bluuebunny/crossref_metadata_2025 huggingface dataset:
Misoprostol in the treatment of duodenal ulcers in the people's Republic of China: A comparative, double‐blind, multicenter study
Authors: Dajani Esam Z. , Wang Baoen , Pei Ying , Pan Gaozhong , Chen Shoubo , Zheng Zhitian , Li Yinong , Zhu Wunan , Wang Jiyao , Yuan Shizhen , Yu Yongoda , Yao Zhi Jian
Published: January 2005

In recent years, it has become mandatory for many pharmaceutical companies to conduct country‐specific clinical studies which are needed for obtaining regulatory approvals for their drugs. Such studies are important to delineate possible racial or environmental (lifestyle) differences which could not have been predicted from data obtained in other populations. A double‐blind, randomized, double‐dummy, multiclinic, comparative trial examined the tolerance and efficacy of misoprostol (200 μg QID) and cimetidine (200 mg QID) for the treatment of duodenal ulcers in the People's Republic of China. The trial characteristics and monitoring complied with the standards in the United States of America and the People's Republic of China. Two hundred consenting outpatients of either sex, aged 18–75 years, who had duodenal ulcers (not less than 0.3 cm in longest diameter and not more than 2 ulcers) were enrolled. Endoscopy, physical examination, and laboratory assessments wereperformed on entry and after 4 weeks of treatment. The effects of the treatment on ulcer healing, dyspeptic symptoms, tolerance, and adverse drug reactions were determined. Both treatment groups were well matched for demographic characteristics and disease severity at entry to the study. Misoprostol showed equal efficacy to cimetidine in inducing ulcer healing (60.7% vs. 67.9% for misoprostol and cimetidine, respectively, P > 0.05) and resolving dyspeptic pain. The extent of duodenal ulcer healing achieved by misoprostol in this study is essentially similar to the ulcer healing rates noted in many other worldwide studies, indicating the absence of racial differences in response to misoprostol. The adverse effects observed for misoprostol and cimetidine were also very similar. Both drugs were very well tolerated; however, slightly more patients experienced transient diarrhea with misoprostol (6.4%) than with cimetidine (3.8%). In conclusion, this trial supports the world‐ wide efficacy and tolerance of misoprostol for the treatment of duodenal ulcers and indi‐ cates the absence of racial influences on the safety and efficacy of misoprostol. © 1992 Wiley‐Liss, Inc.
Inability of β‐amyloid (25–35) to bind to central nervous system neurokinin 1 receptors
Authors: Lee John M. , Weinstein David A. , Kowall Neil W. , Beal M. Flint
Published: January 2005

β‐Amyloid (1–40) has recently been shown to exhibit both neurotoxic and neurotrophic properties. The putatively active moiety is β‐(25–35), which has a structural homology to the human tachykinin substance P. Substance P, which preferentially binds to neurokinin 1 (NK1) receptors in the central nervous system (CNS), has been shown to block the neurotoxic effects of β‐amyloid (1–40). These data suggest that effects of β‐amyloid may be mediated by an NK1 receptor‐mediated process. However, in the present study, we demonstrate that β‐(25–35) is unable to competitively inhibit the binding of 0.15 nM 125I‐substance P from rat CNS NK1 receptors. Therefore, the mechanisms of action of β‐amyloid neurotoxic effects are probably not to be mediated through a NK1 receptor‐mediated process. © 1992 Wiley‐Liss, Inc.
Protection and reversal by memantine and atropine of carbofuran‐induced changes in biomarkers
Authors: Gupta Ramesh C. , Goad John T. , Kadel Wade L.
Published: January 2005

Male Sprague‐Dawley rats injected with a single acute dose of carbofuran (1.5 mg/kg, sc) developed chewing movements and fine tremors within 5–7 min. The signs of maximal severity with hypercholinergic preponderance including muscle fasciculations, convulsions, tracheobronchial secretions, and diarrhea were evident within 15–30 min and lasted for about 2 h. Various antidotal drugs, alone or in combination with atropine sulfate (ATS), were administered as pretreatment or as therapeutic measures to alleviate carbofuran‐induced cholinergic toxicity. In fact, pyridine‐2‐aldoxime methylchloride (2‐PAM) or diazepam alone or in combination with ATS did not provide any beneficial antidotal effects. Combined pretreatment with memantine (MEM, 18 mg/kg, sc) and ATS (16 mg/kg, sc) provided complete protection against carbofuran toxicity and reversal of clinical evidence when given therapeutically. Carbofuran intoxication caused significant alterations in the activities of biomarker enzymes such as creatine kinase (CK) and lactic dehydrogenase (LDH) and their isoenzymes patterns in serum as a result of their leakage from the target organs (brain, muscles, and heart). Significant increases in the levels of transaminases (GOT and GPT) and glucose were also noted, MEM in the aforementioned parameters, in addition to similar protective effects reported on target enzyme acetylcholinesterase (AChE). These results, along with those reported previously, indicate that MEM antagonizes carbamates toxicity by maintaining cell membrane permeability and integrity through multiple mechanisms, in addition to muscarinic receptor blocking effect of ATS. © 1993 Wiley‐Liss, Inc.
Diadenosine polyphosphate (ApxA) as new neurotransmitters
Authors: Pintor Jesúas , Miras‐Portugal M. Teresa
Published: January 2005

