bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacological studies on a new dihydrothienopyridine calcium antagonist, S‐312‐d: Therapeutic effects of s‐312‐d on cerebral metabolic impairment in stroke‐prone spontaneously hypertensive rats
Authors: Matsunaga Kazuki , Masui Masao , Ueda Motohiko
Published: January 2005

The therapeutic effects of S‐312‐d on cerebral metabolic impairment were investigated in the stroke‐prone spontaneously hypertensive rats (SHRSP) with apparent stroke symptoms. S‐312‐d was orally administered 10 mg/kg/day (25 μmol/kg/day) to the SHRSP group (SP‐312) for 3 weeks. Several stroke symptoms such as piloerection, hyperreactivity, and limb paralysis in SHRSP were markedly alleviated in SP‐312. Their body weight and food intake also increased. The hypotensive and positive chronotropic effects with S‐312‐d were recovered to pre‐drug levels at 24 h after daily administration. The increases of water, Na+ and Ca2+ and the decreases of K+ and Mg2+ in the cortex of SHRSP administered 1% gum arabic solution (SP‐cont) were significantly improved in SP‐312. The increases of glucose and lactate/pyruvate ratio in the cortex of SP‐cont were also significantly reduced in SP‐312, while the recoveries of the decreased ATP and creatine phosphate in the cortex of SP‐312 were slight. The cholinergic and monoaminergic neurotransmitters in the brain were generally decreased in SP‐cont. The decreased acetylcholine (ACh) and choline acetyltransferase activity (CAT) in the cortex of SP‐cont were significantly restored in SP‐312. In the cortex, the decreased dopamine (DA) in SP‐cont was significantly restored, while the decreased norepinephrine (NE) and 5‐hydroxytryptamine (5‐HT) in SP‐cont were only slightly recovered in SP‐312. However, the decreased NE and 5‐HT in SP‐cont showed marked recovery in the hippocampus of SP‐312. Many biochemical deteriorations in cerebral organs such as marked edema, increases of Na+ and Ca+ contents, and decreases of several neurotransmitters in symptomatic SHRSP, which had some characteristic symptoms of stroke, seemed to be improved by the several pharmacological effects resulting from Ca2+ antagonistic effects of S‐312‐d. These data suggests that S‐312‐d can prevent the deteriorating metabolic changes in SHRSP following the cerebral stroke. © 1994 Wiley‐Liss, Inc.
Versatility of positional scanning synthetic combinatorial libraries for the identification of individual compounds
Authors: Pinilla Clemencia , Appel Jon R. , Blondelle Sylvie E. , Dooley Colette T. , Eichler Jutta , Ostresh John M. , Houghten Richard A.
Published: January 2005

Positional scanning synthetic combinatorial libraries (PS‐SCLs) offer a unique and rapid approach for the identification of individual active compounds from libraries made up of millions of compounds for basic research and drug discovery. As presented here, PS‐SCLs are free to interact in solution, and therefore can be screened in virtually any assay system to rapidly identify compounds. For example, a PS‐SCL made up of hexapeptides consists of six separate positional libraries, each composed of mixtures having a single position defined with an amino acid and the remaining positions as mixtures of amino acids. The screening of PS‐SCLs, in most instances, permits the identification of the most active amino acids at each position of a peptide in a single assay. To illustrate the versatility of this combinatorial library approach, three different hexapeptide PS‐SCLs are described: (1) N‐terminal acetylated, (2) N‐terminal non‐acetylated (both composed of L‐amino acids), and (3) N‐terminal acetylated composed of D‐amino acids. Each of the PS‐SCLs is composed of more than 50 million peptides; they are used here to identify: an antigenic determinant recognized by a monoclonal antibody; non‐acetylated peptide sequences that bind to δ opioid receptors; acetylated and non‐acetylated peptide inhibitors of melittin's hemolytic activity; and D‐amino acid peptide inhibitors of trypsin. © 1994 Wiley‐Less, Inc.
Application of one‐bead one‐structure approach to identification of nonpeptidic ligands
Authors: Staňková Magda , Issakova Olga , Sepetov Nikolai F. , Krchňák Viktor , Lam Kit S. , Lebl Michal
Published: January 2005

A synthetic chemical library comprised of alkylated and acylated amino acids was synthesized and screened to determine structures that bind to a model target, streptavidin. The library was prepared using “split synthesis” and screened in a solid phase binding assay. The structure of positively reacting compounds was determined using mass spectroscopy. Positive compounds, together with various structural analogs were synthesized and their binding confirmed. Structures containing both an imidazole moiety and a substituted aromatic residue demonstrated binding. © 1994 Wiley‐Less, Inc.
Voltage‐dependent interactions: The influence and significance of membrane potential on drug‐receptor interactions
Authors: Ertel Eric A. , Cohen Charles J.
Published: January 2005

Some major drugs exert their therapeutic effect by inhibiting currents through voltage‐gated ion channels. In particular, Na channels are blocked by local anesthetics, Class I antiarrhythmics, and some anticonvulsants (phenytoin and carbamazepine) whereas Ca channels are blocked by dihydropyridines (nifedipine), phenylalkylamines (verapamil), and benzothiazepines (diltiazem). Although their binding site is often present in many different tissues, most of these compounds have a good therapeutic index and are relatively tissue‐specific in their action. Many such drugs have been studied in considerable detail and their mechanisms of action were often found to be similar. In general, drug binding is strongly modulated by the pattern of electrical activity associated with the target channel and is most potent for patterns associated with pathological conditions. The most widely held hypothesis suggests that this happens because nearly all the therapeutically useful blockers of voltage‐gated ion channels have an allosteric interaction with the gating mechanism of the target channel, such that drug binding is greatly favored by specific conformations of the channel. In this review, we describe the different models that have been proposed to account for time‐ and voltage‐dependent block of Na and Ca channels, with particular emphasis on recent advances in our understanding of these phenomena. We also discuss the use of similar principles to describe the action of channel activators and we suggest possible future directions. © 1994 Wiley‐Liss, Inc.
Na+ channels: Structure, function, and classification
Authors: Kirsch Glenn E.
Published: January 2005

