bluuebunny/crossref_metadata_2025_split huggingface dataset:
Simultaneous 31P nuclear magnetic resonance spectroscopy and mechanical function in working heart models affected by drugs
Authors: Cohen Sheila M. , Werrmann Jeffrey G. , King Brian W. 
Published: January 2005

AbstractA working heart model was designed which enabled simultaneous measurement of the physiological function of the heart and the levels of high‐energy phosphates and inorganic phosphate, as well as intracellular pH, by high‐resolution 31P NMR spectroscopy. Careful control of conditions, such as temperature and metallic ions, produced rabbit heart preparations that had stable work output, heart rate, and ATP levels for more than 7 hr. Rat hearts were stable for at least 3 hr. As an example of the utility of the model, the effect of ischemia and two drugs were studied. Global ischemia of a rabbit heart at 36.2°C resulted in almost complete loss of phosphocreatine (PCr) wth 7 min and slower loss of ATP, which reached a plateau at 40% of its initial concentration with 12 min. ntracellular pH fell form 7.01 to 6.03 during 21 min of ischemia. Post‐ischemia, the heart's power output and ATP concentration both returned to about 70% of pre‐ischemia levels, whereas PCr overshot its initial value by 33%. BRL 34915, a K+ channel activator, produced an age‐ and species‐dependent negative inotropic effect in non‐ischemic hearts, with only minor changes in ATP, PCr or pH. In hearts obtained from rats pretreated for 2 days with enalapril, an inhibitor of the angiotensin‐converting enzyme, post‐ischemia power output returned to 74 ± 7% of preischemia levels, compared with 33 ± 11% in hearts from sham‐treated rats (N = 6). Enalapril also lessened the decline of ATP during 20 min of global ischemia and enhanced the recovery of ATP in post‐ischemic hearts (both about 30% greater than control). 31P NMR of working heart preparations enable the effect of drugs and/or ischemia on intracellular energy levels to be determined concurrently with function of the heart. A reproducible method in inducing global ischemia in working hearts facilitates the study of drug effects on functional and metabolic recovery.
Effects of buspirone in the geller‐seifter conflict test with incremental shock
Authors: Howard James L. , Pollard Gerald T. 
Published: January 2005

AbstractThe novel anxiolytic buspirone has weak or inconsistent activity in most of the animal models commonly used to identify anxiolytics. Among the six published studies of the effects of buspirone on punished level‐pressing in the rat, only one reported a clear effect (at two doses), and the peak effect was half that of diazepam. In the present study, in which rats responded for food in Geller‐Seifter conflict procedure with incremental shock, five factors were examined for influence on the effects of buspirone upon punished lever‐pressing: (1) fixed‐ratio 10 vs. fixed ratio 1 in the punishment portion of the multiple schedule, (2) drug‐naive vs. drug‐experienced rats, (3) albino vs. hooded rats, (4) SC vs. PO injection, and (5) time course up to 2 hr. The benzodiazepine chlordiazepoxide robustly increased responding punished by foot‐shock, but under none of the conditions did buspirone produce more than a small, inconsistent increase. Punished level‐pressing in the rat appears not to be an adequate method for identifying buspirone‐like anxiolytics.
Measurement and block of potassium channel currents in the heart: Importance of channel type
Authors: Kass Robert S. , Arena Joseph P. , Walsh Kenneth B. 
Published: January 2005

AbstractIn heart as in other excitable tissues, potassium channel currents play an important role in maintaining the normal cell resting potential and controlling the action potential duration. In this study both theoretical and experimental procedures were used to examine the properties of the cardiac delayed rectifier potassium current (IDR) and the inward rectifier potassium current (IIR) and to determine the role that each plays in the repolarization of the action potential. IIR, a relatively time‐independent current, conducts potassium ions more readily in the inward than outward direction with outward current observed solely over the voltage range of ‐70 through ‐30 mV. Because of this behavior, IIR contributes only to the final stages of action potential repolarization. In contrast, IDR, a time‐dependent current with slow kinetics, conducts potassium ions outward over a broad positive voltage range and thus plays a dominant role in initiating and sustaining repolarization. A number of approaches, including single channel analysis and pharmacological interventions, have been begun to further characterize these two important ion currents.
Current concepts and animal models of sudden cardiac death for drug development
Authors: Chan Peter S. , Cervoni Peter 
Published: January 2005