The presence of diadenosine polyphosphates (ApxA), diadenosine tetraphosphate (Ap4A), diadenosine pentaphosphate (Ap6A), and diadenosine hexaphosphate (Ap6A), has been described in secretory granules of chromaffin cells, Torpedo synaptic vesicles, and rat brain synaptosomes. The release of these compounds by the action of secretagogues and depolarizing agents, in the presence of calcium, increases their importance as active neurotransmitters. Two high affinity receptors have been described in the three neural models, with Kd values ranging from 0.08 to 0.40 nM for the first binding site and from 5.6 to 18nM for the second lower affinity binding site. Both binding sites exhibit a P2y‐like profile in chromaffin cells and Torpedo synaptic terminals and a different pattern in rat brain synaptosomes, suggesting the presence of a novel P2‐purinoceptor tentatively named P2d. Studies about the second messenger linked to this receptor, in chromaffin cells, demonstrate the mobilization of calcium from internal stores. ApxA receptors at the extracellular milieu are responsible for the inhibition of catecholamine release stimulated by secretagogues. Finally, all diadenosine polyphosphates are destroyed by the action of an ecto‐phosphodiesterase which, in chromaffin cells, shows Km values ranging from 1 to 4 μM. © 1993 Wiley‐Liss, Inc.
Prevention of ischemic brain injury by adenosine receptor activation
Authors: Phillis John W. , O'Regan Michael H.
Published: January 2005

The abilities of the xanthine oxidase inhibitor, oxypurinol, and the adenosine deaminase inhibitor, deoxycoformycin, to alleviate cerebral ischemic damage were evaluated in gerbil and rat models. Cerebral ischaemia of 5 min duration was induced in unanesthetized Mongolian gerbils by bilateral occlusion of the carotid arteries. Cerebral damage was assessed behaviorally by the elevation of motor activity and by histological assesment of neuronal degeneration in the CA1 area of the hippocampus. Oxypurinol (40 mg/kg) administered either prior to or 30 min after and ischaemic episode significantly reduced both the hypermotility and hippocampal damage observed in saline‐treated control ischemic gerbils. Deoxycoformycin (500 μg/kg) was effective only when administered prior to ischemia. Rats with a focal ischaemic lesion (unilateral occlusion of a middle cerebral artery combined with tandem occlusion of the ipsilateral common carotid artery) were used to model strokes. The degree of ischaemic damage was evaluated by measuring the contralateral neurological deficits at 24 and 48 h post infarction and by calculating the volume of infarcted tissue after brain slices had been stained with 2,3,5‐triphenyl, 2H‐tetrazolium chloride (TTC) solution. Oxypurinol (40 mg/kg) administered 30 min prior to or 1h after the onset of focal ischaemia significantly reduced the infarct size, brain swelling, and neurological deficits. Deoxycoformycin (500 μg/kg) was effective only when administered preischemia. These findings suggest that oxypurinol and deoxycoformycin may be useful for the prevention and treatment of ischaemic brain injuries. © 1993 Wiley‐Liss, Inc.
Action of a novel potassium channel opener, SR 47063, on human bronchi and on guinea‐pig trachea in vitro: comparison with cromakalim
Authors: Martin Corinne A. E. , Naline Emmanuel , Advenier Charles
Published: January 2005

Potassium channels are present on airway smooth muscle cells and their activation results in hyperpolarization and relaxation. Because these effects may have therapeutic relevance to asthma, the aim of our study was to examine the activity of SR 47063, a potassium channel opener (KCO), against a variety of spasmogens or against electrical field stimulation in guinea‐pig isolated trachea and in human isolated bronchi in vitro; the effects of SR 47063 were compared with those of cromakalim, isoprenaline, and theophylline. Like cromakalim, SR 47063 reduced the contractility of guinea‐pig isolated trachea and the human isolated bronchus in basal tone with pD2 of 7.79 ± 0.01 and 7.83 ± 0.09, respectively, or during precontractions induced by acetylcholine 10−4 M, histamine 10−5 M, or low concentrations of KCl (<30 mM), but not by high KCl concentrations (≥30 mM); these effects were antagonized by glibenclamide 10−5 M. This spectrum of action is typical of the compounds known as potassium channel openers. Electrical field stimulation (EFS: 16 Hz, 1 ms, 320 mA for 10 sec in the presence of indomethacin 10−6 M and propranolol 10−6 M) of guinea‐pig isolated main bronchi induced 2 successive contractile responses. Both contractions were reduced significantly by SR 47063 and cromakalim. Although we have not studied the effects of KCOs on exogenous neurokinin A‐ or substance P‐induced contractions, it might be suggested as a hypothesis that this inhibition seems to take place presynaptically and to affect the release of neuromediators produced by electrical field stimulation. In conclusion, SR 47063 exerts in vitro on the bronchial smooth muscle an inhibitory effect which seems to be due to the opening of glibenclamide‐sensitive potassium channels. SR 47063 is 3‐ to 10‐fold more potent than cromakalim. © 1993 Wiley‐Liss, Inc.
Effects of linopirdine, HP 749, and glycyl‐prolyl‐glutamate on transmitter release and uptake
Authors: Zaczek Robert , Tinker William J. , Logue Andrew R. , Cain Gary A. , Teleha Christopher A. , Tam S. William
Published: January 2005

Linopirdine, HP 749, and glycyl‐prolyl‐glutamate (GPE) are compounds that have been reported to alter the release of neurotransmitters. This study compares the potassium‐stimulated neurotransmitter release enhancing properties maximal release enhancement. HP 749 increased the extracellular concentrations of the catecholamines, [3H]NE and [3H]DA, but not [3H]ACh or [3H]d‐Asp. HP 749 was a potent inhibitor of both [3H]NE and [3H]DA uptake, and this may, in part, be responsible for the apparent release enhancing activity of the drug. GPE was devoid of release enhancing activity under the conditions of these compounds in parallel. While not affecting the apparent release of [3H]norepinephrine ([3H]NE), linopirdine at a concentration of 10 μM enhanced the potassium evoked release of cerebral cortical and hippocampal [3H]acetylcholine ([3H]ACh) release by 143% and 200% over control, respectively, and striatal [3H]dopamine ([3H]DA) and hippocampal [3H]d‐aspartate ([3H]d‐Asp) release by 236% and 65% over control, respectively. The release enhancing effects of linopirdine were not due to inhibition of high‐affinity uptake processes, since the drug did not inhibit neurotransmitter uptake at the concentration (10 μM) which caused used in the present study. © 1993 Wiley‐Liss, Inc.
Effects of the PAF antagonists bepafant and L‐659, 989 in endotoxic and septic shock
Authors: Tang Hai Ming , Teshima Dick Y. , Lum Bert K. B.
Published: January 2005

