bluuebunny/crossref_metadata_2025_split huggingface dataset:
Promise of nicotinic‐based therapeutic treatments
Authors: Levin Edward D. , Rosecrans John A. 
Published: January 2005

AbstractNicotine has a wide variety of pharmacological effects. Some of these, such as improved attentiveness and memory, quickened reaction time, reduced appetite, and lessening of stress can be viewed as beneficial and may partially underlie tobacco use. They also suggest therapeutic uses of nicotine. Like any drug, nicotine has adverse effects as well, such as convulsant actions and cardiovascular effects. Also, like a variety of therapeutic drugs from caffeine to codeine, nicotine has the adverse potential to become habit forming or addictive. Many of the health damaging effects of tobacco use, such as cancer and lung disease, seem to result from compounds present in tar. Eliminating the more than 4,000 different compounds present in tar goes a long way in reducing adverse effects associated with nicotine intake. When developing nicotine for therapeutic use, it is critical to determine the mechanisms of its actions so that its beneficial effects can be maximized and its adverse effects can be minimized. This might be achieved with alternate routes of delivery of nicotine such as the skin patch or with novel nicotinic ligands currently under development. © 1994 Wiley‐Liss, Inc.
Effects of nicotinic agonists and antagonists on spatial working memory in normal adult and aged rats
Authors: Widzowski Daniel V. , Cregan Edward , Bialobok Paul 
Published: January 2005

AbstractThe present study had two goals (1) to examine the effects of treatments with nicotinic agonist (nicotine) and antagonist (mecamylamine) on working memory in normal adult rats (14 months of age), and (2) to determine if treating aged (36 to 42 months of age), memory‐impaired rats with nicotine could improve their memory function. Memory testing was carried out using a delayed non‐matching to position paradigm in a T‐maze. Rats were trained to run down one arm of the maze (e.g., right) on an information run and then, after a variable memory delay period of 10, 90, or 180 sec, run down the other arm (e.g., left). In normal adult rats after water injection, memory accuracy was inversely related to memory delay (> 90, 75, and 67% accuracy at the 10, 90, and 180 sec delays, respectively). Administration of nicotine (0.1 or 0.4 mg/kg), or mecamylamine (2.5 or 5 mg/kg), or combinations of these drugs had no significant effects on memory in these rats. However, mecamylamine alone or in combination with nicotine reduced running speed in the T‐maze in normal adults, indicating that the drugs did produce some behavioral effects. In aged rats, memory accuracy after water injection was much lower than that of younger adults, averaging 64, 57, and 50% at 10, 90, and 180 sec delays. Interestingly, nicotine injections of 0.1 or 0.4 mg/kg resulted in highly significantly improved accuracy in the memory task. The deficit in memory accuracy in aged rats, evident even at the shortest delay period (10 sec), suggests that the rats may have had impairments in attention or visual discriminatory ability. If this is so, then the beneficial effects of nicotine observed in this study may be more related to its effects on attention rather than memory directly. © 1994 Wiley‐Liss, Inc.
Effect of sertindole on raised mesolimbic dopaminergic activity in the rat
Authors: Domeney Annette M. , Arnt Jörn , Costall Brenda , Naylor Robert J. , Sánchez Connie , Smith Annie G. 
Published: January 2005

AbstractThe effect of sertindole in models of mesolimbic dopamine excess in the rat was evaluated. Sertindole (0.0057–0.011 μmol/kg = 2.5–5 μg/kg, sc) and haloperidol (0.13–0.27 μmol/kg = 50–100 μg/kg, ip) inhibited the hyperactivity caused by the acute intra‐accumbens injection of amphetamine (20 μg). The administration of sertindole (0.0057–2.8 μmol/kg = 2.5 μg–1.25 mg/kg, sc daily), haloperidol (0.027–0.40 μmol/kg = 10–150 μg/kg, ip bd) or clozapine (15–31 μmol/kg = 5–10 mg/kg, ip, bd) during a 13‐day period of dopamine infusion (25 μg/24 h) into the nucleus accumbens reduced the dopamine‐induced hyperactivity response to control levels, except at the highest dose which reduced activity to below control levels. Locomotor activity remained at control levels after discontinuing the dopamine/sertindole treatment regimen, whereas discontinuation of the dopamine/haloperidol treatment regimen resulted in rebound hyperactivity. Sertindole (0.0057 μmol/kg = 2.5 μg/kg, sc) given either once daily or once every 2 days prevented the development of hyperactivity in the intra‐accumbens dopamine infusion model. One injection given every 4 days failed to modify the response to a dopamine infusion. Sertindole (0.0057 μmol/kg = 2.5 μg/kg, sc daily) inhibited hyperactivity caused by unilateral infusion of dopamine (50 μg/24 h, 13 days) into the left amygdala of rats having right hemispheric dominance (as measured in a turn preference test). In contrast to haloperidol, sertindole failed to initiate circling behaviour following unilateral, intrastriatal injection. In conclusion, sertindole, like haloperidol and clozapine, can reduce raised mesolimbic dopaminergic activity in the rat. Sertindole differs from haloperidol by its ability to return the hyperactivity response to control levels. © 1994 Wiley‐Liss, Inc.
Chronic toxicity study with the serotonin antagonist amesergide administered nasogastrically to rhesus monkeys for one year
Authors: Seyler David E. , Murphy‐Farmer Candice M. 
Published: January 2005

