D (although certain related studies were commissioned by OTA). Second, the report is not unexpected, given the political‐economic context in which drug prices have historically been discussed. © 1993 wiley‐Liss, Inc.
Preventive effect of the thromboxane A2 receptor antagonist S‐1452 (d‐s‐145 Ca) on arachidonate‐induced sudden death and cerebral infarction in rabbits
Authors: Jyoy Hirokuni , Kurosawa Atsushi
Published: January 2005

The thromboxane A2 (TXA2) receptor antagonist S‐1452, d‐S‐145 Ca, calcium 5(Z)‐1R,2S,3S,4S‐7‐[3‐phenylsulfonylaminobicyclo[2.2.1]hept‐2‐yl]‐5‐heptenoate dihydrate, prevented sudden death induced by arachidonate or U46619 in rabbits when given in a dose range between 0.1 mg/kg and 1 mg/kg, p.o. OKY‐046 and aspirin were also effective in this thromboembolism model, but 10 to 30 times larger doses were needed. Orally administered S‐1452 successfully prevented the incidence of cerebral infarction in the rabbit, which was elicited by infusion of 10 mg/ml sodium arachidonate at a rate of 0.1 ml/min for 30 min via a left internal carotid artery. Significant reduction of the infarction grade was observed in dosing above 3 mg/kg of this compound 1 to 4 h before the arachidonate infusion. OKY‐046 was effective similarly, but less active than S‐1452 (the minimum effective dose: 10 mg/kg). Ticlopidine and aspirin were entirely inactive in this model even after much larger doses. S‐1452 is a useful compound for prevention of TXA2‐mediated thrombosis in the brain. © 1993 wiley‐Liss, Inc.
Differential effects of pretreatment with nicotine and lobeline on nicotine‐induced changes in body temperature and locomotor activity in mice
Authors: Decker Michael W. , Buckley Michael J. , Brioni Jorge D.
Published: January 2005

Although lobeline and nicotine are both potent ligands at neuronal nicotinic cholinergic receptors, chronic lobeline does not produce the upregulation of nicotinic receptors found with chronic nicotine or the less potent agonist anabasine. Since agonist‐induced receptor upregulation is believed to result from receptor desensitization during chronic treatment, this suggests that lobeline may not desensitize neuronal nicotinic receptors. We addressed this question by comparing lobeline‐ and nicotine‐induced desensitization of the actions of nicotine, using body temperature and locomotor activity as dependent variables. Nicotine pretreatment reduced the hypothermia and locomotor suppression produced by a subsequent nicotine challenge, whereas lobeline pretreatment did not. When tested alone, both nicotine and lobeline reduced locomotor activity and body temperature to a similar degree, but lobeline was significantly less potent. The reductions in activity and temperature produced by nicotine were significantly attenuated in chlorisondamine‐treated mice, whereas treatment with this long‐lasting nicotinic cholinergic antagonist did not alter the effects of lobeline. Thus, nicotine and lobeline appear to differ in their ability to produce desensitization. Furthermore, the effects of these two compounds on locomotor activity and body temperature may be mediated via different mechanisma. © 1994 Wiley‐Liss, Inc.