Many of the pathophysiological effects of endotoxin (ETX) can be mimicked by the administration of platelet activating factor (PAF), and the latter has been implicated as a possible mediator of the derangements seen in endotoxic shock. In this investigation, two new potent PAF antagonists, bepafant (WEB‐2170) and L‐659,989, were studied for their effects in experimental endotoxic and septic shock in rats. Pretreatment with the PAF antagonists, 15 min prior to the iv administration of Escherichia coli endotoxin (ETX), was found to be highly effective in decreasing the mortality caused by the lipopolysaccharide. The antagonists were less effective in reducing mortality when given as post‐treatment 15 min after ETX, and were ineffective when post‐treatment was delayed until 30 min after ETX. Administration of ETX caused manifestations of disseminated intravascular coagulation (DIC), including thrombocytopenia, prolongation of prothrombin time (PT) and partial thromboplastin time (PTT), hypofibrinogenemia, elevation of serum fibrin(ogen) degradation products (FDP), and gastrointestinal hemorrhage. With the exception of the thrombocytopenia, the PAF antagonists reduced or abolished all of the hematological manifestations of DIC caused by ETX. Septic shock was produced by ligation and puncture of the cecum in rats. The PAF antagonists, given as two iv doses (an initial 2.0 mg/kg dose administered 1.5 or 2.5 h after cecal puncture and a second dose given 5 h later), significantly reduced the cumulative 24‐h mortality. These results provide added evidence of the importance of PAF and DIC in the pathophysiology of ETX and suggest that PAF antagonists may be useful in the clinical management of septicemia/endotoxemia. © 1993 Wiley‐Liss, Inc.
Further characterization of the 5‐hydroxytryptamine1‐like receptors mediating the increase in external carotid blood flow in the dog
Authors: Villaón Carlos M. , Terrón José A. , Hong Enrique
Published: January 2005

It has recently been shown that the increase in external carotid blood flow (external CBF) produced by 5‐hydroxytryptamine (5‐HT) in the anaesthetized dog, being mimicked by 5‐carboxamidotryptamine, potently blocked by methiothepin and resistant to blockade by ritanserin and MDL 72222, is mediated by 5‐HT1‐like receptors. In the present investigation, we have further characterized these 5‐HT1‐like receptors. Like 5‐HT, 1 min intracarotid (i.c.) infusions of the 5‐HT1A receptor agonist, indorenate, produced an increase in external CBF without modifying mean arterial blood pressure or heart rate. Contrasting with indorenate, 1 min i.c. infusions of the 5‐HT1A receptor agonists, 8‐hydroxy‐2(di‐N‐propylamino)tetralin (8‐OH‐DPAT), buspirone and ipsapirone, or the 5‐HT1A/5‐HT1B receptor agonist, 5‐methoxy‐3‐[1,2,3,6‐tetrahydro‐4‐pyridinyl]‐1‐H‐indol succinate (RU 24969), resulted in dose‐dependent decreases in external CBF; furthermore, both the 5‐HT1C/5‐HT2 receptor agonist, 1‐(2,5‐dimethoxy‐4‐iodophenyl‐)‐aminopropane (DOI) and the 5‐HT3 receptor agonist, 2‐methyl‐5‐hydroxytryptamine (2‐methyl‐5‐HT), were essentially inactive. Thus, only indorenate increased the external CBF in the dog; this effect of indorenate was not antagonized by intravenous (i.v.) administration of the 5‐HT1 and 5‐HT2 receptor antagonist, methiothepin, or completely abolished after sympathectomy. Unlike methiothepin, the 5‐HT1A and 5‐HT1B receptor antagonist, (±)‐pindolol, did not block indorenate‐induced external carotid vasodilatation. Together, the above results support the notion that indorenate is acting on the 5‐HT1‐like receptors involved in the increase in external CBF in the dog. These receptors, which are probably located on carotid sympathetic nerve endings, do not seem to correspond to either the 5‐HT1A, 5‐HT1B, or 5‐HT1C binding sites. © 1993 Wiley‐Liss, Inc.
Alcohol‐induced reinforcement: Dopamine and 5‐HT3 receptor interactions in animals and humans
Authors: Johnson Bankole A. , Cowen Philip J.
Published: January 2005

Alcohol abuse is a major health problem worldwide. Whatever the treatment goal, be it abstinence or “controlled” drinking, the outcome from both pharmacological and nonbiological treatments remains disappointing. Behavioural experiments in animals have suggested that the reinforcing properties of alcohol, like other drugs of abuse, are critical to drug‐seeking behaviour. Dopaminergic fibres running from the ventral tegmental area to the nucleus accumbens may play a central role in mediating the reinforcing effects of drugs of abuse including alcohol. Thus, alcohol increases extracellular levels of dopamine in the nucleus accumbens and dopamine receptor antagonists decrease alcohol consumption in a number of behavioural paradigms. A recently described subtype of serotonin (5‐HT) receptor, the 5‐HT3 receptor, appears to modulate the effects of alcohol on dopamine release in the nucleus accumbens. In rodents, 5‐HT3 receptor antagonists inhibit alcohol‐induced dopamine release in the nucleus accumbens. Further, in behavioural studies, 5‐HT3 receptor blockade decreases alcohol consumption in a free‐choice paradigm. In humans, reinforcement is difficult to measure directly. Nevertheless, the pleasurable subjective effects of alcohol are important behavioural correlates of the reinforcement process. Our preliminary findings in humans suggest that the 5‐HT3 receptor antagonist, ondansetron, can attenuate some of the pleasurable effects of a small dose of alcohol including the subjective desire to drink. We speculate, although we have no direct evidence for this at present, that in humans this effect could also be due to a blockade of alcohol‐induced dopamine release in the nucleus accumbens as has been demonstrated in animals. Further studies with clinical populations are required to assess the effects of 5‐HT3 receptor antagonists on drinking behaviour and to explore their potential in the management of alcohol abuse. © 1993 wiley‐Liss, Inc.
Intracerebroventricular nicotine and mecamylamine alter radial‐arm maze performance in rats
Authors: Brucato Frederic H. , Levin Edward D. , Rose Jed E. , Swartzwelder H. Scott
Published: January 2005