AbstractThe chronic toxicity of amesergide, a selective (5HT2/5HT1c) serotonin antagonist, was evaluated in rhesus monkeys given daily nasogastric doses of 0, 5, 10, or 22.5 mg/kg for 1 year. An initial high dose of 25 mg/kg was reduced after approximately 1 week of dosing due to severe behavioral effects, including lethargy, a trance‐like appearance, and rigidity, that interfered with the animal's ability to eat and drink. The behavioral effects, although still present at the new high dose of 22.5 mg/kg were less intense and subsided prior to subsequent daily dosing. All animals survived the treatment period. Clinical signs associated primarily with early treatment at the 25‐mg/kg dose level resulted in reductions of body weights and food consumption. After the high dose was reduced from 25 mg/kg to 22.5 mg/kg, there were no significant effects on body weight gain or food consumption when compared to controls. Plasma concentrations of amesergide and its metabolites increased in a dose‐dependent fashion. Areas under the plasma concentration‐time curve (AUC) and peak plasma concentrations (Cmax) decreased substantially as the study progressed. Stress‐related decreases occurred in leukocytic and erythrocytic parameters of high‐dose males, but values returned to near pretest by study termination. Organ weights as well as gross and histological examination of tissues from animals of all treatment groups revealed no treatment‐related lesions. No adverse effects occurred at daily doses of 5 or 10 mg/kg. © 1994 Wiley‐Liss, Inc.
Amylin and Syndrome‐X
Authors: Young Andrew A. , Rink Timothy J. , Vine William , Gedulin Bronislava 
Published: January 2005

AbstractA 37 amino‐acid peptide, amylin, is secreted from the pancreatic β‐cell in response to stimuli similar to those causing insulin secretion. Plasma amylin levels are generally elevated under circumstances where insulin is elevated, including in insulin resistance and in essential (obesity‐related) hypertension. Several of amylin's actions may contribute to key features of insulin resistance and the insulin resistance syndrome (Syndrome‐X). Actions on muscle glycogen metabolism, Cori cycle activity, and endogenous glucose production may contribute to glucose intolerance while amylin's effects to suppress β‐cell secretion could account for the secretory defect observed in early glucose intolerance. Amylin also potently increases plasma renin activity, and could contribute to the hypertension that is associated with obesity and insulin resistance.
Anxiolytic properties of (+) s 20499, a novel serotonin 5‐HT1A full agonist, in the elevated plus‐maze and social interaction tests
Authors: Curle Peter F. , Mocaer Elisabeth , Renard Pierre , Guardiola Béatrice 
Published: January 2005

AbstractPrevious studies have shown that (±) S 20244 (8‐(4‐[N‐(5‐methoxychroman‐3‐yl)N‐propylamino] butyl) 8‐azaspiro[4,5]decane‐7,9 dione) and its isomers (+) S 20499 and (−) S 20500 are full agonists at 5‐HT1A receptors. In the present study, the effects of these three compounds were investigated in two animal models of anxiety, the elevated plus‐maze and social interaction tests. Subcutaneous administration of (±) S 20244 (19 μmol/kg−1.9 μmol/kg), (+) S 20499 (470 μmol/kg) or (−) S 20500 (94–940 μmol/kg) or per os administration of (+) S 20499 (190 μmol/kg−19 μmol/kg) produced anxiolytic‐like effects in the elevated plus‐maze while per os administration of (−) S 20500 was without effect. Subcutaneous administration of (±) S 20244 (19 μmol/kg−1.9 μmol/kg) or per os administration of (+) S 20499 (190 μmol/kg−19 μmol/kg) also produced anxiolytic‐like effects in the social interaction test. With both substances, bell‐shaped dose‐response relationships were found. The absence of activity of (−) S 20500 when administered per os suggests that the distribution and/or absorption kinetics of the two isomers may be different. In conclusion, (±) S 20244 and (+) S 20499 both display anxiolytic‐like activity in the elevated plus‐maze and social interaction tests.
Recent advances in the generation of chemical diversity libraries
Authors: Desai Manoj C. , Zuckermann Ronald N. , Moos Walter H. 
Published: January 2005