AbstractSudden cardiac death (SCD) or sudden coronary death, occurring in patients with unstable angina (angina at rest), myocardial ischemia with or without myocardial infarction (MI), and congestive heart failure (CHF), emerges as one of the most important challenges in cardiovascular medicine at present. Of the 1.5 million cases of myocardial infarction that occur each year in the U.S., about 540,000 patients will die and more than 300,000 of these will die before they reach a hospital, mostly due to ventricular fibrillation (VF) and/or SCD. About 4.8 million people alive in the U.S. have a history of myocardial infarction, angina pectoris, or both and are prime candidates for SCD. About 3 million people in the U.S. have congestive heart failure (CHF) and about 400,000 new cases are reported each year. One year mortality due to CHF is 33–58% and about 45% of the deaths are sudden. These patients were not those who had deleterious hemodynamic parameters whose demise could be predicted; they were those that died suddenly and unexpectedly of VF. Current pharmacological intervention in patients with a documented myocardial infarction with marketed antiarrhythmic agents has not reduced the overall mortality of SCD significantly. This suggests that an efficacious antiarrhythmic/antifibrillatory agent for the prevention of SCD does not exist at present and that there is an urgent need for such an agent.
Nonclinical regulatory considerations for wound‐healing growth factors
Authors: Weissinger Judi 
Published: January 2005

AbstractInitial evaluation of the safety of wound‐healing growth factors, whether manufactured by biotechnology or not, is dictated by the extent of knowledge of the physiologic, pharmacologic, and toxicologic effects, in vitro and in vivo in animals, and in man at the proposed dose and duration of administration. Prior to Phase 1 clinical study, products are studied to establish evidence of pharmacologic activity, understand the mechanism of action, evaluate the potential human risk, and establish a clinical study dose range. It is difficult to establish a generic plan and generic protocols for the preclinical development of wound‐healing growth factors because the toxicologic concerns and suggested studies are tailored to the uniqueness of each product. The quantity of useful information which can be gained from preclinical studies is considered for each product on a case‐by‐case basis, taking into account the availability of a relevant model. Preliminary information regarding (1) production of the active moiety, (2) ingredients in the final formulation as it is to be marketed, (3) characterization of the growth factor, (4) the proposed dose and route of administration, (5) the known actions and effects, (6) the similarity to the endogenous growth factors, and (7) the proposed target clinical study population is needed to determine the most appropriate preclinical pharmacological and toxicologic studies. Use of this information and additional data relating the pharmacokinetic and toxicologic profiles will be discussed with respect to generalizations in study concepts for pharmacology and toxicology studies and individualization of these preclinical studies which may occur, based upon the uniqueness of the compound.
Effects of metrifonate, a long‐acting cholinesterease inhibitor, in alzheimer disease: Report of an open trial
Authors: Becker Robert E. , Colliver Jerry , Elble Rodger , Feldman Eleanor , Giacobini Ezio , Kumar Vinod , Markwell Stephen , Morieatry Pamela , Parks Randolph , Schillcutt Samuel D. , Unni Latha , Vicari Sandra , Womack Cindy , Zec Ronald F. 
Published: January 2005

AbstractThis is the first study of a multiple‐dose trial of metrifonate (Met), a long‐acting cholinesterase (ChE) inhibitor, conducted over a prolonged period of time in humans. We have administered Met to 20 patients who met NINCDS‐ADRDA criteria for probable Alzheimer disease (AD). Patients were given, under open conditions, single oral doses of Met. 2.5, 5, 7.5, and 15 mg/kg/wk. A statistically significant improvement in the Alzheimer Disease Assessment Scale (ADAS) scores was observed with the 5 mg/kg/wk dose. Maximal improvement on the ADAS was associated with a mean 55.9% (± 12.6% standard deviation) activity level of red blood cell (RBC) acetylcholinesterase (AChE). Over 80% inhibition of plasma and RBC ChE was achieved with only minor side effects. Cholinesterate inhibition in the CSF of two patients was 37% and 47.5% 24 hr after a second dose of 5 mg/kg/wk of Met separated by 7 days from the first dose.Twenty‐seven minor side effects were reported: none on 2.5 mg, 5 on 5 mg, 9 on 7.5 mg, and 13 on the 15 mg dose. None of the side effects was clinically significant or drug related or required termination of treatment of dosage adjustment. We conclude that Met is a useful pharmacological probe of cholinergic function in the central nervous system and that double‐blind evaluation of Met in AD is warranted.
Some behavioral effects of repeated d‐amphetamine administrations
Authors: Katz Jonathan L. , Witkin Jeffrey M. , Dworkin Steven I. , Dykstra Linda A. , Carter Richard B. 
Published: January 2005

