bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of beta‐endorphin and related peptides in the pathogenesis and treatment of Alzheimer's disease
Authors: Riekkinen Paavo , Helkala Eeva‐Liisa , Jolkkonen Jukka , Riekkinen Paavo , Soininen Hilkka 
Published: January 2005

AbstractBeta‐endorphin (B‐EP)‐like immunoreactivity of cerebrospinal fluid (CSF) was compared in patients with Alzheimer's disease (AD) and Parkinson's disease (PD). Somatostatin (SS)‐like immunoreactivity (SLI) was measured in AD patients. We were able to demonstrate a decrease in both B‐EP and SS during the progression of Alzheimer's disease. The decline of SS had occurred already in moderately affected patients, reflecting the pathological changes of cortical interneurones. The decline of B‐EP reached significance in severely demented patients, which demonstrated the spread of cell death into hypothalamic neurones. The different time courses observed for alterations of CSF, SS, and B‐EP levels in AD fit well with the proposed chronological progression of the disease. B‐EP levels of the PD group did not differ from the values of the control group, which supports the idea of different pathological changes in AD. We failed to show any clear‐cut differences between the behavioral correlates of SS and B‐EP deficits using various cognitive tests and clinical rating scale. The effects of ACTH 4‐9 derivate (ORG 2766) were evaluated in 77 AD patients. The effects observed in experimental animals on the memory function and CSF monamine markers could not be replicated in humans; nor could we find any slowing of the changes on EEG after drug treatment.
Prophylactic effects of novel dihydropyrazolopyridine (83‐0256) and dihydrothienopyridine (83‐0312, 83‐0327) calcium antagonists in stroke‐prone spontaneously hypertensive rats
Authors: Masui Masao , Kawakami Masaru , Nakajima Masatoshi , Hara Seijiro , Ueda Motohiko , Ito Hiroyuki 
Published: January 2005

AbstractThe prophylactic effects of several Ca antagonists against the incidence of cerebral stroke in stroke‐prone spontaneously hypertensive rats (SHRSP) (9‐17 weeks of age) fed a stroke‐prone (SP) diet (Na, 0.39%) were investigated for 8 weeks. The control SHRSP administered 1% gum arabic solution showed 87.5% mortality due to cerebral stroke during the experimental period. Daily oral administration of nifedipine or dihydrothienopyridine derivatives (83‐0312, 83‐0327) at 3 mg/kg or of nicardipine or dihydropyrazolopyridine derivative (83‐0256) at 10 mg/kg markedly inhibited the incidence of cerebral stroke and decreased mortality in SHRSP. Also markedly inhibited were the early appearances of proteinuria and occult blood in the urine observed with control SHRSP. Potencies of prophylactic effects of Ca antagonists on the incidence of stroke decreased in the following order: 83‐0327 > nifedipine ≥ 83‐0312 ≥ 83‐0256 > nicardipine. These potencies corresponded well with those of the acute antihypertensive effects. The most potent prophylactic effect against stroke was observed following the administration of 83‐0327 and this effect was considered to be intimately related with its lasting antihypertensive effect.
Does AAMI constitute a real disease entity? A placebo‐controlled double‐blind study with sabeluzole (R58 735) in a patient population with real memory problems
Authors: Tritsmans Luc , Clincke Gilbert , Peelmans Boudewijn 
Published: January 2005

