bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pathomorphologic effects of N‐methyl‐D‐aspartate antagonists in the rat posterior ingulate/retrosplenial cerebral cortex: A review
Authors: Fix Andrew S. , Long Gerald G. , Wozniak David F. , Olney John W. 
Published: January 2005

AbstractThis review discusses available information on the neurotoxicity of N‐methyl‐D‐aspartate (NMDA) antagonists in the posterior cingulate/retrosplenial (PC/RS) cortex of rats. NMDA antagonists block the NMDA receptor, a central nervous system ionotropic glutamate receptor, and are neuroprotective since they reduce injury in animal models of ischemia. There is interest in the development and use of NMDA antagonists in treating human cerebrovascular diseases. However, with certain NMDA antagonists, dose‐dependent vacuolization of neurons in the neuroanatomically localized PC/RS cortex occurs as a side effect in rats. NMDA antagonists that cause vacuolization also appear to induce heat shock protein expression and heightened glucose metabolism in the same cortical region. Electron microscopy has shown that after treatment with MK‐801 (dizocilpine maleate), a prototypic noncompetitive NMDA antagonist, the onset of vacuolization is very rapid. Additional studies with MK‐801 have indicated that susceptibility to vacuolization increases between 30 and 90 days of age. Histologic time course studies have demonstrated that as the dose of MK‐801 is increased, some vacuolated neurons become necrotic. Necrotic neurons are readily evident by light microscopy in routine preparations. At a given dose of MK‐801, neuronal necrosis is more extensive in female rats than male rats. Furthermore, necrosis increases along an anterior to posterior gradient within the susceptible PC/RS cortex. A number of compounds with varied central nervous system (CNS) pharmacologic activity (anticholinergics, GABAmimetics, antipsychotics, and general anesthetics) partially or completely prevent neuronal vacuolization. These data suggest a complex pathogenesis for NMDA antagonist‐mediated neurotoxicity and indicate variables which require consideration when designing and interpreting studies with these compounds. Since recent reports have described failure of some NMDA antagonists to produce these side effects, the issues discussed in this review may or may not apply to all NMDA antagonists.
Models used to assess renal function
Authors: Chiu Peter J. S. 
Published: January 2005

AbstractThe kidney as a primary excretory organ is a major route of elimination for numerous xenobiotic agents. In the process, it is liable to the hemodynamic and injurious actions of drugs due to their concentration in the kidney. In this brief review, a number of methods for assessing kidney function (e.g., serum creatinine, enzymuria, inulin, and PAH clearances, etc.), with their advantages and limitations, are described. Various acute and chronic animal models (rats and dogs) commonly used in performing safety evaluation of drugs are described; several antihypertensive drugs are cited as examples. These models can be modified with varying number of measurements, depending on the pharmacological activity of test drugs, animal species, specific issues (e.g., vascular vs. tubular effects), pathophysiological conditions, etc.
Microdialysis assessment of the impact of (+)3,4‐methylenedioxymethamphetamine, cocaine, and cocaethylene on serotonergic neurons
Authors: Bradberry Charles W. 
Published: January 2005

AbstractThis overview summarizes the results of microdialysis studies into the effects of several psychoactive drugs on extracellular serotonin (5‐HT) levels in rat brain. The effects of (+)3,4‐methylenedioxymethamphetamine (MDMA, ecstasy) were examined in the brain slice preparation for comparison with parallel electrophysiological studies of the impact of (+)‐MDMA on dorsal raphe 5‐HT neuronal firing. (+)‐MDMA induced the release of 5‐HT from slices of dorsal raphe. The release was inhibited by fluoxetine, and augmented by tryptophan pretreatment. The results support a mechanism of action whereby (+)‐MDMA inhibits 5‐HT neuronal firing by releasing 5‐HT which then acts upon somatodendritic autoreceptors. In other studies, the effects of cocaine and cocaethylene (the psychoactive metabolite of concurrent cocaine/ethanol consumption) on extracellular 5‐HT and dopamine levels in the chloral hydrate‐anesthetized rat were examined. Both the intravenous and intraperitoneal routes were examined. By intravenous route, both drugs had equivalent effect at increasing dopamine levels. Cocaine significantly increased 5‐HT levels, while cocaethylene had no impact. By intraperitoneal route, cocaethylene was able to increase 5‐HT levels, but cocaine remained more potent. Route‐dependent differences in bioavailability were evident from studies of brain levels using microdialysis. By intravenous administration, equivalent amounts of both drugs entered the brain, whereas by intraperitoneal route, levels of cocaethylene were half those of cocaine. © 1994 Wiley‐Liss, Inc.
Rifampicin induced hepatotoxicity in rats: Protective effect of picrolive effect of picroliv
Authors: Saksena Seema , Rastogi Ravi , Garg Narendra K. , Dhawan Bhola N. 
Published: January 2005