The isolation and characterization of cloned Na channels have given new insights into structure‐function relationships. In particular, recent mutational analyses of the tetrodotoxin binding site and the inactivation gate have begun to clarify the structural basis for the phenomena of drug block at the extracellular mouth of the ion‐conducting pore, and regulation of ion conductance by gating at the intracellular mouth. However, much more work remains to be done, particularly in regard to the receptors for the inactivation gate and for the local anesthetic class of drugs. This paper reviews the background, and some of the recent advances and future direction in Na channel structure‐function studies. © 1994 Wiley‐Liss, Inc.
Selective fluorescent ligands for pharmacological receptors
Authors: Baindur Nandkishore , Triggle David J.
Published: January 2005

Receptor‐selective fluorescent ligands have come into increasing use as scientific tools for the study of receptor physiology and pathophysiology at the cellular and even the subcellular level. Furthermore, they are being increasingly investigated as tools in drug discovery research. In both cases, techniques employing receptor‐selective fluorescent ligands have proved to be complementary to, and in several cases even superior to, the traditional‐radioligand based techniques. Increasing costs and public concerns associated with radioactive isotope use and dispersal are also making the use of fluoresecent ligands more attractive in research and diagnostic use. With the increasing rate of discovery of new receptors and receptor subtypes and newer more potent and/or selective receptor ligands and drugs, there will be an accompanying need for the design and development of new highly potent and selective fluorescent ligands to aid in the investigation of the physiological and pathophysiological functions of these new receptors and also in the development of drugs acting specifically at these receptors. This review presents a background of development of selected fluorescent ligands, primarily those for small molecule and small peptide based ligands. © 1994 Wiley‐Liss, Inc.
Histamine receptor‐subtype affinities, selectivities, and potencies of emedastine, a novel H1‐selective antagonist, and other ocularly employed antihistamines
Authors: Sharif Najam A. , Xu Shouxi , Yanni John M.
Published: January 2005

Emedastine, a novel ocular antihistamine, exhibited nanomolar affinity (Ki = 1.26 nM; pKi = 8.9) for the histamine H1‐receptor and had a markedly lower affinity for histamine H2‐(Ki = 39.8 μM; pKi = 4.4) and H3‐(Ki = 12.6 μM; pKi = 4.9) receptor subtypes. Emedastine was the most H1‐selective antagonist tested, being 31,200 and 10,080 times more active at the H1‐receptor than at H2‐ and H3‐receptors, respectively. In contrast, while other ocularly employed antihistamines like pyrilamine, ketotifen, levocabastine, antazoline, and pheniramine had relatively high affinities for the H1‐receptor, they exhibited significantly lower H1‐selectivities than emedastine. In general, the H1‐receptor affinities of the compounds compared well with their potencies for antagonizing histamine‐induced phosphoinositide (PI) turnover. Emedastine exhibited antagonist potencies (IC50 values) of 1.8, 1.58, and 0.5 nM in human conjunctival epithelial cells, transformed human trabecular meshwork cells, and human corneal fibroblasts, respectively. In conclusion, emedastine is a high affinity and high potency histamine receptor antagonist with a superior H1‐selectivity than other antihistamines tested. Emedastine may therefore be a useful antihistamine for treating symptoms of ocular allergic diseases. © 1994 Wiley‐Liss, Inc.
Sertindole: A limbic selective neuroleptic with potent anxiolytic effects
Authors: Sánchez Connie , Arnt Jørn , Costall Brenda , Domeney Annette M. , Kelly Elisabeth , Naylor Robert J.
Published: January 2005

The anxiolytic potential of the putative neuroleptic sertindole was assessed in various animal models of anxiety in rodents and in the marmoset human threat test. Sertindole facilitates the exploratory behaviour of mice and rats in the black and white two‐compartment box over a large dose range. Sertindole is more potent than diazepam, i.e., minimal effective doses (MED) in the mouse are 0.00023 nmol (0.1 ng/kg) and 0.46 μmol/kg (0.13 mg/kg), respectively, and MED in the rat are 0.23 nmol/kg (0.10 μg/kg) and 35 nmol/kg (10 μg/kg), respectively. Sertindole increases the time that pairs of rats spend in active social interaction (unfamiliar high light conditions) at extremely low doses (MED = 0.000023 nmol/kg [0.01 ng/kg]) being some 19 million‐fold more active than diazepam (MED = 0.44 μmol/kg; 0.13 mg/kg). Sertindole inhibits isolation‐induced aggressive behaviour in the mouse, but only at high doses, and sertindole does not inhibit shock‐induced suppression of drinking or footschock‐induced ultrasonic vocalization in rat. Sertindole similarly shows potent anxiolytic‐like activity in the marmoset human threat test (MED = 23 nmol/kg; 10 μg/kg). The range between anxiolytic doses and sedative doses is very large for sertindole, i.e., sedation is observed at 2,300 nmol/kg (1 mg/kg). © Wiley‐Liss, Inc.
Ganglionic nicotinic acetylcholine receptor activation by the novel agonist ABT‐418
Authors: Briggs Clark A. , Hughes Marion L. , Monteggia Lisa M. , Giordano Tony , Donnelly‐Roberts Diana , Arneric Stephen P.
Published: January 2005