AbstractSabeluzole was studied in patients complaining spontaneously about their memory. They were screened and only included if they fitted into the AAMI‐criteria and if, additionally, they were poor performers on a Selective Reminding Procedure (SRP). Fifty‐three patients (aged between 52 and 90 years) were thus treated in a double‐blind manner with either sabeluzole 10 mg b.i.d. or placebo for 2 months. No intergroup differences were seen for any of the tests used. In the sabeluzole group, however, the learning of new semantic entities, consisting of a noun and an accompanying adjective (U, Td) in a Cued Recall Task, increased significantly (P = 0.04). Additionally, a higher Word Fluency score was obtained after sabeluzole treatment (P = 0.002), an effect not present in the placebo group. Objective improvements were paralleled by subjective improvements, as measured on Visual Analogue Scales, in the sabeluzole‐treated patients. The study drug was very well tolerated and no serious adverse reactions were seen. However, AAMI, even with the more stringent criteria we used, does not seem to define a homogeneous study population, which reflects a clinical entity. Therefore, the use of AAMI‐criteria as a research tool is questionable.
Imidazobenzodiazepine RO15‐4513 augments ethanol‐induced wheel‐running suppression in the rat
Authors: Bixler Michael A. , Lewis Michael J. 
Published: January 2005

AbstractThe ability of RO15‐4513 to block ethanol‐induced motor incapacitation and was assessed via ethanol‐induced suppression of wheel‐running. However, either ethanol or RO15‐4513 administration alone produced an equivalent decrease (75% and 72%, respectively) in wheel‐running performance. Administration of RO15‐4513 at 2.5, 1.25, 0.625, 0.312, 0.156, and 0.078 mg/kg doses produced a dose‐dependent suppression of wheel‐running. Finally, ethanol administration following pretreatment with RO15‐4513 (3.0 mg/kg) produced greater suppression of wheel‐running (89%) than ethanol administration alone (55%). These results demonstrate intrinsic suppressant effects of RO15‐4513, and the lack of generality in the previously reported antagonism of ethanol‐induced intoxication by RO15‐4513.
GABA receptors and GABAergic synapses as targets for drug development
Authors: Taylor Charles P. 
Published: January 2005

AbstractGamma‐amino butyric acid (GABA) is perhaps the most abundant and important rapid inhibitory neurotransmitter in the mammalian brain. Many previous studies have indicated that GABAergic synapses are involved in drug treatments or disease processes for epilepsy, anxiety, movement disorders, depression, and psychosis. In particular, the GABAA receptors, which rapidly open chloride ion channels and thereby clamp neuronal membrane potential to near the resting level, have received extensive study. GABAB receptors are functionally and structurally quite distinct, and there are subtypes of both GABAA and GABAB receptors. This brief review describes strategies that have been used to study GABA receptors and the pharmacology of drugs that act on GABAergic synapses. The eight reports that follow in this issue of Drug Development Research focus on the pharmacology of GABAA agonists and GABA uptake inhibitors as potential therapeutic agents, and they were first presented as a satellite symposium of the 1989 meeting of the Society for Neuroscience. The following reports give special reference to Cl‐966, a novel inhibitor of GABA uptake that was developed as a potential anticonvulsant based on animal studies [Taylor et al., 1990]. Unfortunately, Cl‐966 caused severe and unexpected neurological and psychological disturbances in initial clinical studies with healthy human volunteers and has been discontinued from further development [Sedman et al., 1990]. This brief review aims to give some perspective to the following papers on GABAA agonists and GABA uptake inhibitors.
GABA‐A agonists and GABA uptake inhibitors: Structure‐activity relationships
Authors: Falch Erik , Larsson Orla M. , Schousboe Arne , Krogsgaard‐Larsen Povl 
Published: January 2005