AbstractRifampicin, an anti‐tubercular drug, at 100 mg/kg (122 μmol) body weight (daily single ip injection for 6 days) caused changes in most of the biochemical parameters of the liver and serum in rats, 24 h after the last injection. These included significant increase in the activities of hepatic γ‐glutamyl transpeptidase, acid ribonuclease, acid phosphatase and decrease in the activity of succinate dehydrogenase. The levels of RNA, total proteins, bilirubin, total lipids, phospholipids, cholesterol, lipid peroxides in liver and bilirubin in serum increased while hepatic glycogen and serum proteins decreased. At a lower dose (50 mg/kg; 61 μmol/kg) the changes were less as compared to 100 mg/kg dose. When Picroliv (12 mg/kg body weight), a standardized iridoid glycoside mixture of Picrorhiza kurroa was administered simultaneously with rifampicin, most of the biochemical changes in liver and serum were prevented. These results indicate protective effect of Picroliv against rifampicin‐induced hepatotoxicity in rats. © 1994 Wiley‐Liss, Inc.
Potassium channel blockers as antiarrhythmic drugs
Authors: Colatsky Thomas J. , Argentieri Thomas M. 
Published: January 2005

AbstractSelective prolongation of cardiac repolarization is an effective means of suppressing a variety of cardiac arrhythmias, particularly those arising from a re‐entrant mechanism. Over the past several years, a variety of novel compounds have been discovered that increase cardiac action potential duration without slowing conduction. Most of these agents (e.g., dofetilide, E‐4031, MK‐499) act by selectively blocking the rapidly activating component of delayed rectification (IKr), although some (e.g., ibutilide, azimilide, terikalant) have been proposed to work via alternate mechanisms. While the overall efficacy of these agents against tachyarrhythmias appears to be greater than obtained for the sodium channels blockers, primary concerns remain about the ability of these agents to prolong repolarization at fast heart rates (i.e., reverse use‐dependence) and to exert proarrhythmic effects at slow heart rates (i.e., torsade de pointes). The limited clinical results obtained to date suggest that these potential limitations may be less important than previously thought, although clear pharmacodynamic differences among the various agents are beginning to emerge. While the effects of some class III agents on repolarization and refractoriness are clearly attenuated at rapid cycle lengths (e.g., sematilide, d‐sotalol), the effects of others appear to be largely rate‐independent, at least down to cycles as short as 350 msec. Also, the currently available data suggest that the risk of serious proarrhythmia may be lower (1–3%) and considerably more predictable than that seen during treatment with the class I agents. In summary, the rational design of selective blockers of cardiac K channels for development as antiarrhythmic drugs appears to have been relatively successful and continues to show considerable promise as a therapeutic approach. © 1994 Wiley‐Liss, Inc.
Antimuscarinic properties of vamicamide, a novel compound for the treatment of pollakiuria
Authors: Yamamoto Takao , Matsuo Masahiko , Yamazaki Shunji , Ueshima Koji , Sawada Tadashi , Furuichi Atsuko , Ozaki Reiko , Nishii Misako , Miura Shintaro , Kusunoki Takahiro , Sato Natsuki , Koibuchi Yasushi , Esumi Kimio , Ohtsuka Minoru 
Published: January 2005