In rats, the effects of an intracerebroventricular (ICV) nicotinic agonist nicotine (NIC), the nicotinic antagonist mecamylamine (MEC), and combinations of NIC + MEC were assessed in a radial‐arm maze (RAM). In experiment 1, exploratory behavior was assessed in untrained rats (N = 13). The rats received 4 μg, 8.65 nmol NIC (NIC 4), 200 μg, 0.98 μmol MEC (MEC), and saline (SAL) ICV infusions. NIC 4 caused a significant increase in choice distribution compared to SAL (P < 0.025). In experiment 2, rats (N = 10) were trained to perform a working memory task for food reinforcement in the RAM. ICV doses of SAL, NIC 4, NIC 8, MEC, MECNIC 4, and MECNIC 8 were administered after completion of the training period. MEC caused a significant deficit in choice accuracy when compared to SAL (P < 0.025). This deficit was reversed when NIC 8 was coadministered with MEC (P < 0.05). There were no significant effects on choice latency for either study. The effects of ICV NIC and MEC on RAM performance are generally similar to their systemic effects in that NIC improves and MEC impairs choice accuracy. The reversal of the MEC‐induced choice deficit by ICV NIC administration has not been reported with systemic administration. ICV MEC induces a choice accuracy deficit without increasing choice latency. This has not been seen with systemic MEC administration. The current result implies that the MEC‐induced choice accuracy deficit did not result from MEC‐induced sedation. The data indicate that previously reported changes in choice accuracy from peripherally administered NIC and MEC result from their central effects. © 1994 Wiley‐Liss, Inc.
Nicotine interactions with dopamine agonists: Effects on working memory function
Authors: Levin Edward D. , Eisner Batya
Published: January 2005

Nicotine has been found to improve memory performance in a variety of tests including the radial‐arm maze. Nicotine may have effects mediated by promoting the release of dopamine. The present study was conducted to determine the interactions of nicotine with D1 and D2 agonists. Rats were acutely administered nicotine, the D1 agonist SKF 38393, and D2/D3 agonist quinpirole, and nicotine together with each of these agonists. Nicotine significantly improved choice accuracy in the radial‐arm maze. The D1 agonist SKF 38393 significantly impaired choice accuracy. Nicotine was effective in reversing this effect. The D2/D3 agonist quinpirole showed a trend toward potentiating the improvement in choice accuracy caused by 0.2 mg/kg (0.43 μmol/kg) of nicotine. These data show that, as with the nicotinic antagonist mecamylamine, there are significant interactions of dopamine systems with nicotine effects. © 1994 Wiley‐Liss, Inc.
Effects of anabaseine‐related analogs on rat brain nicotinic receptor binding and on avoidance behaviors
Authors: Meyer Edwin M. , de Fiebre Christopher M. , Hunter Bruce E. , Simpkins Christopher E. , Frauworth Neal , de Fiebre Nancy Ellen C.
Published: January 2005

Several novel anabaseine‐derived compounds were investigated with respect to their ability to displace high affinity [3H]cytisine binding in rat brain membranes, as well as their ability to improve passive and active avoidance behaviors in nucleus basalis‐lesioned rats. The relative potencies for displacement of 1 nM [3H]cytisine binding IC50 in parentheses: anabaseine (70 nM) > DMAB (140 nM) = DMXB (150 nM) > anabasine (270 nM) > DMAC (420 nM). Passive avoidance behavior in bilaterally nucleus basalis‐lesioned rats was improved by each of these drugs to an extent comparable to that observed with (–)‐nicotine. The relative potencies of these compounds for improving this behavior exhibited a pattern very similar to their affinities for displacing [3H]cytisine binding (nicotine > anabaseine > DMXB > DMAB = DMAC > anabasine). Acquisition of active avoidance behavior was slower in unilaterally and bilaterally nucleus basalis‐lesioned rats than unlesioned controls; (−)‐nicotine improved acquisition behavior only in the former group. At doses that improved passive avoidance behavior, DMXB also improved acquisition of active avoidance behavior in unilaterally lesioned rats, while DMAB and DMAC did not. (−)Nicotine and DMXB had no effect on escape behavior in the active avoidance task at doses that improved retention of avoidance behavior itself. These results suggest that anabaseine and several of its analogs bind to brain α4β2 nicotinic receptors and mimic non‐spatial, memory‐related behaviors in a nicotine‐like manner. © 1994 Wiley‐Liss, Inc.
Alkyl‐modified side chain variants of anatoxin‐a: A series of potent nicotinic agonists
Authors: Thomas Philip , Brough Paul A. , Gallagher Timothy , Wonnacott Susan
Published: January 2005