ABT‐418 was functionally characterized as a neuronal nicotinic acetylcholine receptor (nAChR) channel agonist using preparations that contain nAChRs characteristic of the ganglionic subtypes. In PC12 cells, ABT‐418, like (−)nicotine, activated an inward current that decayed within seconds in the continued presence of agonist. ABT‐418 was 4‐fold less potent than (−)nicotine (EC50 = 214 ± 30 μM and 52 ± 4 μM, respectively) while the efficacy of ABT‐418 was not significantly different from (−)nicotine when the peak response amplitude was measured. Responses to 300 μM ABT‐418 were reversibly inhibited 81 ± 3% by 10 μM mecamylamine, 38 ± 1% by 10 μM dihydro‐β‐erythroidine, and 82 ± 2% by 100 μM dihydro‐β‐erythroidine. These nAChR antagonists affected the response to (−)nicotine similarly. Furthermore, responses to maximal concentrations of ABT‐418 (3 mM) and (−)nicotine (1 mM) were not additive, consistent with ABT‐418 and (−)nicotine acting through the same receptor(s). However, the Hill coefficient for ABT‐418 (1.18 ± 0.20) was smaller than that for (−)nicotine (1.77 ± 0.18), and high concentrations of ABT‐418 appeared to elicit a more rapidly decaying response than did (−)nicotine. In the rat superior cervical sympathetic ganglion also, ABT‐418 was 2.5‐fold less potent than (−)nicotine in blocking nicotinic transmission, presumably through nicotinic receptor desensitization. These studies provide the most direct evidence that ABT‐418 activates nicotinic cholinergic channels, and suggest that ABT‐418 would have reduced potency compared to (−)nicotine in peripheral ganglia, consistent with the reduced side effect liability of this novel nAChR agonist. © Wiley‐Liss, Inc.
Limitations in the use of tubulin polymerization assays as a screen for the identification of new antimitotic agents: The potent marine natural product curacin A as an example
Authors: Hamel Ernest , Blokhin Andrei V. , Nagle Dale G. , Yoo Hye‐Dong , Gerwick William H.
Published: January 2005

Curacin A is a newly isolated lipid natural product that binds in the colchicine site of tubulin and inhibits mitosis. We have examined its effects on tubulin polymerization, studied by turbidimetry, under three reaction conditions. In 1.0 M glutamate + 1.0 mM MgCl2, with a 37°C reaction temperature, we could find no concentration of curacin A that completely inhibited polymerization. A maximal inhibitory effect on turbidity development (about 50%) was observed with 5 m̈M drug. Higher drug concentrations induced an abnormal polymerization reaction, which at 40 m̈M differed little from the control reaction except for slightly delayed depolymerization in response to reducing the temperature to 0°C. In 0.8 M glutamate (no MgCl2), with a 30°C reaction temperature, complete inhibition did occur at 3–5 m̈M drug, but higher drug concentrations again induced an abnormal polymerization reaction. With 40 m̈M curacin A this reaction was also similar to the control reaction, except that cold‐induced depolymerization was slightly enhanced relative to the control. When polymerization was induced by microtubule‐associated proteins, maximal inhibition of turbidity development (about 70%) occurred with 2 m̈M drug, with higher curacin A concentrations inducing abnormal polymerization reactions that reached about 60% of the control turbidity readings. Under all three reaction conditions the polymer induced by high concentrations of curacin A consisted of large aggregates of tightly coiled spiral fibers that had a 2–3 filament substructure. The implications of these findings with curacin A are discussed in terms of the use of tubulin polymerization assays as a screen for identifying new antimitotic drugs. © 1995 Wiley‐Liss, Inc.

This article is a US Government work and, as such, is in the public domain in the United States of America.
Site‐directed delivery of anthracyclines for treatment of cancer
Authors: Trail Pamela A. , Willner David , Hellström Karl Erik
Published: January 2005

The efficacy of cancer treatment is often limited by the lack of selectivity of anticancer agents for malignant cells. A promising approach for increasing both the efficacy and therapeutic index of anticancer agents is to utilize antibodies, directed against tumor‐associated antigens, to selectively deliver anticancer agents to tumor cells. Antibodies have been used to deliver a variety of anticancer agents including chemotherapeutic drugs, plant and bacterial toxins, and radionuclides. This review concentrates on the chemistry and preclinical biology of immunoconjugates made with members of the anthracycline group of antibiotics. © 1995 Wiley‐Liss, Inc.
Immunotoxins as cancer chemotherapeutic agents
Authors: Siegall Clay B. , Wolff Edith A. , Gawlak Susan L. , Paul Leland , Chace Dana , Mixan Bruce
Published: January 2005

Immunotoxins, composed of antibodies linked to protein toxins, are cell‐specific cytotoxic reagents that have been constructed as both chemical conjugates and fusion proteins. A variety of different toxins derived from plants, such as ricin, saporin, and bryodin, and bacteria, including Diphtheria toxin and Pseudomonas exotoxin, have been utilized to construct extremely cytotoxic immunotoxin molecules. Single‐chain immunotoxin fusion proteins composed of cloned antibody variable regions directly fused to toxins have several advantages over chemically conjugated forms, most importantly, enhanced in vivo antitumor activity. BR96 sFv‐PE40 is a single‐chain immunotoxin fusion protein that targets a Lewis‐Y related antigen expressed on the surface of solid tumor cells. Complete regression and, in certain cases, cure of established tumor xenografts have been observed with BR96 sFv‐PE40 administration into rodents. Clinical utility of immunotoxins has shown some promise but has been limited by many factors, most notably vascular leak syndrome (VLS). Our finding that rats serve as a model to study BR96 sFv‐PE40 mediated VLS has led to identification of potential inhibitors of this dose‐limiting toxicity. In summary, immunotoxins, especially single‐chain forms, offer exciting possibilities for therapy of cancer. © 1995 Wiley‐Liss, Inc.
7‐OH‐DPAT, a dopamine D3‐selective receptor agonist, produces contralateral rotation in 6‐hydroxydopamine‐lesioned rats
Authors: McElroy John F. , Ward Kathryn A.
Published: January 2005