AbstractEffects of daily administrations of d‐amphetamine were studied on key peck responses of pigeons maintained under a multiple fixed‐interval 2‐min, fixed‐ratio 30‐responseschedule. Under the fixed‐interval schedule, a pause was followed by a transition to increasing rates of responding until food presentation. Under the fixed‐ratio schedule, higher sustained rates of responding were maintained. Low to intermediate doses (0.3‐1.0 mg/kg) of d‐amphetamine changed the temporal patterns and occasionally increased rates of responding under the fixed‐interval schedule. Higher doses decreased rates of responding under bothschedules. With daily injections of 1.0 mg/kg d‐amphetamine prior to experimental sessions, the effects of this dose on rates and patterns of responding were attenuated, and d‐anphetamine dose‐effect curves were shifted to the right, primarily under the fixed‐ratio schedule. Similar results were obtained with daily presession injections of 5.6 mg/kg d‐amphetamine in a second group of pigeons, except that rates of responding under both schedules were decreased by this daily dose, and did not return completely to control values with repeated injections. In a third group of pigeons, 1.0 mg/kg d‐amphetamine administered daily, after experimental sessions, did not alter dose‐effect functions for d‐amphetamine. In a second experiment, pigeons were trained to peck one response key when given 1.0 mg/kg d‐amphetamine and a different key when given presession water injections. Increasing doses of d‐amphetamine produced incresing percentages of d‐amphetamine‐key responses. Repeated administration of 5.6 mg/kg d‐amphetamine shifted these dose‐effect functions to the right one‐half log unit. Results suggested that decreases in reinforcement frequency are not a necessary condition for the development of behavioral tolerance to d‐amphetamine.
In vivo binding properties of non‐sedating antihistamines to CNS histamine receptors
Authors: McQuade Robert D. , Richlan Kimberly , Duffy Ruth A. , Chipkin Richard E. , Barnett Allen 
Published: January 2005

AbstractA series of antihistamines were examined for their ability to inhibit the in vivo binding of 3H‐mepyramine to mouse brain membranes. All of the seven antihistamines tested inhibited the in vitro binding of 3H‐mepyramine, but loratadine and terfenadine were the only compounds which did not cause an inhibition of the in vivo binding. Conversely, diphenhydramine, chlorpheniramine, astemizole, mequitazine, and cetirizine all resulted in a significant (P < 0.05) decrease in the binding of 3H‐mepyramine, in vivo. These results suggest that loratadine and terfenadine are antihistamines which are unable to cross the blood‐brain barrier and therefore possess a low sedative liability.
In vivo dopamine agonist and antagonist activities of a series of substituted dihydrophenalenes
Authors: Tan Andrew H. , Franklin Stanley R. , Code Robert A. , Althaus John S. , Vonvoigtlander Philip F. , Darlington William H. , Szmuszkovicz Jacob 
Published: January 2005

AbstractA series of structurally rigid compounds (2‐amino‐2, 3‐dihydro‐3H‐phenalenes) has been synthesized for dopamine (DA) agonist activities. One member (U‐66444B) in the series has been reported as a potent and selective agonist for presynaptic DA receptors. Among close analogues of U‐66444B, we have identified two compounds with DA antagonist activities by behavioral and biochemical endpoints. The distinguishing chemical features of these two antagonists are methyl substitutions on the amino nitrogen and a phenolic hydroxy group having a most proximal position to the amino group. The structure‐activity relationship in this series of compounds may contribute to future design of DA agonists and antagonists.
Inhibition of cardiovascular low‐Km cAMP phosphodiesterase activity by medorinone
Authors: Silver Paul J. , Hamel Linda T. , Bentley Ross G. , Dillon Kathleen , Connell Mary J. , O'Connor Bernard , Ferrari Richard A. , Pagani Edward D. 
Published: January 2005