AbstractMuscimol is a potent but non‐selective GABA‐A agonist. Structure‐activity studies on the (S)‐ and (R)‐forms of chiral muscimol analogues have disclosed a high degree of agonist stereoselectivity of the GABA‐A receptors. THIP (4,5,6,7‐tetrahydroisoxazolo[5,4‐c]pyridin‐3‐ol) is a specific GABA‐A agonist, which has been the subject of clinical studies in different groups of patients. Even minor alterations of the structure of THIP result in substantial or complete loss of GABA‐A agonist activity. 4‐PIOL (5‐(4‐piperidyl)isoxazol‐3‐ol) shows in vivo GABA‐A agonist activity on spinal neurones, whereas the in vitro pharmacological effects in brain tissue preparations are consistent with a GABA‐A antagonist profile of 4‐PIOL in the brain. Whereas nipetcotic acid and related GABA uptake inhibitors are substrates for the neuronal and glial transport carrier, the glia‐selective GABA uptake inhibitors THPO (4,5,6,7‐tetrahydroisoxazolo[4,5‐c]pyridin‐3‐ol) and probably also THAO (5,6,7,8‐tetrahydro‐4H‐isoxazolo[4,5‐c]azepin‐3‐ol) are not being transported by the glial uptake carrier. Introduction of the DPB (4,4‐diphenyl‐3‐butenyl) or BEE (benzhydryl ethyl ether) substituents on the basic nitrogen atoms of GABA uptake inhibitors, including nipecotic acid and THPO, results in markedly more potent inhibitors. However, unlike THPO, N‐DPB‐THPO interacts non‐selectively with neuronal and glial GABA uptake, and, in contrast to nipecotic acid, N‐DPB‐nipecotic acid (SKF‐89976‐A) has been shown not to be transported by the neuronal or glial GABA carriers. Whereas N‐DPB‐ and N‐BEE‐GABA are weak inhibitors of synaptosomal GABA uptake, N‐methylation of these compounds gives potent uptake inhibitors.
Neuropharmacological evidence for an interaction between the GABA uptake inhibitor Cl‐966 and anxiolytic benzodiazepines
Authors: Giusti Pietro , Guidotti Alessandro , Danysz Wojciech , Auta James , Costa Erminio 
Published: January 2005

Abstract[1‐[2‐[bis(trifluoromethyl)‐phenyl]methoxy]ethyl]‐ 1,2,5,6‐tetrahydro‐3‐pyridine‐carboxylic acid, HCl (Cl‐966, Parke‐Davis) is a new specific inhibitor of GABA uptake to neurons that is severalfold more potent than for inhibition of glycine or glutamate uptake. Cl‐966 crosses the blood‐brain barrier and when injected intravenously into rats (doses up to 10.5 μM/Kg = 5.0 mg/kg) produces only marginal behavioral effects. Cl‐966 also produces a modest reversal of punished‐suppressed drinking behavior in thristy rats both in the conflict and phenylenetetrazole (PTZ)‐induced proconflict Vogel test. However an inactive dose of Cl‐966 (6.3 μM/kg i.v., 90 min prior to the test) significantly potentiated the anticonflict and anti‐PTC‐induced proconflict action of diazepam and alprazolam. The anticonflict/antiproconflict ED50 ratio for diazepam was shifted from 1.2 to 1.0 and that of alprazolam from 13.0 to 7.0 after pretreatment with Cl‐966.These results suggest that Cl‐966, while it may produce increasing GABAergic tone throughout the CNS, selectively enhances the action of GABA at GABAA receptor subtypes whose sensitivity is preferentially increased by administration of positive allosteric modulators. Therefore Cl‐966 may represent a very useful drug to study modifications of animal behavior in relation to the function of GABAergic transmission in specific brain areas.
Influences of cholecystokinin and analogues on memory processes
Authors: Itoh Shinji , Lal Harbans 
Published: January 2005

AbstractEvidence is reviewed to assign the role of cholecystokinins in the cognitive and memory processes. Rat brain contains about 550 ng of CCK‐8. When injected, icv or sc, in doses of less than 100 ng of CCK or caerulein, these peptides prevent experimental amnesia and prolong extinction of the already‐learned tasks. Caerulein is nearly 10 times as potent as CCK‐8, and the effects of both peptides are long‐lasting. Pretreatment with these peptides also prevents scopolamine‐induced amnesia, and reverses the ACh depletion in the frontal and temporal cortices as well as in the hippocampus. CCK‐8 antagonists in small doses produce complete amnesia, further supporting the hypothesis that endogenous CCK‐8 modulates the memory processes in the brain. Neurochemical data suggest participation of the NMDA receptors, protein kinase C, and protein synthesis in the action of CCK‐8 and caerulein. Sub‐diaphragmatical vagotomy abolishes the memory‐enhancing effects of these peptides when administered peripherally. Thus, CCK‐8 and caerulein are likely to affect not only the receptors localized in the CNS, but also to stimulate peripheral receptors associated with the vagus. Alternatively, the vagus may be the major pathway for CCK transport from the visceral organs to the brain.
Pharmacological profile of RWJ 20085: A new, potent, long‐acting local anesthetic
Authors: Dubinsky Barry , Shriver David A. , Sanfilippo Pauline J. , Press Jeffery B. , Tobia Alfonso J. , Rosenthale Marvin E. 
Published: January 2005