The purpose of the present study was to characterize the rotational behavior in unilateral 6‐OHDA‐lesioned rats produced by the high affinity and selective dopamine D3 receptor ligand 7‐OH‐DPAT. Qualitatively similar to the direct‐acting DA agonist apomorphine, 7‐OH‐DPAT causes rats to rotate in a direction contralateral to the side of the nigrostriatal DA pathway lesion. This effect is dose‐dependent and the minimum effective dose is 0.03 mg (0.12 m̈mol)/kg. 7‐OH‐DPAT‐induced rotation is blocked in a dose‐dependent manner by oral pretreatment with the “D2‐like” receptor antagonists haloperidol, eticlopride, or clozapine, but not by the “D1‐like” antagonist SCH 23390. The rank order potency for inhibition of 7‐OH‐DPAT rotation for haloperidol [ID50 = 0.067 mg (0.18 m̈mol)/kg], eticlopride [ID50 = 0.41 mg (1.2 m̈mol)/kg], clozapine [ID50 = 13 mg (40 m̈mol)/kg], and SCH 23390 [ID50 > 90 mg (313 m̈mol)/kg] closely parallels their rank order affinity for binding to either the D2 or the D3 receptor. Pretreatment with the non‐DA receptor antagonists ritanserin (serotonin 5HT2), scopolamine (muscarinic cholinergic), propranolol (betaadrenergic), or naltrexone (opiate), each at relevant pharmacological doses, failed to reduce 7‐OH‐DPAT rotation. Taken together, these results are consistent with mediation of 7‐OH‐DPAT‐induced rotational behavior via an agonist interaction with one or more DA receptors. ©1995 Wiley‐Liss, Inc.
Terlakiren: An orally active renin inhibitor in the guinea pig
Authors: Mangiapane Michael L. , Wester Ronald T. , Holt William F. , Ellery Suzanne S. , Simpson Kelly A. , Schelhorn Teresa M. , Smith Andrew H. , Purcell Irene M. , Murphy William R.
Published: January 2005

Human and monkey renin are very similar, but differ from the renin of species commonly used in screening antihypertensive agents (i.e., dog and rat). This has necessitated the evaluation of renin inhibitors (Rls) in primate models. We have found that many Rls are also active against guinea pig (GP) renin, and thus may be evaluated for mean arterial pressure (MAP) lowering in this species. One such Rl is terlakiren (isopropyl N‐[N‐(4‐morpholinocarbonyl)‐L‐phenylalaninyl‐S‐methyl‐L‐cysteinyl]‐2‐(R)‐hydroxy‐3(S)‐amino‐4‐cyclohexybutanoate, formerly CP‐80,794), an orally active renin inhibitor which lowers MAP and plasma renin activity (PRA) in sodium‐deficient cynomolgus and marmoset monkeys. In vitro, terlakiren's IC50 against primate renin (including man) is ∼ 0.6 and 0.3 nM against GP renin. At iv doses of 0.3–3.0 mg (0.48–4.8 m̈mol)/kg in sodium‐depleted GPs, terlakiren produced 20–30 mmHg falls in MAP which returned to control values in 30–150 min. Oral administration of terlakiren at 30 mg (48.3 m̈mol)/kg reduced MAP 10–15 mmHg and MAP returned to control levels in ∼150 min. Increasing the dose of terlakiren to 50 mg (81 m̈mol)/kg (po) decreased MAP 25–30 mmHg, with a total duration of effect >5 h. Cardiac output and heart rate were unaffected, indicating that the fall in MAP was totally due to decreased total peripheral resistance. Terlakiren had minimal effects on MAP in GPs on a normal sodium diet. The effect of terlakiren on PRA was evaluated in separate studies. Control PRAs for the sodium‐deficient GPs ranged from 15–20 ng Al/ml/h. After 50 mg (81 m̈mol)/kg (po) of terlakiren, there was 81% suppression of PRA (vs. control) at 240 min and 62% suppression at 5 h. Thus, terlakiren was orally active against renin and blood pressure in the sodium‐depleted guinea pig, which appears to be a very good non‐primate alternative for the evaluation of renin inhibitors. ©1995 Wiley‐Liss, Inc.
Mutational analysis of the human complement 5a receptor: Identification of a potential role of asp 37 and asp 82 in ligand binding
Authors: Whitman Mary Maureen , Munro Robin , Assal Amy A. , Jarvis Michael F. , Saltzman Alan
Published: January 2005

