bluuebunny/crossref_metadata_2025_split huggingface dataset:
The behavioral pharmacology of Ay‐27,110, a novel nonergot dopaminergic agonist
Authors: Voith Katherine 
Published: January 2005

AbstractAY‐27,110 is the pharmacologically active enantiomer of a troponylpiperazine derivative. At low doses, the compound induced contralateral rotational behavior in rats with a unilateral 6‐OHDA lesion of the nigrostriatal pathway, at higher doses it caused weak stereotypy and in dogs in elicited emesis. The actions of AY‐27,110 were dose‐dependently antagonized by haloperidol and pimozide, but were not diminished by α‐MPT or reserpine pretreatment. These results indicate that AY‐27,110 is a chemically novel dopaminergic agonist that should be useful as an anti‐parkinson drug. Since the effects of AY‐27,110 are independent of intact catecholamine synthesis and storage mechanisms, the compound should be efficacious in patients with advanced Parkinson's disease. AY‐27,110 was compared to several ergot‐derived dopamine agonists, namely bromocriptine, lisuride, and pergolide, in order to predict its potency, side‐effect liability, and potential therapeutic advantages.
Further studies on the distinctive sleep‐wakefulness profiles of antihistamines (astemizole, ketotifen, terfenadine) in dogs
Authors: Wauquier A. , van Den Broeck W. A. E. , Awouters F. , Janssen P. A. J. 
Published: January 2005

AbstractThe effects of the antihistamines astemizole, ketotifen, and terfenadine, given orally at the dose of 10 mg/kg, were investigated on 16‐hr sleep‐wakefulness patterns in dogs. As determined in the Ascaris allergy test in dogs, this dose had marked antihistaminic activity for at least the total duration of the recording. Using a computerized on‐line analysis and automatic sleep classification, a differentiation was made between wakefulness, transition to sleep, slow‐wave sleep, and REM (or paradoxical) sleep. Astemizole did not significantly change sleep‐wakefulness patterns. Ketotifen significantly increased slow‐wave sleep and significantly decreased REM sleep. Terfenadine significantly decreased wakefulness and significantly increased both slow‐wave sleep and REM sleep. With both ketotifen and terfenadine, REM latency was prolonged. Two different mechanisms appear to be involved in the REM sleep effects seen with terfenadine: an early REM sleep suppressant effect and a late but large REM sleep‐enhancing effect. This study shows central effects of terfenadine that are not completely typical for H1 antagonists but which are very pronounced at a dose producing much weaker peripheral antihistamine activity than the same dose of ketotifen and astemizole.
Neuropathological processes in Alzheimer's disease
Authors: Price Donald L. , Struble Robert G. , Whitehouse Peter J. , Kitt Cheryl A. , Cork Linda C. 
Published: January 2005

AbstractDuring the past few years, substantial progress has been made in understanding the neuropathology of Alzheimer's disease (AD) and its late‐life variant, senile dementia of the Alzheimer's type. Neurofibrillary tangles have been shown to be composed of cross‐linked, highly insoluble paired helical filaments. The disease selectively affects certain populations of nerve cells, including those in the amygdala, hippocampus, neocortex, locus coeruleus and basal forebrain cholinergic (Ch) system. Changes in the latter system account, in substantial part, for the decrease in cortical Ch markers which, to date, appear to be the earliest and most consistent abnormalities in the brains of individuals with AD. Neuritic plaques have been shown to be foci of axonal/synaptic pathology consistent with the concept that these changes may be associated with a chronic distal axonopathy involving certain populations of nerve cells. Recent studies in aged nonhuman primates suggest that some of the abnormal axons/terminals in neuritic plaques may be derived from the basal forebrain Ch system. Understanding the biological mechanisms leading to these structural changes is essential if we are to understand the pathogenesis of the clinical manifestations of AD and if we are to design rational therapeutic approaches to treat this disorder.
Is it possible to design rational treatments for the symptoms of Alzheimer's disease?
Authors: Davies Peter 
Published: January 2005