AbstractRWJ 20085 is a potent, long‐acting local anesthetic that has been studied in vivo and in vitro relative to several clinically active agents. In mice, RWJ 20085 [ED50 = 0.0078% (0.0053–0.011%)] was more potent by perineural infiltration than bupivacaine [ED50 = 0.035% (0.026–0.046%)], etidocaine [ED50 = 0.025% (0.016–0.035%)], or lidocaine [ED50 = 0.18% (0.13–0.26%)]. The onset of action of each compound was 5 minutes, and the duration was 90 minutes for RWJ 20085 and 30 minutes for bupivacaine or etidocaine while lidocaine was active for only 15 minutes. In the rabbit corneal assay, RWJ 20085 [ED50 = 0.012% (0.0049–0.023%)] was more potent than bupivacaine [ED50 = 1.4% (0.47–3.05%)]. The lowest topical local anesthetic ED50 of each agent was observed within 5 or 15 minutes after administration, and RWJ 20085 was active for 300 minutes, whereas bupivacaine and etidocaine were active for 90 or 45 minutes, respectively. In the guinea pig intradermal assay RWJ 20085 [ED50 = 0.017% (0.0094–0.028%)], bupivacaine [ED50 = 0.016% (0.0078–0.028%)], and etidocaine [ED50 = 0.02% (0.0093–0.042%)] were equipotent while lidocaine [ED50 = 0.072% (0.040–0.12%)] was less potent. The onset of action of each compound was 5 minutes. The duration of action of RWJ 20085 and etidocaine was 60 minutes, whereas bupivacaine and lidocaine were active for 45 and 15 minutes, respectively. In the frog isolated‐sciatic nerve preparation, similar concentrations of RWJ 20085 (2.5 × 10−3M) and lidocaine (5.0 × 10−3M) produced a 50% reduction of the amplitude of the pretreatment action potential; however, bupivacaine and etidocaine were each effective at a lower concentration (5.0 × 10−4M). When their intramuscular therapeutic ratios (TR = lethal dose LD50/local anesthetic ED50) were calculated in mice, the therapeutic ratio of RWJ 20085 (82) was less than that of etidocaine (103) but was larger than that of either lidocaine (36) or bupivacaine (29). Calculation of the therapeutic ratios by using the intravenous LD50 values suggests that lidocaine would have the smallest margin of safety if inadvertently administered by the intravenous route. The therapeutic ratios of the other agents were larger than that of lidocaine; however, there was little difference among them. RWJ 20085 has a low potential for dermal irritation as shown in rabbits and has no liability for contact sensitization as shown in guinea pigs. RWJ 20085 may have clinical utility as an injectable and/or topical local anesthetic.
Moclobemide (Ro 11‐1163) vs. clomipramine in the treatment of depression: A double‐blind multicenter study in Belgium
Authors: Cattiez P. H. , Dierick M. , Troisfontaines B. , van Audenrode L. , Defleur J. , Hermans W. , Roelandts A. , Stenier P. , Wolfrum C. 
Published: January 2005