AbstractMedorinone (5‐methyl‐1, 6‐naphthyridin‐2(1H)‐one) is a structurally novel cardiotonic/vasodilator agent. The purpose of the present study was to evaluate the effects of medorinone on subcellular systems involved in the contractile‐relaxation processes of cardiac and vascular smooth muscle (VSM); cyclic nucleotide phosphodiesterase (PDE), Ca2+‐regulated contractile proteins, and sarcolemmal Na+‐K+ ATPase. Medorinone produces concentration‐related inhibition (IC50 values between 0.38 and 1.3 μ) of the cGMP‐inhibitable, low‐Km cAMP PDE (peak III PDE from a DEAE‐cellulose column) present in guinea pig and canine cardiac and vascular smooth muscle. The potency of medorinone is similar to that of milrinone and papaverine, less than CI‐930, and greater than imazodan, piroximone, and amrinone. Medorinone is approximately 300–400 × less potent an inhibitor of the low‐Km cAMP PDE. Medorinone appears to be a non‐linear mixed inhibitor of the low‐Km cAMP PDE having a Ki value of approximately 0.3 μM. Medorinone is also an equipotent inhibitor (IC50 values between 0.23 and 0.35 μM) of the low‐m cAMP PDE present in soluble and particulate fractions obtained from normal and myopathic human hearts, with no differences in potency observed between normal and myopathics. Medorinone (10 and 100 μM) does not affect VSM myosin light chain phosphorylation or VSM actomyosin superprecipitation. Moreover, medorinone does not affect cardiac myofibrillar ATPase activity or cardiac sarcolemmal Na+‐K+ ATPase activity. In summary, these data are consistent with the hypothesis that inhibition of the low‐Km cAMP PDE isozyme by medorinone in cardiac and vascular smooth muscle is a mechanism by which this agent produce both positive cardiac inotropy and VSM relaxation.
Effects of arotinolol on regional cerebral blood flow in hypertensive patients with a history of stroke
Authors: Naritomi Hiroaki , Murata Shinji , Shimizu Takao , Nakamura Masaichi , Sasaki Masahiro , Sawada Tohru 
Published: January 2005

AbstractAlthough optimal blood pressure control is important for managing stroke patients, the use of antihypertensives in stroke patients often causes cerebral blood flow reduction leading sometimes to deterioration of symptoms. Effects of arotinolol, a β‐blocker with a moderate α‐blocking action, on the regional cerebral blood flow (rCBF) were investigated in 10 hypertensive patients with a history of stroke by using a noninvasive 133Xe inhalation method. The rCBF was measured before and after administration of 15 mg/day arotinolol (three times a day) for 2–3 weeks. After the administration, the blood pressure was reduced in all the patients showing a change in average values of from 176/105 mmHg to 152/90 mmHg. The rCBF in the infarcted and healthy hemispheres was 44.3 ± 4.4 and 44.6 ± 5.0 ml/100 g/min before arotinolol and 44.9 ± 6.4 and 45.3 ± 6.5 ml/100 g/min after arotinolol, respectively. No significant rCBF change was observed after arotinolol in both hemispheres. During the administration, none of the patients suffered from dizziness or other ischemic symptoms. The above results suggest that arotinolol exerts little influence on the cerebral circulation and may be useful for the management of hypertension in stroke patients.
Distribution of GABAA and GABAB receptors in mammalian brain: Potential targets for drug development
Authors: Young Anne B. , Chu Dorothy 
Published: January 2005

AbstractGABA is the major inhibitory neurotransmitter in mammalian brain. GABA receptors and the metabolism of GABA are significant targets for new centrally acting drugs to treat neurological and behavioral disorders. The simple neutral amino acid is likely to subserve a neurotransmitter role at 25–50% of all synapses in the central nervous system. GABA's actions are mediated by two different receptors, GABAA and GABAB receptors. GABAA receptors are ligand‐gated chloride channels that are sensitive to the convulsant alkaloid bicuculline and modulated by benzodiazepines and barbiturates. GABAB receptors affect calcium and potassium conductance through GTP binding proteins and are insensitive to bicuculline and sensitive to the agonist baclofen. Both receptors are widely distributed in cerebral cortex, hippocampus, basal ganglia, thalamus, cerebellum, and brainstem.
GABAmimetic drugs in hyperkinetic involuntary movement disorders and their effects on mental status
Authors: Tamminga C. A. , Thaker G. K. 
Published: January 2005

AbstractGABAmimetic drugs are effective in the treatment of hyperkinetic involuntary motor disorders like tardive dyskinesia. Several therapeutic pharmacologic strategies have been identified, including direct‐acting agonists, reuptake blockers, and degradation inhibitors. This pharmacologic response, in addition to providing clinical efficacy data, has led to the speculation that GABA is pathophysiologically involved in tardive dyskinesia. The most potent GABAmimetic compounds have psychotomimetic effects, but some of the weaker GABA agonists are clinically effective for dyskinesias without severe cognitive side effects. Thus, GABA agonists are likely to be available soon as practical treatments for tardive dyskinesia.
New class of hallucinogens: GABA‐enhancing agents
Authors: Hollister Leo E. 
Published: January 2005