AbstractIn recent years, screening in combination with a diverse compound collection has become a powerful method for discovering leads for the ever‐increasing number of new biologically active peptides, proteins, receptors, and enzymes discovered continually. As a result, the rapid generation and screening of compound libraries (collections) have recently become important major tools in the search for novel lead structures. Diverse collections of compounds have been acquired by many strategies; these include (1) natural products from plants, fermentation, marine organisms, insect toxins, and ethnic pharmacotherapies; (2) recombinant randomized peptide libraries (often referred to as biological diversity); (3) multiple peptide synthesis; and (4) non‐peptidic synthetic libraries. The present review provides an overview of the recent advances in the field of peptide and non‐peptidic synthetic libraries. The progress made thus far is broadly divided into two categories: (1) Amide based libraries. These libraries share the concepts of the peptide library strategies; much of the referenced work thus refers to peptides, reflecting the bias of the literature to date. (2) Non‐amide based libraries. This promising technology combines solid phase synthesis with classical organic synthesis to provide large numbers of compounds with desirable bioavailability and pharmacokinetics for screening. The basic premise behind the second approach is that the high affinity ligands, when identified, will be much more likely to become useful therapeutic agents than the compounds discovered from amide based libraries. Synthesizing small heterocyclic ring systems that use ligands of diverse biological activity via combinatorial strategies is a fast developing branch of medicinal chemistry. We are at an early state in the development of combinatorial chemistry. However, this dramatic convergence of technologies represents a fundamental advance in medicinal chemistry and promises to play a major role in future drug discovery efforts. © 1994 Wiley‐Less, Inc.
Membrane pathways for drug/ion channel interactions: Molecular basis for pharmacokinetic properties
Authors: Herbette Leo G. 
Published: January 2005

AbstractThis review focuses on the interactions of certain classes of drugs that are known to bind to membrane‐bound ion channel/receptors. The concepts described here have broad applications to various ion channels as well as membrane bound receptors that are not ion channels such as the superfamily of G protein coupled receptors. Since data spanning from the molecular to the clinical field currently exists for drugs that bind to the voltage gated calcium channel, this review will highlight this rather narrow scope. It is to be appreciated that the concepts, as described, may have applicability to other membrane‐bound receptors. The focus will be on the calcium channel antagonist drugs of the 1,4 dihydropyridine type that bind to the L type calcium channel. Clearly an evolution in their molecular design has been brought to a point where these molecules are not only amphiphilic but increasingly lipophilic. Simply stated, this means that these drugs can readily transport across cell membranes accessing both hydrophilic and hydrophobic environments, although they have also become more soluble in the membrane bilayer. From an equilibrium point of view these molecules prefer to reside in the lipid bilayer hydrocarbon core; from a kinetic point of view they spend more time, on average, solvated within membranes than outside membranes, but their rates of entry into and exit from membranes do not appear to be related solely to their intramembranal equilibrium concentration. This biophysical understanding appears not only to define the molecular pathways for drug binding to the calcium channel receptor, but also to explain differences in the overall clinical pharmacokinetics observed for different drugs in this class. The potency of calcium antagonists is primarily related to their binding affinity to the calcium channel with a variable degree of dependency on the solvation of the drug in the membrane. The pharmacokinetic profile of calcium antagonists, although influenced to some degree by interactions with the target receptor, appears to be largely dictated by their interactions with the cell membranes at the molecular level. These interactions are distinctly different for each calcium antagonist but they can be classified into a few subgroups to explain drug onset and duration of action. © 1994 Wiley‐Liss, Inc.
Biochemical and biophysical studies of the interaction of class I antiarrhythmic drugs with the cardiac sodium channel
Authors: Zamponi Gerald W. , Duff Henry J. , French Robert J. , Sheldon Robert S. 
Published: January 2005