AbstractThe antimuscarinic profile of vamicamide, a novel compound for the treatment of pollakiuria, was investigated in both in vitro and in vivo preparations. Vamicamide (10 nM–10 μM) inhibited the contractile response of isolated guinea‐pig detrusor muscle to transmural electrical stimulation. In isolated guinea‐pig detrusor muscle, vamicamide also inhibited contractile response to carbachol with an IC50 value of 0.71 μM, whereas it had little or no effect on detrusor contractions induced by KCl, BaCl2, or α, β‐methylene ATP. In binding studies with dog membrane preparations, the dissociation constant (Ki) of vamicamide against tritiated N‐methylscopolamine ([3H]NMS) binding was 172 ± 8 nM for the urinary bladder, which was lower (P < 0.01) than those for the heart (322 ± 31 nM), stomach (317 ± 29 nM), and salivary gland (321 ± 32 nM). The Ki value for the cerebral cortex (95 ± 4 nM) tended to be lower than that for the urinary bladder. In binding studies with cloned human muscarinic receptor subtypes (m1–m3), the dissociation constant (Ki) of vamicamide against [3H]NMS binding was 89.0 ± 3.5 nM for the m3 receptor subtype, which was lower than those for the m1 (235 ± 5 nM, P < 0.05) and m2 (593 ± 49 nM, P < 0.01) receptor subtypes. In anesthetized dogs, vamicamide (3.2–100 μg/kg; 11–336 nmol/kg, iv) inhibited the carbachol‐induced contractile responses of the urinary bladder with an ID50 value of 16.1 μg/kg (54 nmol/kg), the stomach with a value of 31.3 μg/kg (105 nmol/kg), the descending colon with a value of 10.1 μg/kg (34 nmol/kg), and secretory response of the salivary gland to carbachol with a value of 43.3 μg/kg (146 nmol/kg); the inhibitory effects of the compound on the stomach and salivary gland were weaker (P < 0.01) than that on the urinary bladder. Furthermore, duration of the action of vamicamide was longer on the urinary bladder and descending colon than those on the stomach and salivary gland. These results suggest that vamicamide has a selective binding affinity to the muscarinic m3 receptor subtype and exhibits greater and longer inhibitory action on the urinary bladder than the other organs examined. © Wiley‐Liss, Inc.
Design and development of sequence selective lexitropsin DNA minor groove binders
Authors: Lown J. William 
Published: January 2005

AbstractThe concept of lexitropsins, or information‐reading molecules, is introduced within the antigene strategy as an alternative to, and complementary with, the antisense approach for cellular intervention and gene control. Consideration is given to alternative approaches to the development of DNA sequence selective binding agents because of their potential applications in diagnosis and treatment of cancer as well as in molecular biology. The chemical, physical, and pharmacological factors involved in the design of effective lexitropsins are discussed and illustrated with experimental results. Among the factors contributing to the molecular recognition processes are: the presence and disposition of hydrogen bond accepting and donating groups, ligand shape, chirality, stereochemistry, flexibility, and charge. For longer ligands, such as are required to target unique sequences in biological systems (14–16 base pairs), the critical feature is the phasing or spatial correspondence between repeat units in the ligand and the receptor. The recently discovered 2:1 lexitropsin‐DNA binding motif provides a further refinement in molecular recognition in permitting discrimination between GC and CG base pairs. The application of these factors in the design and synthesis of novel agents which exhibit anticancer, antiviral, and antiretroviral properties, and in the inhibition of critical cellular enzymes including topoisomerases, is discussed. The emerging evidence of a relationship between sequence selectivity of the new agents and the biological response they invoke is also described. © 1995 Wiley‐Liss, Inc.
Cellular electrophysiological effects of MS‐551, a new class III antiarrhythmic agent
Authors: Ishii Masaaki , Kamiya Joji , Hashimoto Keitaro 
Published: January 2005