The potent nicotinic agonist anatoxin‐a has a semi‐rigid structure amenable to chemical synthesis and modification, making it an attractive candidate for exploring the structure‐activity relationships of ligands at nicotinic acetylcholine receptors. Racemic anatoxin‐a and a series of three analogues with one or more methine or methylene units added to the acetyl sidechain were synthesised and designated homoanatoxin, propylanatoxin, and isopropylanatoxin. In competition binding assays on two neuronal nicotinic receptors in rat brain membranes, labelled with [3H]nicotine and [125I]αbungarotoxin, the analogues retained or exceeded the potency of the parent structure. Ki values for anatoxin‐a, homoanatoxin, propylanatoxin, and isopropylanatoxin were 19, 5.5, 24 and 7.5 nM, respectively, at the [3H]nicotine site and 900, 340, 40, and 120 nM, respectively, at the [125I]αbungarotoxin site. Thus propylanatoxin appears to show a preference for the latter receptor site. Functional potencies of homoanatoxin and isopropylanatoxin were determined at neuronal α7 nicotinic receptors reconstituted in Xenopus oocytes, by two electrode voltage clamp recording. EC50 values of 0.72 μM and 0.66 μM were determined, similar to that previously published for (+)anatoxin‐a. Molecular modelling of anatoxin‐a and its alkyl‐modified analogues shows them to have very similar energy profiles, consistent with their similar potencies. In the preferred (low energy) conformation, the enone moiety adopts an s‐trans arrangement, although this configuration does not fit the classical pharmacophore model for nicotinic ligands. This series of alkyl‐modified analogues based on anatoxin‐a provides some novel potent nicotinic agonists and with propylanatoxin, receptor subtype selectivity may be emerging. This rational approach to ligand design also enables us to explore further the requirements for ligand recognition through the application of computational chemistry. © 1994 Wiley‐Liss, Inc.
Effects of repeated treatments with an extract of Ginkgo biloba (EGb 761) and bilobalide on glucose uptake and glycogen synthesis in rat erythrocytes: An ex vivo study
Authors: Rapin Jean R. , Provost Philippe , DeFeudis Francis V. , Drieu Katy
Published: January 2005

The metabolic action of an extract of Ginkgo biloba (EGb 761) has been examined in an ex vivo study of rat erythrocytes. Oral administration of EGb 761 (100 mg/kg/day) for 5 days to Wistar rats caused an increase in the in vitro uptake of glucose by erythrocytes, especially in high‐glucose (13.32 mM) medium, an effect that was associated with an increase in intracellular energy metabolism and reflected as a significant reduction in free glucose concentration. In contrast, the lactate concentration of the erythrocytes and lactate release to the bathing medium were not modified. Conversion of glucose into glycogen was significantly increased in the erythrocytes of EGb 761‐treated animals. Taken together, these findings indicate that in vivo administration of EGb 761 exerts an action favoring the transformation of glucose into glycogen, its storage form. Oral administration of the EGb 761 constituent bilobalide (4 or 8 mg/kg/day) for 5 days caused similar changes in the uptake of glucose and its conversion into glycogen. However, in contrast to the total extract, bilobalide treatment did not increase the energy‐yielding consumption of glucose. © 1994 Wiley‐Liss, Inc.
Effects of linopirdine (DuP 996) and X9121 on age‐related memory impairments and on the cholinergic system
Authors: Baxter Mark G. , Rohrbach Kenneth W. , Tam S. William , Zaczek Robert , Frick Karyn M. , Golski Stephanie , Wan Rui‐Qian , Olton David S.
Published: January 2005

Linopirdine (DuP 996) has been shown to enhance K+‐stimulated release of acetylcholine from cerebral cortex, striatum, and hippocampus of rats in vitro. X9121 is a structurally different compound identified as having similar release properties. The present experiments compare the effects of linopirdine and X9121 on cognitive deficits in aged rats, and on the pharmacological properties in young rats. For cognitive testing, aged male Fischer‐344 rats (24 months old, n = 116) received either vehicle or one of 5 doses of linopirdine or X9121 prior to behavioral testing; young rats (4 months old, n = 13) were controls and received vehicle prior to testing. Place discrimination and repeated acquisition were tested in the water maze, and a variety of sensorimotor tasks were given. Aging impaired performance in all tasks. Linopirdine (0.25, 2.5, and 8.5 mg/kg po [0.64, 7.4, and 25 μmol/kg]) and X9121 (0.85 and 8.5 mg/kg po [2.1 and 24 μmol/kg]) moderately improved place discrimination. None of the doses tested improved repeated acquisition or sensorimotor function. No behavioral indications of toxicity were observed. Acetylcholine release, acetylcholinesterase (AChE) inhibition, and nicotinic and muscarinic binding were measured in vitro in cerebral cortical tissue from young male Wistar rats (2 months old). Both linopirdine and X9121 enhanced K+‐stimulated release from cerebral cortex; X9121 produced greater release with a broader range of active concentrations. Linopirdine weakly inhibited AChE (1,000 × weaker than physostigmine) and X9121 did not. Neither drug bound significantly to muscarinic or nicotinic cholinergic receptors. These results support the hypothesis that linopirdine and X9121 have some cognition enhancing properties which may be due to enhancement of stimulation induced acetylcholine release. These results suggest that linopirdine and X9121 may be useful in treating disorders involving cognitive impairment. © 1994 Wiley‐Liss, Inc.
Mechanisms for the increase in electrically stimulated [3H]norepinephrine release from rat cortical slices by N‐(n‐propyl)‐N‐(4‐pyridinyl)‐1H‐indol‐1‐amine
Authors: Smith Craig P. , Petko Wayne W. , Kongsamut Sathapana , Roehr Joachim E. , Effland Richard C. , Klein Joseph T. , Huger Francis P.
Published: January 2005

N‐(n‐propyl)‐N‐(4‐pyridinyl)‐1H‐indol‐1‐amine (HP 749) is currently in clinical trials for the treatment of Alzheimer's disease (AD). While HP 749 has many pharmacological properties, the biochemical basis for its efficacy in animal models for AD remains unexplained. To this end, we have investigated some biochemical properties of HP 749 as they relate to its effect on electrically stimulated [3H]norepinephrine (NE) release. HP 749 was found to inhibit both [3H]NE uptake and [3H]yohimbine binding to cortical μ2‐adrenergic receptors. Consistent with this profile, HP 749 (1 and 10 μM) enhanced electrically stimulated release of [3H]NE from rat cortical slices. Both clonidine (1 μM) and nomifensine (10 μM) inhibited the effect of HP 749 (1 μM). The enhancement of [3H]NE release produced by the μ2 adrenergic antagonist, idazoxan (0.1 μM), was completely reversed by the μ2 agonist, clonidine (1 μM), but was not affected by the NE uptake inhibitor, nomifensine (10 μM). These results indicate that the HP 749 enhancement of electrically stimulated [3H]NE release is due, at least in part, to a combination of presynaptic μ2‐adrenergic receptor antagonism and NE reuptake blockade. These mechanisms may contribute to some of the adrenergic effects of HP 749.
Characterization of arbutamine: A novel catecholamine stress agent for diagnosis of coronary artery disease
Authors: Young Mark , Pan Wei , Wiesner Jim , Bullough David , Browne Gene , Balow Guity , Potter Scott , Metzner Kurt , Mullane Kevin
Published: January 2005