AbstractThis paper reviews and discusses the evidence that the primary cause of the symptoms of Alzheimer's disease is a deficiency of acetylcholine in cerebral cortex and hippocampus. Data on other neurotransmitters in this disease are briefly reviewed. Possible means of treating acetylcholine deficiences are discussed.
Development of cholinergic drugs for the treatment of Alzheimer's disease
Authors: Johns Celeste A. , Haroutunian Vahram , Greenwald Blaine S. , Mohs Richard C. , Davis Bonnie M. , Kanof Phil , Horvath Tom B. , Davis Kenneth L. 
Published: January 2005

AbstractAlzheimer's Disease (AD) is characterized neurochemically by a profound loss of choline acetyl transferase activity and histologically by a selective degeneration of cholinergic neurons originating in the nucleus basalis of Meynert (nbM). The clinical relevance of this cholinergic deficit and its implications for the development of treatment strategies was explored in animal studies and in patients with carefully diagnosed AD. A hypocholinergic animal model was developed by chemical ablation of the nbM in rats. These rats demonstrated significant impairment of learning and memory as measured by long‐term habituation of locomotor activity and retention of a one‐trial passive avoidance task, which was substantially improved after the administration of the cholinergic drug physostigmine. In AD patients, in vivo assessment of cholinergic markers in cerebrospinal fluid showed decreased acetylcholine and choline activity in proportion to the patient's degree of cognitive impairment. Physostigmine was administered to AD patients both intravenously and orally in an attempt to enhance central cholinergic activity. Significant improvement of long‐term memory encoding followed administration of intravenous physostigmine, and modest improvements in cognition and behavior resulted when oral physostigmine was given to some AD patients. These results support the hypothesis that cholinergic deficits are manifested in symptoms of AD and suggest that administration of cholinomimetic agents is a rational treatment strategy in AD.
Interaction of astemizole and other drugs with passive cutaneous anaphylactic and histamine‐, serotonin‐, and compound 48/80‐induced skin reactions in the rat: A Procedure to determine anti‐allergic effectiveness
Authors: Awouters Frans , Niemegeers Carlos J. E. , Janssen Paul A. J. 
Published: January 2005

AbstractPassive cutaneous anaphylactic (PCA) reactions in rats were induced simultaneously with skin reactions to intradermally injected histamine, serotonin, and compound 48/80. In this test compounds with widely different pharmacological profiles were studied to evaluate the significance of anti‐allergic activity. Five cromoglycatelike drugs, injected i.v. 5 min before antigen challenge, were either devoid of activity or significant inhibition of PCA reactions was associated to inhibition of histamine and compound 48/80 reactions. Two histamine H1‐antagonists, astemizole and ketotifen; the serotonin S2‐antagonist ketanserin; and the α‐adrenergic blocking agent prazosin were tested over a wide dose range 2 hr after s.c. administration. Prazosin, as a result of systemic hemodynamic effects, significantly inhibited the four reactions (primarily PCA), but complete inhibition was not obtained. Ketanserin primarily inhibited serotonin reactions, and inhibition of other reactions required high doses. Ketotifen was a very potent and apparently competitive inhibitor of histamine reactions, with a significant effect on PCA and compound 48/80 reactions. Astemizole primarily inhibited histamine and PCA reactions; complete inhibition was reached for the four reaction types. In terms of a practical definition of anti‐allergic drugs, i.e., compounds capable of fully suppressing the consequences of allergen challenge in the absence of nonspecific systemic effects, astemizole appears to be a prototype.
Cardiovascular actions of an experimental antitumor agent, homoharringtonine, in anesthetized dogs
Authors: Lokhandwala Mustafa F. , Sabouni Majd H. , Jandhyala Bhagavan S. 
Published: January 2005

AbstractCardiovascular actions of homoharringtonine, a plant extract currently being tested for clinical efficacy as an antitumor agent, were investigated in anesthetized mongrel dogs. Intravenous administration of homoharringtonine (4 mg/M2) produced significant reductions in heart rate, cardiac output, and arterial blood pressure, while myocardial contractility or total peripheral resistance were not altered. These results suggest that the bradycardia could account for decreases in both cardiac output and blood pressure. In additional experiments performed to evaluate the actions of homoharringtonine on cardiac sympathetic neurotransmission it was discovered that this compound caused significant impairment of the tachycardia elicited during stimulation of cardiac sympathetic nerves. The positive chronotropic effects of either norepinephrine or isoproterenol were not altered by homoharringtonine. In these animals in which both vagi and the right cardioaccelerator nerve were sectioned, the hypotensive and bradycardiac effects were of lesser magnitude than that seen in neurally intact animals. These results show that a dose of homoharringtonine comparable to that used in clinical trials produces hypotension and bradycardia which may result from inhibition of sympathetic nerve function caused by the compound.
Effect of secoverine HCl on motor and myoelectrical activity of the sigmoid colon in man
Authors: Meshkinpour Hooshang , Hoehler Fred 
Published: January 2005