AbstractThe cellular electrophysiological effects of MS‐551, a pure class III antiarrhythmic agent lacking beta‐blocking activity, were compared with those of d‐sotalol and dofetilide in canine Purkinje fibers and ventricular muscles and in guinea pig atrial muscles using the standard microelectrode technique. MS‐551 prolonged the action potential duration (APD) of these cardiac tissues to the same extent in a concentration‐dependent manner (10−6−10−4 M). MS‐551 did not affect other action potential parameters of these tissues except for the Vmax, which was depressed approximately 10% at 10−4 M MS‐551. The extents of prolongation after 10−5 M of MS‐551 were 36, 27, and 35% for canine Purkinje and ventricular muscle and guinea pig atrial muscle, respectively. d‐Stalol at a concentration 10 times higher than MS‐551 produced a similar prolongation of the APD of canine cardiac tissues but only a slight prolongation of the APD of guinea pig atrial muscles. Dofetilide at a concentration 30 times lower than MS‐551 produced a prolongation of the APD of canine Purkinje fibers but a relatively slight prolongation of the APD of both canine ventricular muscles and guinea pig atrial muscles. In canine Purkinje fibers, MS‐551 did not prevent the APD shortening induced by high extracellular potassium (8 and 12 mM), but the APD under these conditions was lengthened compared with controls. Under simulated ischemic conditions (pO2 25–30 mmHg, pH 6.5, extracellular K 8 mM and no glucose) for 30 min, the APD was abruptly shortened during the first 5 min, then gradually shortened further up until 30 min. MS‐551 did not prevent the abrupt APD shortening, but slowed the later gradual shortening. The APD prolonging action of MS‐551 was enhanced at low frequency. These data indicate that (1) MS‐551 is a pure class III antiarrhythmic agent with electrophysiological characteristics basically similar to d‐sotalol and dofetilide; (2) MS‐551 has a relatively greater potency in guinea pig atrial muscle than d‐sotalol and dofetilide; (3) the APD prolonging action of MS‐551 is preserved under high K+ or simulated ischemic conditions; and (4) MS‐551 exhibits a reverse use‐dependence in prolonging APD. © 1995 Wiley‐Liss, Inc.
Doses of acetyl salicylic acid and morphine in combination which provided either maximal levels of analgesia or the highest potentiation effect in the rat
Authors: Lopéz‐Muñoz Francisco J. , Villalón Carlos M. , Terrón José A. , Salazar Luis A. 
Published: January 2005

AbstractThe analgesic efficacy of the combination of acetyl salicylic acid (ASA), a nonsteroidal anti‐inflammatory drug (NSAID), and morphine, a μ‐opiate receptor agonist, was evaluated in the pain‐induced functional impairment in the rat (PIFIR) model. Groups of 6 rats received either vehicle, ASA (175.4, 311.9, 555.1, 986.9, 1,755.2, or 3,121.3 μmol/kg p.o.), morphine (3.1, 5.5, 9.8, 17.5, 31.1, or 55.2 μmol/kg s.c.), or a combination of ASA and morphine (24 different combinations). This allowed us to detect the profile of analgesic interaction of the combinations. Furthermore, we set out to determine the optimal degree of potentiation obtained with a specific combination of the above drugs by means of the “surface of synergistic interaction” of the combinations. The ED50 values for ASA and morphine were 1,167.9 ± 6.7 and 18.4 ± 3.7 μmol/kg, respectively. Eleven combinations of ASA and morphine produced a level of analgesia significantly greater than can be accounted for by simple addition of the analgesic effects of each analgesic drug alone (P < 0.01). The combination of ASA (3,121.3 μmol/kg) and morphine (31.1 μmol/kg) produced the maximum analgesic effect. However, three combinations of ASA + morphine (555.1 + 31.1, 986.9 + 9.8, and 1,755.2 + 9.8 μmol/kg, respectively) produced the highest potentiation effects (P < 0.01). The surface of synergistic interaction clearly showed which combination of these analgesic drugs produced the highest degree of potentiation in the rat. This study showed that it is possible to rationally predict the specific combinations of analgesic drugs and their dosages which will provide either maximal levels of analgesia or the highest potentiation effect in the rat. © 1995 Wiley‐Liss, Inc.
An FDA perspective on general pharmacology studies to determine activity and safety
Authors: Green Martin D. 
Published: January 2005

AbstractGeneral pharmacology studies are conducted to determine various pharmacological activities, as part of drug discovery or to define some specific issues which are relevant to safety. Regulatory submissions of biological products, unlike other therapeutics classes of agents, e.g., drugs, are frequently accompanied by extensive information regarding their preclinical aspects of physiology, biochemistry, and pharmacology. Although not true in every instances, biologic products exert their effects in a highly specific manner. Various fundamental aspects of protein chemistry and receptor function combine to restrict the spectrum of pharmacological and toxicological effects likely to occur. General pharmacology studies may be conducted either separately or nested in larger studies assessing general toxicity. Pharmacology studies are used best in an attempt to answer specific questions and are particularly effective when complementing other tests of safety. © 1995 Wiley‐Liss, Inc.
Pharmacological testing of recombinant human erythropoietin: Implications for other biotechnology products
Authors: Dempster A. Marguerite 
Published: January 2005