AbstractHallucinogenic drugs are of interest to psychiatrists as possible models of schizophrenia. Possibly some of the mechanisms by which these drugs elicit altered mental states might lead to a better understanding of schizophrenia. GABA‐enhancing drugs, such as muscimol and CI‐966, produce mental states that differ in various ways from those of other hallucinogens. The mechanism of action also differs from the others, which may be mediated by receptors for serotonin (LSD), acetylcholine (scopolamine), or NMDA (phencyclidine). Whether the GABAA receptor will provide clues to schizophrenia remains to be elucidated.
Magnesium aspartate HCl and magnesium chloride hexahydrate OROS: Comparative absorption of magnesium in dogs
Authors: Coram Willie Mae , Foster Clarence E. , Senft Carl J. , Douglas Frank L. , Weiss George B. 
Published: January 2005

AbstractThe absorption of magnesium (Mg2+) was measured after oral administration to dogs as a sustained‐release MgCl2·6H2O OROS formulation (MgCl2) or as magnesium aspartate hydrochloride (MAH). The compounds and their respective placebos were given at five 90 min intervals in 7.5 mEq doses (sequential protocol) or in ascending daily doses of 7.5, 22.5, and 45 mEq over 3 days (ascending protocol). Urinary excretion of Mg2+ over 24 hr was significantly increased compared to placebo in the dogs given sequential MgCl2 or MAH and was two‐fold greater in the MgCl2‐treated group compared to the MAH group. Plasma Mg2+ increased more rapidly in the MgCl2‐treated dogs but was identical in both groups 1 hr after the fifth sequential dose. Ascending daily doses of MgCl2 and MAH increased urinary Mg2+ and plasma Mg2+ maximally 2–4 hr after each dose; the magnitude of the effect was dose‐dependent in the MgCl2 group. Sequential doses of MgCl2 or MAH increased urinary Ca2++ excretion by 1.06 and 1 mEq/24 hr respectively while the ascending doses of 22.5 and 45 mEq MgCl2 produced significantly greater urinary Ca2+ excretion than the same doses of MAH. Plasma Ca2+ was not changed by either Mg2+ salt in either dose regimen. The data indicate that Mg2+ is readily absorbed after oral administration in the form of either MgCl2 or MAH, but MgCl2 is absorbed more rapidly. Increased urinary excretion of Ca2+ after MgCl2 or MAH may reflect a displacement of tissue Ca2+ by Mg2+.
5‐HT1D serotonin receptors: Results of a structure‐affinity investigation
Authors: Glennon Richard A. , Ismaiel Abd M. , Chaurasia Chandra , Titeler Milt 
Published: January 2005

AbstractAs a prelude to the design of 5‐HT1D agents, we systematically investigated the structure‐affinity relationships for the binding of indolealkylamines and related derivatives at 5‐HT1D serotonin receptors. The results of the investigation reveal that (a) methylation of a 5‐hydroxyl group decreases affinity by 2‐fold, (b) replacement of a 5‐hydroxyl group by hydrogen reduces affinity by an order of magnitude, (c) α‐methylation of the side chain reduces affinity by approximately 50‐fold, (d) N,N‐dimethylation decreases affinity by 4‐fold, (e) methylation at the 2‐position reduces affinity by 300‐fold, (f) small alkyl substituents are not well tolerated at the C7‐ and N1 ‐Positions, (g) shortening of the side chain by one methylene unit reduces affinity by two orders of magnitude, (h) cyclization of the side chain to a β‐carboline dramatically reduces affinity, and (i) the 5‐hydroxy group can be replaced by a carboxamido, benzyloxy, or chlorobenzyloxy moiety without any decrease in affinity. These studies led to the evaluation of certain non‐indolealkylamines and to the finding that (a) simple phenylalkylamines and phenylpiperazines bind with low affinity, but that their benzfused counterparts bind with significantly higher affinity, and (b) the 7‐methoxy analog of 1‐(1‐naphthyl)piperazine (7‐OMe 1‐NP) binds at 5‐HT1D sites with an affinity (Ki = 2 nM) comparable to that of serotonin itself. Various leads were developed that might aid the subsequent design of 5‐HT1D‐selective agents.