Arbutamine, 1,2‐Benzenediol,4‐[1‐hydroxy‐2‐[[4‐(4‐hydroxyphenyl)butyl[amino]ethyl]rsqb;rsqb; hydrochloride, (R), is a new catecholamine being developed as a pharmacologic stress agent for the diagnosis of coronary artery disease and myocardial ischemia. The pharmacology of arbutamine was studied in vitro using receptor binding assays and functional bioassays of α‐ and β‐adrenoceptor activity, and in vivo using the hemodynamic responses to intravenous infusion in anesthetized and conscious dogs. In isolated membranes, receptor binding studies demonstrated Ki values of 196 ± 12 nM and 147 ± 11 nM for β1‐ and β2‐adrenoceptors, and 265 ± 4 nM and 867 ± 40 nM for α1‐ and β2‐adrenoceptors, suggesting that arbutamine is a mixed β1+2‐adrenoceptor agonist with significant affinity for β1‐adrenoceptors. This was supported by in vitro bioassay data, where arbutamine increased spontaneous atrial rate (β1‐activity, ED50 = 16 ± 6 nM), relaxed isolated tracheal rings (β2‐activity, ED50 = 13 ± 5 nM), and contracted aortic rings (α‐activity, ED50 = 430 ± 80 nM), indicating 25–30‐fold selectivity for β‐adrenoceptor activation. In conscious or anethetized dogs, arbutamine elicited dose‐dependent increases in heart rate and LV dP/dt with little fall in mean arterial pressure. The data demonstrate that arbutamine exhibits similar degrees of intropic and chronotropic activity, while eliciting less peripheral vasodialation than isoproteronal and less inotropic activity than dobutamine. Moreover, there was rapid termination of the tachycardia, as heart rate resolved to 50% of the maximal effect within 7.2 ± 1.1 min following arbutamine, compared to 5.5 ± 1.0 min following isoproterenol and 5.9 ± 1.4 min following dobutamine. This hemodynamic profile and rapid pharmacodynamic offset makes arbutamine ideally suited for use as a pharmacologic stress agent.
Species differences in ligand affinity at central A3‐adenosine receptors
Authors: Ji Xiao‐Duo , Lubitz Dag Von , Olah Mark E. , Stiles Gary L. , Jacobson Kenneth A.
Published: January 2005

Binding affinities of purine derivatives at A3 adenosine receptors in different species were compared. Binding was carried out using the novel high affinity agonist ligand [125I]AB‐MECA (3‐iodo‐4‐aminobenzyladenosine‐5′‐N‐methyluronamide) in the presence of 1.0 μM XAC (8‐[4‐[[[[(2‐aminoethyl)amino]carbonyl]methyl]oxy]phenyl]‐1,3‐dipropylxanthin), an A1‐ and A2a‐adenosine antagonist. XAC was added to eliminate binding to non‐A3 receptors. In rat brain membranes [125I]AB‐MECA exhibited saturable, specific binding with a Kd of 2.28 nM and a Bmax of 43 fmol/mg protein. The affinity of [125I]AB‐MECA at the gerbil and rabbit brain A3‐receptors was similar to the rat, suggesting that the affinity of this agonist is not highly species dependent. The affinity of various xanthine derivatives was measured in [125I]AB‐MECA competition binding assays. Gerbil and rabbit brain A3‐receptors were similar in the affinity of antagonists whose potency order in both species was: BWA522 ≥ CPX > XCC, XAC, SPX, BWA1433 > theophylline. The affinities of 8‐arylxanthines at the rat, rabbit, and gerbil brain A3 receptors were considerably less than the previously reported affinities at cloned sheep and human A3 receptors. Species differences in agonist affinity were assessed by comparing Ki values at cloned rat brain A3 receptors expressed in CHO cells with cloned sheep and human A3 receptors. Human and rat brain A3 receptors were highly similar in the relative affinities of agonists, and sheep brain A3 receptors were unlike either human or rat A3 receptors in agonist affinity. © 1994 Wiley‐Liss, Inc.
Marine biodiversity as a source of chemical diversity
Authors: De Vries David J. , Hall Michael R.
Published: January 2005

Total global biodiversity is estimated at between 3 and 500 × 106 species of prokaryote and eukaryote organisms spread across 70 or more phyla. The marine macrofauna alone are estimated between 0.5 and 30 × 106 species and represents a broader range of taxonomic diversity than that found in the terrestrial environment, which has been the traditional source of natural products. With a typical eukaryote possessing 50,000 genes, the global marine macrofauna are the source of 2.5 × 1010 to 1.5 × 1012 primary products and an associated extensive range of secondary products. However, only a few thousand novel compounds from marine organisms have been described. These compounds have proven unique in chemical and pharmacological terms but, as yet, no therapeutic agents have resulted. Given a broader drug discovery strategy, and facilitated by technological advances, it is predicted that the characterisation of marine chemical diversity will be accelerated. Strategies for drug discovery from the virtually untapped chemical diversity of marine organisms are discussed. © 1994 Wiley‐Less, Inc.
EP1 receptor antagonist blocks the diarrheagenic, but not cytoprotective, actions of a synthetic prostaglandin
Authors: Lanthorn Thomas H. , Bianchi Robert G. , Perkins William E.
Published: January 2005