AbstractThe development of recombinant DNA and large‐scale cell culture technologies has introduced a wide range of biotechnology products or “biologics” including cytokines, vaccines, peptides, hormones, growth factors, and monoclonal antibodies that are being used in the diagnosis, prevention, and treatment of various diseases. As with any new drug development program, pharmacologic evaluation is critical to an understanding of that new drug entity. A well‐designed general/safety pharmacology program contribues to the overall safety assessment of that new entity, provides important information to the design of early clinical trials, assists in resolving any issues that arise during preclinical or clinical development, and assists in deciding whether to continue its development. This has been the case for many small molecular weight compounds and is no less important for the new biotechnology products. Because of their complex structural and biological characteristics, biotechnology products present unusual challenges in their development, resulting in pharmacology programs designed on a “case by case” basis. The pharmacologic evaluation of r‐HuEPO may well serve as an model for understanding some of the potential issues associated with the development of biologics. With r‐HuEPO being marketed worldwide for approximately five years, clinical data are available to assess the predictive value of the pharmacology studies. An analysis of these data serves as a guide to determine which preclinical studies best reflect the clinical data. Appropriate design of a pharmacology program depends on an understanding of the structure of the molecule, the mechanism of action at the cellular level, species specificity, and the clinical plan. On this basis a program can be developed to accurately assess the potential non‐pharmacologic effects and ultimately establish a benefit‐to‐risk ratio. © 1995 Wiley‐Liss, Inc.
Safety pharmacology program for pharmaceuticals
Authors: Kinter Lewis B. , Dixon Lon W. 
Published: January 2005

AbstractSafety pharmacology data is used by clinicians, toxicologists, discovery scientists, and regulators involved in developing and registering new pharmaceutical products. We recently developed a safety pharmacology program to meet the needs of these diverse customer groups at Sterling Winthrop. We identified three classes of safety pharmacology studies: Core (cardiovascular, respiratory, renal, and CNS), having the broadest value to all customers; Special (ocular, auditory, etc.), occasionally needed to address compound or class effects; and Ancillary (GI, autonomic, behavioral), needed to complete international registration requirements. We established a tiered approach to the conduct of these studies that is efficient and cost‐effective, and developed general guidelines for designs of Core studies. The proposed program meets or exceeds all international regulatory requirements and insures that the necessary results are available for each customer group within the time frame that the data are most useful. © 1995 Wiley‐Liss, Inc.
Animal models of dementia
Authors: Porsolt Roger D. , Roux Sylvain , Wettstein Joseph G. 
Published: January 2005

AbstractThe major use of animal models for dementia is in the development of new therapeutic drugs. In contrast to other areas in psychopharmacology, where the predictive validity of animal models can be established by examining their response to known therapeutic agents, the search for antidementia drugs is hampered by the absence of recognized clinically effective reference compounds. Research scientists are therefore obliged to validate their models in terms of their similarity to the clinical condition. A second problem is the therapeutic target. Although antidementia drugs are intended to improve cognition in a general sense, the foremost therapeutic targets are the deficits in memory and attention associated with aging. The aging animal would appear to represent the best available model providing it can be shown that the cognitive deficits observed are similar to those observed in old age in humans. A logical consequence of this approach is to validate other experimental models in terms of their resemblance to naturally occurring age‐related impairments.To illustrate these points, this paper reviews data obtained in aging animals in various behavioral models and the effects of drugs thereon. Comparisons are made between drug effects in aged animals with those observed in experimental models in young animals in which cognitive deficits are induced by anticholinergic drug treatment or lesions to cholinergic‐rich brain regions. It is concluded that aging induces cognitive deficits mainly associated with short‐term memory but that other aspects of cognition, namely attention and information processing speed, also decline with age. Putative antidementia drugs, particularly those facilitating cholinergic transmission, appear frequently to have more marked effects in experimental deficit models than in aged animals themselves. © 1995 Wiley‐Liss, Inc.