The receptor for the inflammatory and chemotactic agent complement 5a (C5a) is a member of the G‐protein coupled receptor (GPCR) superfamily. Site‐directed mutagenesis of the human C5a receptor was performed to determine which amino acids were important for ligand binding. Specific regions of the C5a receptor were mutated based on their similarities to the ligand binding domain of other GPCRs. These mutated receptors were then transiently expressed in COS‐7 cells in order to test their ability to bind [125|]C5a. Because of the basic nature of the ligand, we concentrated on mutating acidic amino acid residues located at the N‐terminal and transmembrane regions of the receptor. Mutation of Asp 37, located near the first transmembrane domain, or Asp 82, located within the second transmembrane domain, to valine resulted in a total loss of specific [125l]C5a binding to membrane preparations of transfected cells. Furthermore, mutation of Asp 82 to alanine, leucine, or glutamate also resulted in an absence of specific binding. However, mutation of Asp 82 to asparagine did not eliminate the ability of the receptor to bind [125l]C5a. Mutation of each of the N‐terminal extracellular domain aspartate residues, Asp 282 (located within the seventh transmembrane domain), or Glu 179 or Glu 180 (located within the second extracellular loop) to valine also did not significantly affect [125l]C5a binding. These studies thus identified two acidic amino acid residues of the C5a receptor which are important for binding [125l]C5a. © 1995 Wiley‐Liss, Inc.
Good laboratory practices and other regulatory issues: A regulatory affairs view
Authors: Christian Mildred S.
Published: January 2005

Current international approaches differ regarding the definition of safety pharmacology studies, the numbers of these studies required for product support and whether it is necessary to conduct these studies in conformance with Good Laboratory Practices (GLPs). The European Union currently requires conformance with GLPs, Japan has a policy allowing full raw data audits of these studies, and the FDA does not require that these studies conform with GLPs unless they are performed in support of studies in the toxicology package (i.e. drug safety). Although the traditional position has been that it is impractical to conduct these studies in conformance with GLPs, reasons for maintaining this position are often incorrect and based on perception, rather than on understanding of the intent and extent of GLPs. Because it is highly possible that safety pharmacology studies may soon be required to conform with GLPs, this manuscript includes a review of GIP requirements, real, rather than perceived, impediments to GLP conformance, and practical suggestions for defining these types of specialized studies and performing them in such a way that they meet GLP requirments. © 1995 Wiley‐Liss, Inc.
Renal effects of FK453: A potent non‐xanthine adenosine A1 receptor antagonist
Authors: Terai Takao , Kita Yasuhiro , Kusunoki Takahiro , Andoh Takeshi , Nagatomi Itzuo , Horiai Haruo , Akahane Atsushi , Shiokawa Youichi , Yoshida Keizo
Published: January 2005

The renal effects of FK453, a potent and selective non‐xanthine adenosine A1 receptor antagonist, were examined and compared with FR113452 (less active enantiomer of FK453), typical adenosine receptor antagonists, and diuretics. In rats FK453 possessed diuretic activity similar to 1, 3‐dipropyl‐8‐cyclopentylxanthine (DPCPX, adenosine A1 receptor antagonist), hydrochlorothiazide, and furosemide, but neither FR113452 nor CP66713 (an adenosine A2 receptor antagonist) possessed diuretic activity. Urinary uric acid excretion in rats increased with FK453, but other drugs had no effect. These diuretic and uricosuric activities of FK453 were also observed in dogs. In anesthetized dogs, FK453 increased the renal blood flow (RBF), inulin clearance (Cin), and p‐aminohippuric acid clearance (CPAH). However, hydrochlorothiazide had no effect on RBF, Cin, and CPAH. Furthermore, osmolar clearance experiments suggested that the renal site of action of FK453 was different from hydrochlorothiazide and furosemide.

These results demonstrate that FK453 has diuretic activity and increases urinary uric acid excretion and suggest that the diuretic activity of FK453 is related to adenosine A1 receptor antagonism; also, the diuretic mechanism of action and the renal site of action of FK453 are different from those of hydrochlorothiazide and furosemide. FK453 is a useful compound to clarify the physiological role of the adenosine A1 receptor in the kidney. © 1995 Wiley‐Liss, Inc.
Effect of the selective estrogen receptor modulator raloxifene on explanted uterine growth in rats
Authors: Swisher D. Kim , Tague Robert M. , Seyler David E.
Published: January 2005

Raloxifene is a selective estrogen receptor modulator known to have antiestrogenic effects on uterine tissue. In this study, the effects of raloxifene on uterine explant growth were evaluated in rats. Rats were ovariectomized, implanted with an estradiol pellet, and an endometriosis‐like state was artificially created by suturing uterine explants near mesenteric blood vessels. Approximately 21 days after explant surgery, rats with confirmed uterine explant growth were given raloxifene orally at doses of 0 or 10 mg/kg/day for 7 or 14 days. After 7 days of raloxifene treatment, explant weight and volume were significantly decreased. Fourteen days of raloxifene treatment, also caused a decrease in explant weight and volume, though not statistically significant. In addition, raloxifene treatment caused weight of the remaining uterine horn to decrease. Histological examination of the explants confirmed the presence of endometrial tissue similar to that seen in the uterus. In this study, raloxifene suppressed explanted uterine growth in a rat model designed to mimic human endometriosis. © 1995 Wiley‐Liss, Inc.
Cholesterol‐lowering effect of an acyl‐coenzyme A: Cholesterol acyltransferase inhibitor, FR145237, in hypercholesterolemic rabbits fed a high‐cholesterol diet and a cholesterol‐free casein diet
Authors: Matsuo Masahiko , Aketa Miho , Ozaki Reiko , Tomoi Masaaki , Shimomura Kyoichi
Published: January 2005