AbstractA multicenter study to compare the antidepressant efficacy and the tolerance of moclobemide (Ro 11‐1163) to clomipramine was performed in parallel groups of patients with minor depression. The duration of the study was 6 weeks, with weekly assessments by means of Hamilton Scale of Depression (HRDS) and the Clinical Global Impression (CGI). The efficacy of moclobemide was found to be as good as that of clomipramine. The results for tolerability were possibly in favor of moclobemide. It was recommended that consumption of tyramine‐containing foods be kept to a minimum or avoided and no hypertensive crises were reported.
Ouabain pretreatment does not compromise the hemodynamic and myocardial energetic effects of CK‐3197, a selective positive inotropic agent, in dogs with propranolol‐induced heart failure
Authors: Greenberg Stan , Touhey Beatrix , Hom Gary 
Published: January 2005

AbstractWe examined the interaction between ouabain and CK‐3197, a new selective positive inotrope, on the hemodynamic and myocardial energetic parameters of anesthetized dogs with propranolol‐induced heart failure (PIHF). Mongrel dogs (13–18kg) of either sex were anesthetized with pentobarbital sodium (35mg/kg, i.v.) and instrumented for routine hemodynamic measurements using an open‐chest, artificially ventilated preparation. PIHF was produced by decreasing left ventricular (LV) dp/dt max by 50% from control values with an intial infusion of 0.5 mg/kg of propranolol followed by continuous infusion of 0.02 to 0.08 mg/kg of propranolol to maintain PIHF. This was followed by infusion of saline (2ml, i.v., n=8/group) or ouabain (25 μ/kg, i. v., n=8/group). Thirty minutes later one‐half of the saline and ouabain treated animals (Groups I and II;n =4/group) were given two increasing doses of saline or CK‐3197 (0.1 and 0.3 mg/kg, i. v.; n= Groups III and IV; n =4/group) 30 min apart. Hemodynamic paramters were monitored continuously, while myocardial oxygen consumption (MVO2) was monitored 15 and 30 min after each dose of drug. CK‐3197 increased LV DP/dTmax and LV dP/dTmin by 41 and 78%, respectively. Mean arterial pressure increased by 16 and 6%. Heart rate decreased by 6 and 8%, while LV end diastolic pressure (LVEDP) decreased by 3mmHg after CK‐3197 (0.3 mg/Kg, i.v.). CK‐3197 increased LV work and LV contractile efficiency. Ouabain did not affect the hemodynamic and myocardial energetic profile of CK‐3197. These data support the conclusions that CK‐3197 is a selective positive inotrope which increases myocardial contractile efficiency in the dog with PIHF without any significant interaction with ouabain.
Effects of dopexamine hydrochloride, a beta‐adrenergic and dopaminergic agonist, on vascular resistances, and flow distribution between cutaneous and skeletal muscle vasculatures
Authors: Grega George J. , Staniciu Dorina , Murray Melissa , Lokhandwala Mustafa F. 
Published: January 2005

AbstractLocal i.a. infusions of the dopaminergic and β2 adrenoceptor agonist dopexamine HCL (DPX) into collateral‐free, innervated canine forelimbs perfused at constant flow produced dose‐dependent decreases in perfusion pressure, evidence of a vasodilator response in the forelimb vasculature. DPX produced vasodilation in both the skin (cutaneous) and skeletal muscle vasculature of the canine forelimb, as evidenced by the dose‐dependent decrease in total skin and total skeletal muscle vascular resistances. DPX produced comparable dilation of the skin and skeletal muscle vasculatures, as evidenced by the failure of this agent to produce a significant shift in blood flow between the brachial and cephalic venous outflows, that is, between the skin and skeletal muscle vasculatures. In the cutaneous (skin) vascular circuit, DPX failed to affect vascular resistances in the large artery and large vein segments, but produced a dose‐dependent decrease in vascular resistance in the small vessel segment, presumably reflecting primarily arteriolar vasodilation. The vascular smooth muscle relaxation produced by DPX was inhibited by treatment with propranolol, suggesting that the vasodilation primarily results from direct stimulation of forelimb vascular β2 adrenoceptors by DPX.
A pharmacological and biochemical examination of AHR‐16462B, a novel calcium antagonist coronary vasodilator/antihypertensive
Authors: Barrett Richard J. , Appell Kenneth C. , Proakis Anthony G. , Shanklin James R. , Kilpatrick Brian F. 
Published: January 2005