AbstractClass I antiarrhythmic drugs block the cardiac sodium channel and are now used widely for a variety of cardiac arrhythmias. The nature of the interaction of the drugs with these channels, and their mechanism of action, have been areas of considerable recent interest. Here we review several aspects of drug action. Evidence that sodium channel blockade itself is antiarrhythmic arises from experiments in which the sodium channel‐specific toxin tetrodotoxin was shown to prevent ventricular fibrillation in rabbit hearts. A radioligand binding assay for the cardiac sodium channel was then developed using [3H]Batrachotoxinin (BTX) Benzoate and freshly isolated rat cardiac myocytes. Class I antiarrhythmic drug binding identified in this model fits conventional criteria for binding to a receptor. This receptor behaves like an allosteric protein; class I antiarrhythmic drugs appear to bind to and stabilize closed channels. The mechanism of drug binding and electrophysiologic consequences have been examined in a number of model systems by microelectrode studies, whole cell voltage clamping, and more recently voltage clamp studies of single isolated channels in lipid bilayers. Using the latter method, we have shown that lidocaine causes two distinct kinds of sodium channel blockade. The first is a very slow block which can be demonstrated with simple aryl compounds. The second kind of block is a very rapid block which can also be caused by simple alkyl amines. Thus, the two major structural moieties of lidocaine each cause a specific form of block. The structure‐activity relationships of class I drugs were explored with homologs of lidocaine in the radioligand binding assay. With this method the existence of a number of receptor subdomains has been demonstrated, each of which recognizes specific structural moieties of class I drugs. Finally, we have explored both drug proarrhythmia and drug resistance. Drug proarrhythmia may be due to homogeneous slowing of conduction with little effect on refractoriness. One form of drug resistance may be due to induction of synthesis of new cardiac sodium channels by exposure to animals with chronic class I drug administration. Mexiletine induces a three‐fold increase in rat cardiac sodium channels within 3 days due to increased sodium channel mRNA synthesis. Thus drug resistance might be due to drug‐induced increases in the numbers of cardiac sodium channels. © 1994 Wiley‐Liss, Inc.
In vivo pharmacological profile of 9‐hydroxyrisperidone, the major metabolite of the novel antipsychotic risperidone
Authors: Megens Anton A. H. P. , Awouters Frans H. L. 
Published: January 2005

Abstract9‐Hydroxyrisperidone (9OH‐risperidone) is the major metabolite of the new antipsychotic risperidone. 9OH‐risperidone was compared with risperidone in a series of pharmacological tests in rats; ritanserin and haloperidol were included as reference compounds in tests for 5HT2 and D2 antagonism, respectively. 9OH‐risperidone closely resembled risperidone and showed similar effects at closely related doses (respective subcutaneous [sc] ED50s in mg/kg in parentheses): 5HT2 antagonism: reversal of tryptamine cyanosis (0.00059/0.0011), inhibition and blockade of tryptamine seizures (0.032/0.014 and 0.11/0.056), inhibition of tryptamine tremors (0.34/0.049), inhibition and blockade of mescaline head twitches (0.056/0.037 and 0.098/0.049); D2 antagonism: inhibition and blockade of apomorphine behavior (0.34/0.22 and 4.1/1.2), inhibition and blockade of amphetamine agitation (0.15/0.056 and 0.51/0.59) and oxygen consumption (0.049/0.016 and 0.17/0.64), behavioral disinhibition (0.069/0.31) and depression (4.6/4.7) in amphetaminized rats; histamine H1 antagonism: protection from compound 48/80 lethality (0.018/0.014); α1‐adrenoceptor antagonism: protection from norepinephrine lethality (0.17/0.074); α2‐adrenoceptor antagonism: reversal of clonidine's antidiarrheal effect (0.29/0.67), reversal of xylazine loss of righting (16/2.4); and behavioral effects: slight and pronounced catalepsy (2.0/0.59 and 3.6/3.0), slight and pronounced palpebral ptosis (0.30/0.19 and 2.0/0.89), muscular hypotonia (4.7/3.6), hypothermia (4.1/2.0), inhibition of acetic acid writhing (1.2/0.34), and depression of motor activity (0.13/0.062 for vertical, 0.49/0.18 for horizontal, and 5.0/2.8 for total movements). Up to 10 mg/kg, both compounds were devoid of anti‐muscarinic and anti‐nicotinic activity, failed to affect the lethal effects of KCN, nitrogen, BaCl2 and ouabain, and did not block castor oil diarrhea. The acute oral LD50 values of the compounds were comparable. Both 9OH‐risperidone and risperidone differed markedly from haloperidol as indicated by: (1) predominant central 5HT2 antagonism (comparable to that of ritanserin); (2) high doses of catalepsy; (3) gradual depression of motor activity; (4) pronounced behavioral disinhibitory effects in amphetaminized rats; (5) inhibition of amphetamineinduced oxygen consumption preceding inhibition of amphetamine agitation. As metabolic conversion of risperidone to 9OH‐risperidone does apparently not result in any marked change in activity profile, its major consequence seems to be a prolongation of duration of action. © 1994 Wiley‐Liss, Inc.
Administration of a hemoglobin solution decreases hypoxia and increases radiation response in a rat mammary carcinoma
Authors: Teicher Beverly A. , Dupuis Norman P. , Liu Fang , Robinson Michael F. , Menon Krishna 
Published: January 2005