Cholesterol‐lowering effects of a new acyl‐coenzyme A:cholesterol acyltransferase (ACAT) inhibitor, FR145237, in hypercholesterolemic rabbits fed a high‐cholesterol die or a cholesterol‐free casein diet were evaluated. In the cholesterol‐fed rabbits, FR145237 at the doses of 0.032, 0.1, and 0.32 mg/kg/day (0.060, 0.19, and 0.60 μmol/kg/day) reduced the plasma cholesterol level by 37%, 70%, and 94%, respectively. Cholesterol content in the liver was reduced at 0.1 and 0.32 mg/kg/day (0.19 and 0.60 μmol/kg/day). Cholesterol and phospholipid concentrations in the gallbladder bile was also reduced by FR145237 treatment, but bile acids concentration was not affected. In the hypercholesterolemic rabbits fed a cholesterol‐free casein diet, FR145237 also had a plasma cholesterol‐lowering activity but the effective dose [0.5 mg/kg/day (0.93 μmol/kg/day)] was higher than that in cholesterol‐fed rabbits. Cholesterol content in the liver of the casein‐fed rabbits was reduced in a parallel manner. Cholesterol and phospholipid concentrations in the gallbladder bile were not significantly affected, whereas bile acids concentration was significantly elevated by FR145237 treatment. The results suggest that the cholesterol‐lowering activity of ACAT inhibitors may be partly due to their effect on cholesterol metabolism in the liver, especially at the stages of bile acid synthesis, in addition to inhibition of cholesterol absorption in the intestine. © 1995 Wiley‐Liss, Inc.
Position discrimination in the salamander, Ambystoma tigrinum
Authors: Schwartz Joseph M. , Cogan Dennis C.
Published: January 2005

Twenty larval tiger salamanders (Ambystoma tigrinum) were collected from a playa lake in West Texas and maintained in the laboratory for 7 days prior to the beginning of position training. Ten subjects in the larval state were trained on a position problem in a T‐maze for 5 trials per day to a criterion of 80% correct responses, using a self‐correction procedure. Following metamorphosis to the adult stage, these subjects were tested for retention. The remaining 10 subjects were allowed to metamorphose prior to training on the position problem. The results indicate reliably faster learning in the adult (terrestrial) subjects, and reliable retention of the response following metamorphosis. These results, taken in conjunction with informal observation of the behavior of the subjects in the experimental environment, suggest that the performance of the adult subjects was a result of their better perceptual apparatus.
Relative maturity of cebus and squirrel monkeys at birth and during infancy
Authors: Elias Marjorie F.
Published: January 2005

Cebus monkey were less mature at birth than squirrel monkeys in terms of body wieght and brain weight in proportion to adult weight. Postnatally, cebus were slower to develop locomotion, perceptual‐motor capacities, and object permanence. The differences in rate of development between the species increased with age. The findings indicate that the cebus have a longer period of infancy before becoming skilled at locomotion and manipulation. In view of the cebus monkey's recognized skill as a manipulator and problem solver, the long period of infancy suggests that cebus have evolved further in the direction of higher primates.
Brief periods of socialization and later behavior in the rat
Authors: Einon Dorothy F. , Morgan Michael J. , Kibbler Christopher C.
Published: January 2005

Juvenile rats were allowed short daily periods of social contact to see if this would reduce the known effects of isolation rearing upon habituation of locomotor activity and object contact in the open field. Animals totally deprived of social experience (ISOL) were slower to habituate than animals living in small social groups (SOC). Rats allowed 1 hr of social contact (partial isolates, PI), but living otherwise in isolation, were intermediate between ISOL and SOC animals. In further experiments the quality of social interactions in the daily period was altered by drugging one of the partners, either with amphetamine or with chlorpormazine. In later tests in the open field, the rats that had interacted with amphetamine‐injected or chlorpromazine‐injected partners differed from PI animals in the direction of resembling complete isolates (ISOL); this was particularly true of those paired with amphetamine animals. Observation revealed that injection of 1 of the partners considerably altered social interactions in the pair. A further test showed that 1 hr of contact a day considerably alleviated the deleterious effects of isolation rearing upon response reversal. We conclude that normal development in the rat may depend upon the flexibility of behavior encouraged by the early social situation.
Competitive social strategies in groups of deprived and experienced rhesus monkeys
Authors: Anderson Clark O. , Mason William A.
Published: January 2005

Behavior during competition for water was observed in 2 social groups of young rhesus monkeys (3 females, 3 males in each). Monkeys in one group were socially deprived and those in the other were socially experienced (raised with mother and agemates). Social status, based on dyadic recording of displacements at the water bottle, was predictive of a number of measures related to water consumption and social orientation in both groups, but this measure was less reliable and predictive for the experienced group than for the deprived group. A major reason for the comparatively low predictive value and reliability of status among experienced monkeys was their ability to influence the behavior of higher status members through responses directed to a 3rd party and other elaborate social strategies, many of which depended on responding to status relations between 2nd and 3rd parties. The fact that such strategies were only observed in the experienced group is a clear indication that the development of higher orders of social cognition is dependent on early social experience.
Polygraphic studies of kitten development: Respiratory rate and variability during sleep‐waking states
Authors: Stevenson Michael , McGinty Dennis J.
Published: January 2005

The developmental course of respiration rate and variability during sleep states and waking was measured in chronically prepared kittens. Kittens had higher respiration rates during active sleep (AS) as compared to quiet sleep (QS) at all ages, with rates declining developmentally in both sleep states. Compared to waking, respiration rate and variability were decreased during sleep. The decrease was greatest in the youngest animals and during QS. Minute‐to‐minute respiratory variability declined from 10 to 40 days of age for each state, whereas breath‐to‐breath variability declined during the same period only during QS. Respiratory variability was higher in AS than QS in older kittens. Heart rate and variability were found to be correlated with respiratory parameters only during QS. These observations support the hypothesis that the control and development of respiration during sleep is achieved by different processes in QS and AS.
Olfactory and visual differentiation of synthetically scented surrogates by infant squirrel monkeys
Authors: Kaplan Joel N. , Cubicciotti Daniel D. , Redican William K.
Published: January 2005