AbstractA series of pharmacological and biochemical studies were conducted to characterize AHR‐16462B 4‐[bis(4‐fluorophenyl)methyl]‐1‐(2‐naphthalenylmethyl)piperidine (HCI), a novel antagonist of voltage‐sensitive calcium channels. AHR‐16462B displaced [3H]‐nimodipine binding from calcium channels on rabbit skeletal muscle membranes (IC50 = 118 nM) and inhibited depolarization‐induced changes in intracellular free calcium in cultured PC‐12 cells (IC50 = 125 nM), but had virtually no effects on binding of specific radioligands to 5‐HT1a, 5‐HT2, alpha1, alpha2, dopamine2, beta1, beta2, muscarinic M1, or histamine H1 receptors. AHR‐16462B antagonized CaCI2‐induced contractions of depolarized rabbit aortic strips (pA2 = 8.83), but had no negative chronotropic, and only slight negative inotropic effects on isolated guinea pig atria. In anesthetized dogs, cumulative doses of 0.1, 0.4, and 1.4 mg/kg, i. v., AHR‐16462B decreased coronary vascular resistance and blood pressure; the magnitude and duration of these effects were dose related. Heart rate and Lead 2 ECG waveforms remained unaltered at all doses. In conscious spontaneously hypertensive rats (SHR), 3 to 100 mg/kg, p. o., AHR‐16462B produced marked, long‐lasting, and dose‐related antihypertensive actions. Heart rate remained unaltered following 3, 10, and 30 mg/kg AHR‐16462B, and bradycardia was evoked by 100 mg/kg. Effective antihypertensive doses of AHR‐16462B had modest natriuretic and/or chloruretic actions.
Role of growth factors in the uveal tract of the eye as targeted to the development of new drugs
Authors: Tripathi Ramesh C. , Fekrat Sharon , Tripathi Brenda J. , Borisuth Navaneet S. C. 
Published: January 2005

AbstractThe uveal tract of the eye, which consists of the iris, ciliary body, and choroid, is responsible for the primary nutritional supply of the ocular structures, especially the retina and, through the production of aqueous and vitreous humors, for nourishment of avascular intraocular structures such as the lens, cornea, and trebecular meshwork. The growth factors that have been detected in the uveal tract include fibroblast growth factor, epidermal growth factor, transferrin, transforming growth factor‐β, nerve growth factor, epidermal growth factor, and insulin‐like growth factors. These mitogens in the uveal tract influence the metabolism and proliferative activity of intraocular structures, and have major implications for the health and disease of the eye. We discuss the possible therapeutic role of growth factors, as well as the prospects for, and hurdles in, drug development for their use in various ocular disorders such as degenerative and proliferative diseases, neovascularization, glaucoma, ocular ischemic syndromes, cataract, neoplasms, and wound healing well as in the modulation of HLA‐DR expression.
Effects of tianeptine in animal models of anxiety and on learning and memory
Authors: File Sandra E. , Mabbutt P. S. 
Published: January 2005

AbstractOn acute administration tianeptine (2.5–10 mg/kg) was without significant effect in the social interaction test, but after 5 days of administration it produced an overall increase in social interaction. The increase was not more marked in unfamiliar than familiar test arenas and thus the profile differed from that seen with the benzodiazepines. Tianeptine (2.5–10 mg/kg) acutely and after 5 days was without significant anxiolytic effect in the elevated plus‐maze. Overall the pattern of results in these tests of anxiety resembles those of other novel compounds acting on the 5‐HT systems and possibly possessing anxiolytic or antidepressant effects. Tianeptine was without effect on between‐day habituation in the holeboard but tianeptine (10 mg/kg) significantly improved acquisition in a spatial task relying heavily on reference memory. Tianeptine (2.5 mg/kg) significantly reduced errors of working memory in a task in which spatial cues were minimized. These results suggest that rather than impairing memory tianeptine may actually improve some aspects.