AbstractAdministration of an ultrapurified bovine hemoglobin solution (8 ml/kg, iv) to female Fisher 344 rats bearing the 13672 mammary carcinoma implanted subcutaneously in the hind leg reduced the hypoxic fraction of the tumor from 49 to 36% with normal air breathing and to 28% with carbogen (95% oxygen/5% carbon dioxide) breathing. When administration of the hemoglobin solution was followed by single dose (10, 20, or 30 Gray) local radiation therapy, the dose modifying factor was 1.5 with air breathing and 2.7 with carbogen breathing. For fractionated radiation therapy, 2, 3, or 4 Gray was delivered locally daily for 5 days. When the hemoglobin solution was administered prior to each radiation fraction and air breathing maintained, there was a 1.8‐fold increase in tumor growth delay. When daily hemoglobin solution administration was accompanied by carbogen breathing, there was a 2.6‐fold increase in tumor growth delay. Less frquent administration of the hemoglobin solution (alternate days, twice weekly or once weekly) resulted in 1.5‐ to 1.7‐fold increases in tumor growth delay. The greatest increases in tumor oxygenation occurred shortly after administration of the hemoglobin solution; in fact at 12 h post administration of the hemoglobin solution, the tumors appeared to be more hypoxic than prior to administration of the hemoglobin solution. By 24 h post administration of the hemoglobin solution, the oxygen tension profile of the tumors were returning to pretreatment levels. Further investigation of this ultrapurified hemoglobin solution in cancer is warranted. © 1995 Wiley‐Liss, Inc.
Comparison of the proteolytic susceptibilities of homologous L‐amino acid, D‐amino acid, and N‐substituted glycine peptide and peptoid oligomers
Authors: Miller Susan M. , Simon Reyna J. , Ng Simon , Zuckermann Ronald N. , Kerr Janice M. , Moos Walter H. 
Published: January 2005

AbstractA series of homologous L‐amino acid, D‐amino acid, and both parallel and anti‐parallel (retro) sequence N‐substituted glycine peptide and peptoid oligomers were prepared and incubated with a series of enzymes representative of the major classes of proteases. Each respective L‐amino acid containing peptide sequence was readily cleaved by the appropriate enzyme, namely Ac‐L‐ala‐L‐leu‐L‐phe‐L‐ala‐L‐leu‐L‐arg‐NH2 by chymotrypsin, Ac‐L‐ala‐L‐ala‐L‐ala‐L‐leu‐L‐phe‐L‐arg‐NH2 by elastase, Ac‐L‐ala‐L‐phe‐L‐glu‐L‐leu‐L‐ala‐L‐ala‐NH2 by papain, Z‐L‐ala‐L‐his‐L‐phe‐L‐phe‐L‐arg‐L‐leu‐NH2 by pepsin, Ac‐L‐phe‐L‐ala‐L‐arg‐L‐ala‐L‐arg‐L‐asp‐NH2 by trypsin, and Ac‐L‐ala‐L‐tyr‐Lala‐L‐phe‐OH for carboxypeptidase A. In contrast, equivalent D‐amino acid containing and N‐substituted glycine containing oligomers were cleaved minimally or not at all by the respective enzymes. The N‐substituted glycine peptoids represent a new class of combinatorial diversity for lead discovery with improved pharmaceutical characteristics relative to L‐amino acid containing peptides. © 1995 Wiley‐Liss, Inc.