Twelve infant squirrel monkeys were reared with distinctively colored and scented inanimate surrogates (Green/Floral or Black/Clove) and tested monthly from 1 to 6 months of age in 3 paired‐comparison conditions that assessed the efficacy of synthetic olfactory cues and color cues as attractive properties of the surrogates. The infants developed specific attractions to both the rearing odor and color of the surrogates by approximately the end of Month 4, although substantial differences existed between the 2 rearing groups, particularly with respect to color responsiveness. When compared with previous findings on infant squirrel monkeys reared with naturally scented surrogates, odor preferences developed relatively late, suggesting that natural, species‐typical odors may have inherently stronger attractive properties for Saimiri than arbitrary synthetic odors.
The effects of preparturient avoidance conditioning on postnatal caretaker behavior and offspring catecholamine levels and behavior in C57BL/6J mice
Authors: Rohner Evelyn C. , Werboff Jack
Published: January 2005

Avoidance conditioning during pregnancy, changes in caretaker behavior during lactation, and changes in offspring catecholamine levels and behavior were investigated in C57BL/6J mice. Three equal groups of mice were employed. One group was avoidance conditioned prior to pregnancy and continued to avoid shock during pregnancy; a 2nd group was avoidance conditioned during pregnancy; and the 3rd group served as untreated controls. Offspring were crossfostered after birth. During lactation the proportion of time the caretaker spent on the nest was observed. At weaning pups were individually housed. Offspring dopamine concentrations were measured in the corpus striatum at birth and at days 22 and 42 of age. Their performance was evaluated in the open field at Day 42 of age. The results showed that mice receiving avoidance conditioning prior to parturition were more likely to cannibalize their offspring at parturition than were control animals. Furthermore, preparturiently avoidance conditioned mice spent less time on the nest if they reared offspring from biological mothers who had been avoidance conditioned when compared to similarly treated caretakers who reared offspring from untreated control biological mothers. Regardless of postnatal experiences, adult offspring from avoidance conditioned biological mothers had significantly reduced levels of dopamine in tissue from the corpus striatum and were significantly less active in the open field when compared with offspring from control biological mothers. Behavioral results support the findings of others that the prenatal environment plays an important role in shaping the later behavior of offspring. The decrease in dopamine levels suggests that avoidance training as one form of psychosocial stimulation during pregnancy can be disruptive to the development of the dopamine regulatory mechanisms.
Effect of neonatal stunting on development of rats: Large litter rearing
Authors: Fleischer Susan F. , Turkewitz Gerald
Published: January 2005

At nurslings, rat pups reared in large litters showed reduced frequencies of returns to their nest from other parts of the home cage and reached maximum levels of nest returns at older ages than control animals from small litters. These differences were not due to differences in activity level or attraction to the nest but appeared to be perceptual in nature. As adults, animals from large litters showed deficits in learning the 1st 2 problems in a series of visual discriminations in a modified version of the Lashley jumping stand technique in which food reinforcement was not used. The deficits were confined to male animals only and were the result of stronger position habits in the early part of training, rather than an inability to make the discriminations. A comparison of these results with those obtained when other methods of stunting animals are employed revealed that different methods of stunting may result in both common and divergent effects on behavior. One long‐term consequence of large litter rearing appears to be increased emotional response to novel situations.
Development of the acoustic startle response in the rat: Ontogenetic changes in the magnitude of inhibition by prepulse stimulation
Authors: Parisi T. , Ison James R.
Published: January 2005

Three experiments examined the development of the acoustic startle reflex and its modification by a preliminary stimulus in the infant rat during the 2nd and 3rd postnatal weeks. The 1st experiment employed a white noise S1 (20 msec, 70 dB), the 2nd a cutaneous S1 (.5 msec, .5 mA and 1.0 mA shock), and the 3rd identical S1‐S2 pairs (20 msec, 10 kHz, 110 dB tones). The results demonstrate a similar maturation of the prepulse modification pattern over days in the 3 experiments, evidenced mainly in the growth of inhibition. The findings indicate peripheral and central mechanisms that are maturing during the period of life under observation and that contribute to the developmental patterns of modification.
Influence of neonatal injections of testosterone propionate on sexual behavior and plasma testosterone levels in the male house mouse
Authors: Batty Jennifer
Published: January 2005

The effects of neonatal testosterone injections on adult male sexual behavior and plasma testosterone levels were investigated in several strains of male house mice. Both sexual behavior and plasma testosterone levels were increased in the testosterone‐treated groups from some strains, but the 2 variables did not change concomitantly.
The compensatory role of food‐motivation in the maze learning performance of lactationally undernourished rats
Authors: Katz Hillary B. , Rosett Robert E. , Ostwald Rosemarie
Published: January 2005

To test the hypothesis that the motivational effects of neonatal undernutrition might conceal the detrimental effects on learning, we tested previously undernourished and normally nourished Sprague‐Dawley rats on learning of a novel maze pattern under either latent learning (nonappetitive) or food‐motivated conditions. Under the nonappetitive conditions, the previously under‐nourished rats learned significantly less than the normal controls, but when motivated for food, the undernourished rats performed as well as the controls. When learning performance measures are sensitive to motivation, differential motivation between undernourished and normal subjects must be controlled or eliminated.
Ontogenesis of spontaneous activity and habituation of activity in the rat pup
Authors: Shaywitz Bennett A. , Gordon Judith W. , Klopper Jeffrey H. , Zelterman Daniel A. , Irvine John
Published: January 2005