Naturally occurring and synthetic prostaglandins acting at EP type receptors have a number of physiological actions, including cytoprotective and antisecretory effects, that are therapeutically useful. In addition they can produce other effects, such as diarrhea. It is possible that these actions are mediated by different EP receptor subtypes. The actions of a subtype‐selective prostaglandin agonist has suggested that diarrhea is not due to activity at the EP3 receptor, while cytoprotection and antisecretory actions may be. The recent development of a bioavailable EP1 antagonist, SC‐51089, has made it possible to examine this more directly. SC‐30249, the active isomer of misoprostol, protects against indomethacin‐induced gastric lesions and produces diarrhea in rats. SC‐51089, ig, shifted the dose‐response curve for SC‐30249‐induced diarrhea significantly to the right. ED50 values (assessed at 5 hr following administration of SC‐30249) were 13.8 μ/kg (0.036 μmol/kg) for SC‐30249 alone and 110.8 μg/kg (0.290 μmol/kg) for SC‐30249 plus SC‐51089. This antagonism of diarrhea was overcome by higher doses of SC‐30249. SC‐30249 dosedependently inhibited gastric lesions induced by indomethacin (ED50 = 3.4 μg/kg, 0.009 μmol/kg, ig). SC‐51089 did not reduce the cytoprotective effects of SC‐30249 (ED50 = 1.1 μg/kg, 0.003 μmol/kg, ig, SC‐30249 in combination with SC‐51089). These results are consistent with the hypothesis that the EP1 receptor subtype mediates the diarrheagenic effect of EP receptor agonists, but not their cytoprotective actions. These results provide a mechanistic basis for cytoprotective prostaglandins with greatly reduced side effects. © Wiley‐Liss, Inc.
Alzheimer's disease: Tacrine and tacrine metabolite concentrations in plasma and cognitive change
Authors: Davis Kenneth L. , Yang Ren‐Kui , Davidson Michael , Mohs Richard C. , Ryan Theresa M. , Schmeidler James , Knott Peter J. , Thal Leon J. , Gamzu Elkan R.
Published: January 2005

In a clinical trial of tacrine in patients with Alzheimer's disease, improvement, measured by changes on both total (ADAST) and the cognitive sub‐component (ADASC) of the Alzheimer's Disease Assessment Scale (ADAS) over a 6‐week period, correlated significantly with plasma levels of tacrine. Change on the ADAS (both total and the cognitive subcomponent) also correlated significantly with three monohydroxylated metabolites of tacrine 1, hydroxy‐tacrine (1‐OH‐THA), 2, hydroxy‐tacrine (2‐OH‐THA), and 4, hydroxy‐tacrine (4‐OH‐THA). However, changes of the relatively small non‐cognitive component of the ADAS were not significantly correlated with plasma levels of tacrine. Multiple correlational analysis revealed that the combined influences of these metabolites were no greater than the effects of tacrine alone in ameliorating the symptoms of Alzheimer's disease. An alternative measure of cognitive performance, the Mini Mental State Exam (MMSE) did not correlate significantly with plasma concentrations of tacrine or its metabolites. Tacrine and these metabolites are bound to plasma proteins. In 10 patients with Alzheimer's disease receiving tacrine, the percentage of tacrine, 1‐OH‐THA, 2‐OH‐THA, and 4‐OH‐THA, that was free in plasma was found to be 19.7 ± 3.3, 51.3 ± 7.7, 40.7 ± 6.9, and 42.4 ± 6.3 (mean ± SD), respectively. © Wiley‐Liss, Inc.
Impact of biophysical parameters on the biological assessment of peptide nucleic acids, antisense inhibitors of gene expression
Authors: Noble Stewart A. , Bonham Michele A. , Bisi John E. , Bruckenstein David A. , Brown Pamela H. , Brown Stephen C. , Cadilla Rodolfo , Gaul Micheal D. , Hanvey Jeffery C. , Fred Hassman C. , Josey John A. , Luzzio Michael J. , Myers Philip M. , Pipe Adrian J. , Ricca Daniel J. , Su Charles W. , Stevenson Cynthia L. , Thomson Stephen A. , Wiethe Robert W. , Babiss Lee E.
Published: January 2005

Peptide nucleic acids (PNA) are oligodeoxynucleotide (ODN) analogs in which the sugar phosphate backbone of the ODN has been replaced by one derived from units of N‐ethylaminoglycine. PNAs recognize DNA and RNA in a sequence specific manner and form complexes that can be characterized by biophysical methods. The binding motif is context dependent; homopyrimidine PNAs combine with complementary polypurine targets to form stoichiometric 2:1 complexes, whereas PNAs containing both purine and pyrimidine bases afford a 1:1 heteroduplex with mis‐match sensitivity comparable to that found in dsDNA. These complexes mediate the antigene and antisense effects of PNAs via the steric blockade of enzyme complexes responsible for DNA transcription, cDNA synthesis, and RNA translation. PNAs, like ODNs, are taken up by cells via endocytosis leading to their entrapment within intracytoplasmic vesicles. Under circumstances where agent delivery is solved by cell microinjection, PNAs can effect selective inhibition of endogenous and exogenous genes. The impact of biophysical parameters on the biological assessment of PNAs as antisense inhibitors of gene expression is presented and discussed. © 1995 Wiley‐Liss, Inc.
Biological activity of WIN 63759, an orally bioavailable inhibitor of human neutrophil elastase
Authors: Silver Paul J. , Gordan Robert J. , Pagani Edward D. , Johnson Judith A. , Maycock Alan L. , Dunlap Richard P. , Ferguson Edward W. , Franke Catherine A. , Drozd Marion L. , Robinson David T. , Mark Eickhoff W. , Baizman Eugene R. , Subramanyam Chakrapani , Desai Ranjit C. , Hlasta Dennis J. , Newton John F.
Published: January 2005