AbstractSecoverine hydrochloride is a new synthetic tertiary amine with selective muscarine blocking effect. Its tendency to produce parasympathetic side effects has been claimed to be almost 100 times less than atropine. We studied the role of secoverine on meal‐induced colon motor and myoelectrical activity in 12 healthy volunteers. Intraluminal pressure changes, slow wave activity, and spike frequency of the sigmoid colon as well as a pneumogram, blood pressure, and electrocardiogram were monitored. Fifteen minutes after ingestion of a 1000‐kcal meal, subjects received 4 mg secoverine or the same volume of normal saline in separate sessions and recording continued for another 90 minutes. Ingestion of the meal increased colon motor and spike activities; however, these parameters were not influenced by secoverine. Drug treatment did not change the proportion of slow wave activity and did not affect pulse rate, blood pressure, respiration rate, or electrocardiogram in a significant fashion. In conclusion, intravenous injection of 4 mg secoverine had no effect on meal‐stimulated colon motor and myoelectrical activity. Whether this medication at a different dose regimen has therapeutic value remains to be seen. However, this dose of secoverine was well tolerated by the subjects.
AHR‐9377, a new antidepressant agent
Authors: Johnson David N. , Ruckart Robert T. , Turley Brenda G. 
Published: January 2005

AbstractAHR‐9377 is a novel chemical structure with potential antidepressant activity. It was more potent than imipramine in mice, and equipotent with imipramine in rats in blocking tetrabenazine ptosis. Yohimbine toxicity in mice was potentiated by AHR‐9377 in doses less than those of imipramine. The compound had no CNS stimulant properties as judged by behavioral observations and spontaneous motor activity determinations in rats and by its lack of effect on rectal temperature of normothermic rats. In rats made hyperthermic with d‐amphetamine, however, AHR‐9377, like imipramine, prolonged the hyperthermic effect. Contractions of the cat nictitating membrane that were induced by norepinephrine were potentiated by AHR‐9377. Unlike iproniazid, AHR‐9377 had no monoamine oxidase‐inhibiting activity. Electroencephalographic analyses indicated no slowing of cortical activity and no spindle‐type waves in cats after AHR‐9377 administration. These data suggest that AHR‐9377 is a potential antidepressant agent without sedative activity.
Effect of treatment with some atypical antidepressants on 3H‐DHA binding in rat brain
Authors: Pandey Ghanshyam N. , Brown Barbara , Davis John M. 
Published: January 2005

AbstractThe mechanism of therapeutic action of antidepressant drugs has been related to their effects on metabolism and release and reuptake of catecholamines and serotonin. Some atypical antidepressants, however, do not have such pharmacological effects. Recently it has been reported that most of the antidepressant drugs cause down regulation of beta adrenergic receptors in rat brain after chronic treatment. In order to examine if this is a common and specific pharmacologic property of all antidepressant drugs, we have studied the effects of treatment with some atypical antidepressant drugs on beta adrenergic receptor binding in rat cortex using 3H‐dihydroalprenolol (DHA) as the radiolabeled ligand. Our results indicate that chronic treatment with almost all antidepressants studied causes down regulation of beta adrenergic receptors. However, such effects are not observed after treatment with neuroleptics such as haloperidol or chlorpromazine or psychomotor stimulants such as cocaine. This approach thus provides a useful method of screening potential antidepressant drugs.
Modification by diazoxide of canine renal vascular responsiveness to endogenous vasoconstrictors
Authors: Wood William B. , Sticht Frank D. , Igbokwe Emmanuel C. , Cardoso Sergio S. , Elko Edward E. 
Published: January 2005