Individual components of activity and habituation of activity were determined throughout the 1st month of life in the rat pup. Total activity increased from 25% at 8 days of age to 68% at 22 days before declining to 49% at 26 days. Total slight activity (predominantly sniffing) increased to a maximum of 33% at 15 days whereas total very active behavior (predominantly ambulation) reached its maximum of 38% at 22 days. Habituation of activity expressed as the mean slope of decrement of activity over the 1st 30 min of the observation period was observed in rats as young as 8 days of age. By 12 days, habituation of total activity had increased significantly reflecting a 3‐fold increase in habituation of slight activity, an effect observed at 15 days as well. However, by 19 days the slope of activity decrement had declined to half of its 15‐day value, indicating an impairment of habituation and reflecting the attenuation of very active behavior, predominantly ambulation. This decline in habituation continued through 22 days but by 26 days habituation of activity had increased again reaching a maximum for the 1st month of postnatal life. Our results suggest that the phenomenon of behavioral arousal observed in the developing rat pup 19 days of age reflects an inability of the organism to modulate his activity as effectively as the 15‐day‐ or 26‐day‐old animal.
Ontogeny of ultradian and nocturnal activity rhythms in the isolated albino rat
Authors: Teicher Martin H. , Flaum Lawrence E.
Published: January 2005

The activity of isolated rats from 6 to 25 days of age was analyzed at 10‐min intervals. Ultradian peak activity rhythms, with a rough 1‐2‐hr periodicity, developed between 9 and 12 days of age, and reached an extreme at 15 days. Ultradian periods of attenuated activity were however detectable even in 6‐day‐olds. Isolated rats at 15 days of age displayed greatly accentuated profiles characterized not only by heightened activity levels, but by an extreme cyclicity. These subjects spent most of their time oscillating between periods of marked activity and marked inactivity. Both the average and total duration of these extreme periods were greater in 15‐day‐olds than any of the other ages. Free‐running nocturnal activity rhythms were also observed to develop in isolated rats tested in continuous darkness by the 15th day.
Ontogenetic study of the Miwh gene in mice
Authors: Marzetta Carol A. , Nash Donald J.
Published: January 2005

Ontogenetic and adult behavioral tests were conducted on an extreme non‐agouti strain of mice carrying the Miwh mutation. Except for startle response, no significant differences were seen in any aspect of the preweaning reflex and neuromuscular tests. The lack of startle response seen in Miwh/Miwh and Miwh/+ mice can be attributed to abnormalities found in the inner ear of these genotypes. Among adult mice, significant differences were found in the open field and visual cliff tests.
Effects of early undernutrition on motivation and discrimination learning in rats
Authors: Tachibana Toshiaki
Published: January 2005

Offspring were either adequately nourished or undernourished during the suckling period. They had free access to food from weaning, and were given 2 behavioral tests between 13 and 19 weeks of age. Motivation for water was tested on a variable interval (VI) schedule at 3 levels of deprivation and a test of light‐dark discrimination made at 23.5 hr of water deprivation. The results indicated (1) no clear difference in VI response rate, but (2) significant differences in discrimination performance between the 2 groups. A learning ability or certain relevant abilities rather than motivation for water appeared responsible for the difference in discrimination learning.
Developmental changes in open‐field behavior in the kitten
Authors: Frederickson Christopher J. , Frederickson M. H.
Published: January 2005

Seventy‐eight kittens from 3 to 7 weeks of age were studied in an open‐field arena. Three major age‐dependent changes were noted: (1) the number of floor squares entered was markedly higher for 5‐ and 6‐week‐olds than for younger animals, and slightly lower for 7‐week‐olds than for 5‐ and 6‐week‐olds; (2) the tendency to backtrack from 1 square to a just‐vacated square decreased with age, the largest change occurring between 4 and 5 weeks of age; (3) the within‐session decrement in locomotion was largest for 3‐week‐old kittens but was smallest for 4‐week‐olds and increased monotonically with age thereafter. The results suggest a possible role of hippocampal maturation.
Paradoxical effects of d‐amphetamine upon seizure susceptibility in 2 selectively bred lines of mice
Authors: Greer Charles A. , Alpern Herbert P.
Published: January 2005

The ontogeny and substrates of amphetamine‐induced changes in flurothyl‐induced myoclonic and clonic seizure thresholds were investigated in 2 selectively bred lines of mice. The long‐sleep mice exhibited dose‐dependent increases in myoclonic and clonic susceptibility following amphetamine, irrespective of age. The noradrenergic agonist clonidine and the dopaminergic agonist apomorphine produced increases in susceptibility comparable to those seen with amphetamine. The short‐sleep mice, however, exhibited a dichotomous myoclonic response to amphetamine that was age‐dependent. Between 15 and 35 days of age amphetamine decreased seizure susceptibility whereas increases in susceptibility were noted at later ages. With the exception of 80 days, amphetamine did not affect clonic thresholds. In respect to myoclonus, clonidine persisted in producing effects similar to those seen in the long‐sleep mice whereas apomorphine exhibited the same ontogenetic alteration in effect seen with amphetamine. These results confirm that the short‐sleep mice might be a naturally occurring animal model of preadolescent hyperkinesis. Furthermore, the neuropharmacological tests demonstrate that the paradoxical response to amphetamine in the young short‐sleep mice is mediated via a dopaminergic mechanism that must undergo dramatic change during ontogeny.