The proteolytic activity of human neutrophil elastase (HNE) has been implicated in a number of pulmonary diseases. We report on the activity of an orally bioavailable, selective HNE inhibitor, WIN 63759 [6‐methoxy‐4‐(1‐methylethy)‐3‐oxo‐1,2‐benzisothiazol‐2(3H)‐yl]methyl 2,6‐dichloro‐3‐[2‐(4‐morpholinyl)ethoxy] benzoate S, S dioxide. WIN 63759 is a potent inhibitor of HNE (Ki = 14 pM) and is at least 70,000‐fold selective for HNE relative to other serine proteases or receptors. In vivo, WIN 63759 produces dose‐related inhibition of HNE‐induced pulmonary hemorrhage following either intravenous (ED50 = 3 mg/kg; 4.5 μmol/kg) or subcutaneous (ED50 = 19 mg/kg; 28.5 μmol/kg) administration in hamsters. WIN 63759 selectivity inhibits HNE in vivo (relative to chymotrypsin or trypsin), and is equally efficacious following acute or chronic administration in the hamster. WIN 63759 is not orally bioavailable in hamsters, rats, or monkeys, and this lack of bioavailability is related to rapid in vitro metabolism in liver, jejunum, or blood. In contrast, WIN 63759 is stable in canine tissues in vitro and is orally bioavailable in dogs. Bioavailability is enhanced in fed relative to fasted dogs. Bronchoalveolar lavage studies indicate that WIN 63759 is present in the target organ (lung) at concentrations 3–5 X higher than those found in plasma following oral administration of 3–100 mg/kg (4.5–150 μmol) in dogs. These data show that WIN 63759 is a potent, selective, and orally bioavailable inhibitor of HNE. Since oral bioavailability was predictable based on in vitro metabolism, and since in vitro metabolism in humans is similar to that observed with dogs, WIN 63759 and other members of this chemical series may be orally bioavailable inhibitors of neutrophil elastase in man. © 1995 Wiley‐Liss, Inc.
Skilled incompetence in the management of R & D
Authors: Jensen Ivan , Jorgensen Stig , Sapienza Alice M.
Published: January 2005

We use the term skilled incompetence to describe a situation characterized by a mismatch between technical and managerial competence and caused by inadequate, inappropriate, or missing second‐order feedback on managerial behavior. Based on our collective experience with the pharmaceutical industry, we believe that skilled incompetence is prevalent in the management of R & D. In this commentary we explore, using a hypothetical case study as illustration, how skilled incompetence arises and persists. We define the cost of skilled incompetence as the cost of delayed drug development times and thus lost opportunities in the market. We discuss how skilled incompetence manifests itself, how it can be diagnosed, and what general rules should guide any interventions. © 1995 Wiley‐Liss, Inc.
Interaction of three sponge‐derived macrocyclic lactone polyethers (spongistatin 3, halistatins 1 and 2) with tubulin
Authors: Ludueña Richard F. , Roach Mary Carmen , Prasad Veena , Pettit George R. , Cichacz Zbigniew A. , Herald Cherry L.
Published: January 2005

Macrocyclic lactone polyethers of marine origin include a series of compounds which bind to tubulin, the subunit protein of microtubules, and inhibit microtubule assembly and vinblastine binding to tubulin. We have previously studied two of these compounds: halichondrin B and the very similar homohalichondrin B. We have found that halichondrin B enhances the time‐dependent exposure of hydrophobic areas on the tubulin molecule without affecting the exposure of the sulfhydryl groups, while homohalichondrin B has no effect on exposure of hydrophobic areas and slightly suppresses exposure of sulfhydryl groups. The spongistatins (isolated from the marine sponge Spongia sp.) resemble the halichondrins, except for having a smaller ring; spongistatin 1 inhibits vinblastine binding to tubulin and blocks microtubule assembly. Here, we have examined the effect of the closely related spongistatin 3 on the exposure of tubulin sulfhydryl groups and hydrophobic areas. We have found that spongistatin 3 inhibits formation of the same intrachain cross‐link in tubulin as is inhibited by vinblastine. Unlike vinblastine, however, spongistatin 3 has no effect on the exposure of either sulfhydryl groups or hydrophobic areas on the tubulin molecule. In short, spongistatin 3 resembles maytansine in its effects on tubulin more than it does either halichondrin B or homohalichondrin B. We also examined the interaction of tubulin with halistatins 1 and 2, which are close structural analogues of halichondrin B and homohalichondrin B, respectively. Halistatins 1 and 2 are isolated, respectively, from the marine sponges Phakellia carteri and Axinella carteri. We find that both halistatins resemble halichondrin B in that they have no effect on the exposure of sulfhydryl groups. Our results suggest that very small structural changes in these compounds can significantly alter the pattern of their effects on the tubulin molecule. © 1995 Wiley‐Liss, Inc.
Combinatorial chemistry: A conservative perspective
Authors: Lyttle Matthew H.
Published: January 2005

Large biotechnology based initiatives, like the Human Genome Project, in addition to accelerating scientific progress and improving the understanding of basic biological process, are responsible for an increased demand for high quality drug candidates. In this regard, combinatorial libraries have become a subject of intense interest, as chemists and biologists attempt to generate large numbers of compounds that bind to the increasing number of newly discovered and potentially medically relevant proteins. Now that a variety of exploratory combinatorial chemistry efforts have been reported, it is appropriate to evaluate the utility of these procedures which have often outpaced conservative chemical characterization regarding composition and purity of products. The use of assay formats dictated by the needs of the synthetic protocol have also often circumvented disciplined evaluation of how relevant the assay data is to realistic drug‐target interactions. This commentary examines procedural details whereby commonly used combinatorial practices can generate less useful information than anticipated. Concrete, practical suggestions are made for using combinatorial chemistry in a more focused manner in lead generation and development, so that disappointing results can be avoided and the high potential of this technology more effectively realized. © 1995 Wiley‐Liss, Inc.