AbstractDiazoxide‐induced modification of renal vascular responses to norepinephrine and angiotensin II was studied in dogs. Diazoxide was infused directly into the renal artery in order to minimize the effect of high plasma protein binding and to obtain maximum exposure of the test vessel to the administered drug. During the 30‐min infusion period, renal blood flow showed an initial, transitory increase followed by a progressive decline which paralleled the induced fall in systemic blood pressure. In the presence of diazoxide, renal vasoconstrictor responses to intravenous and intraarterial norepinephrine and intravenous angiotensin II were significantly attenuated. In contrast, the renal vasoconstrictor response to intraarterial angiotensin II was not significantly modified by diazoxide. This differential inhibition by diazoxide of renal vasoconstriction to norepinephrine or angiotensin II may warrant consideration when these pressor agents are being used to overcome the excessive hypotension resulting from inadvertent diazoxide overdosage.
A pharmacological analysis of the rat mast cell 5‐HT gastric lesion test and the effects of ketanserin
Authors: Awouters Frans H. L. , Niemegeers Carlos J. E. , Janssen Paul A. J. 
Published: January 2005

AbstractPronounced lesions of the gastric mucosa were induced by Compound 48/80 (1.0 mg/kg, i.v.) in rats protected from lethal shock of released histamine by the experimental histamine H1‐antagonist R 37 617. The intensity score of the lesions correlated with serum pepsinogen levels. Generally the stomachs were greatly distended and contained blood and regurgitated food residues. Compounds from many different pharmacological classes were tested in this procedure. Complete protection was obtained with serotonin antagonists. Also isoproterenol and salbutamol fully protected, apparently by counteracting the serotonin‐induced circulatory stasis. No obvious effect was obtained with antagonists of acetylcholine, dopamine, and histamine, with α‐ and β‐adrenergic blocking agents, with narcotic analgesics, and with various other agents unless doses were administered that by far exceeded the range of their primary activity. The lowest ED50 of ketanserin for protection was 0.15 mg/kg (time—2 hr, both s.c. and p.o.), indicating its high oral effectiveness against venoconstriction induced by endogenous serotonin. These doses also abolished cyanosis and reduced stomach distension, abnormal gastric contents, and serum pepsinogen levels. In view of the recently elucidated differences between serotonin antagonists, the mast cell 5‐HT gastric lesion test appears appropriate to measure the peripheral serotonin S2‐antagonism of compounds.
The activity of nifedipine, diltiazem, verapamil, and lidoflazine in isolated tissues: An approach to the determination of calcium channel blocking activity
Authors: Kenakin Terry P. , Beek Deborah 
Published: January 2005

AbstractA characteristic profile of activity was obtained in six isolated tissues for the calcium channel antagonists nifedipine, diltiazem, verapamil, and lidoflazine. All drugs produced relaxation of K+ depolarized guinea pig ileal longitudinal muscle strips and K+ depolarized canine coronary artery, depression of electrically stimulated basal contractions of guinea pig left atria, and depression of guinea pig right atrial rate. Also, all drugs produced parallel dextral displacement of concentration‐response curves to calcium in guinea pig depolarized taenia caeci. The potency for this effect was quantified by Schild analysis yielding the following pA2 estimates: nifedipine 9.5, diltiazem 7.65, verapamil 7.8, and lidoflazine 7.0. Nifedipine, diltiazem, and lidoflazine produced no relaxation of methoxamine‐contracted rabbit aortae while weak effects were observed with verapamil at concentrations 100 times greater than those required to reverse calcium effects in other tissues. In general, nifedipine and diltiazem displayed selectivity for smooth muscle over cardiac muscle while verapamil showed the least selectivity in this regard.
Alprazolam: Review of pharmacological, pharmacokinetic, and clinical data
Authors: VonVoigtlander Philip F. , Straw Robert N. 
Published: January 2005

AbstractAlprazolam is a recently marketed triazolobenzodiazepine. The animal pharmacological data reviewed here suggest a potent anxiolytic action. But, in addition, an antidepressant activity was revealed in clinical studies and subsequently studied in animal assays. As an extension of these activities, alprazolam also displays efficacy in panic and phobic disorders. Data relating to a wide range of pharmacological activities and pharmacokinetics of alprazolam are also reviewed.
Studies of the antihypertensive effects of CL 242,817, a new angiotensin‐I converting enzyme inhibitor [S−(R*, s*)]‐1‐[(3‐acetylthio)‐3‐benzoyl‐2‐methyl propionyl‐L‐proline]
Authors: Lai F. M. , Cervoni P. , Chan P. S. , Shepherd C. A. , Ronsberg M. A. , Quirk G. J. , Thibault L. , Scully P. , Tanikella T. 
Published: January 2005

AbstractThe antihypertensive activity of CL 242, 817 and captopril were evaluated in conscious, unrestrained aorta‐coarcted hypertensive rats (AHR); spontaneously hypertensive rats (SHR); and in the two‐kidney, one‐clip, Goldblatt renal hypertensive beagle (RH2 dog). In AHR, equimolar oral doses of CL 242,817 (5 mg/kg) and captopril (3 mg/kg) had rapid onsets of action and relatively long durations of action. CL 242,817 was significantly more potent and longer‐acting than captopril. In the SHR, CL 242,817 was effective in lowering blood pressure by oral, intravenous, or intraperitoneal routes of administration, although less effectively than in AHR. In RH2 dogs, pretreated with the diuretic quinethazone, CL 242,817 (20 mg/kg, p.o.) lowered blood pressure more effectively than an equimolar dose of captopril (12 mg/kg). In RH2 dogs sodium‐depleted by furosemide pretreatment and maintained on a salt‐free diet to raise plasma renin activity (PRA) levels, CL 242,817 (20 mg/kg, p.o) was more effective than an equimolar oral dose of captorpril (12 mg/kg) in lowering blood pressure. In RH2 dogs, repletion of body sodium (and reduction in PRA) by maintenance on a normal sodium diet for 14 days decreased the antihypertensive effect of CL 242,817 and abolished that of captopril. The data suggest that angiotensin converting enzyme inhibitors (ACEI) are more effective in models in which PRA is elevated and the hypertension appears to be renin‐dependent. The RH2 dog that is sodium‐depleted by furosemide and mainted on a sodium‐free diet appears to be a suitable model for evaluating the antihypertensive effects of ACEI.
Ophthalmic drug delivery systems
Authors: Shell John W. 
Published: January 2005

AbstractNew ophthalmic drug delivery systems are curently receiving increased attention, in part because of the expected emergence of new drugs with short biological half‐lives whose usefulness may depend on a more continuous drug supply than eyedrops can provide, but also because of the potential of some delivery systems to reduce the side effects of the more potent drugs recently introduced or presently under investigation. Some ophthalmic delivery systems extend the duration of drug action by enhancement of corneal absorption; these systems include soluble gels and emulsions, hydrophilic ocular inserts, ion‐pair associations, prodrugs, and liposomes. Since these systems enhance the “pulse entry” of the drug, they are limited to use with drugs whose dose‐related side effects are not serious. Other delivery systems provide for a controlled release of drugs and therefore minimize the pulse entry with which side effects are associated. They can be based on any of several different mechanisms and include both erodible and nonerodible matrices. The various delivery systems that have recently been developed and those that are currently known to be under investigation are described in this paper, along with some observations regarding the future outlook of ophthalmic drug delivery systems.
Early experience with CGP 4718 A (Sercloremine), a new selective and reversible MAO‐A and 5‐HT‐uptake inhibitor, in the treatment of depressive patients
Authors: Delini‐Stula A. , Fischbach R. , Gnirss F. , Bures E. , Pöldinger W. 
Published: January 2005

AbstractTolerability of CGP 4718 A (sercloremine), a 4‐(5‐chloro‐2‐benzofuranyl)‐1‐methyl‐piperdine, as well as the effects on target symptoms in 22 hospitalized depressed patients, were investigated in an open, multicenter study. In daily doses of 50 to 150 mg, the compound was well tolerated. There were no changes in cardiovascular parameters (blood pressure, ECG) nor were there changes in laboratory values that could be considered of clinical relevance. Of concern, however, were sleep disturbances, which appeared to be aggravated in the majority of treated patients. There were only a few other side‐effects that could be related to the drug treatment, and they were mostly mild and transitory. The therapeutic effects of CGP 4718 A, as judged by the changes in total Hamilton depression rating scores and global assessement, indicated beneficial action of the drug on the core symptoms of depression (except sleep disturbances). The therapeutic effect appeared to be dose‐related and particularly marked in neurotic and reactive depressions. These findings, in line with the predictions made on the basis of preclinical animal studies, encourage further clinical testing of this compound.