bluuebunny/crossref_metadata_2025 huggingface dataset:
Midbrain‐renal dopaminergic axis and control of venous capacitance: Pathological and therapeutic significance in hypertension
Authors: Osborne Melville W. , Kovzelove Francis
Published: January 2005

Acute intravenous infusion of methyldopa in anesthetized normotensive dogs produced a hemodynamic profile which indicates that the decrease in arterial blood pressure occurs secondary to venous pooling. The methyldopa‐mediated venous pooling is blocked by prior treatment with indomethacin. Both acute administration of methyldopa and L‐dopa mediate venous pooling from the midbrain as reactivity to the carotid occlusion reflex is intact. The venous pooling occurs in the cutaneous venous capacitance bed. Chronic treatment with methyldopa causes venoconstriction with a secondary increase in cardiac output. The venoconstriction is accompanied by a significant decrease in plasma renin activity without any effect on plasma aldosterone secretion, cortisol secretion, or serum electrolytes (Na+, K+, Cl−). Renal denervation abolished both the chronic methytldopa venoconstriction and endocrine effects; only venodilation was evident. Chronic treatment with L‐dopa caused only venodilation with a significant increase in plasma aldosterone secretion, but without an effect on plasma renin activity, cortisol secretion, or serum electrolyte values. The primary neuroeffector in the kidney which communicates with the midbrain venomotor center appears to be mediated by a prostaglandins. It is postulated that the alterations in plasma renin activity and aldosterone secretion reported in this investigation are mediated by the brain isorenin‐angiotensin system since alterations in plasma renin activity and aldosterone secretion do not occur in parallel, cortisol secretion is not altered, and the blood pressure‐pressor response to angiotensin I and II is not blocked.
Alpha adrenergic activity and renal function in two‐kidney deoxycorticosterone‐acetate hypertensive swine
Authors: Zambraski Edward J. , Ciccone Charles D.
Published: January 2005

To evaluate the role of alpha‐adrenergic activity in deoxycorticosterone‐acetate (DOCA) hypertensive swine, eight two‐kidney Yucatan miniature swine were implanted with DOCA silicone strips (100 mg/kg) for 12–16 weeks. Mean arterial pressure (MAP) in these animals increased progressively from control values of approximately 1 15 mm Hg to 173 ± 5 mm Hg. Treatment of four conscious animals with phenoxybenzamine (POB) (1 mg/kg) resulted in a significant decrease in MAP from 190 ± 3 to 157 ± 5 mm Hg (P < 0.05). This decline was due to a 21% decrease in total peripheral resistance (TPR) (P < 0.05), while cardiac output (CO) and heart rate (HR) remained unchanged. Pentobarbital anesthesia caused a small insignificant decrease in MAP to 165 ± 5 mm Hg. While under anesthesia, infusion of POB into the left renal artery (0.04 μg/kg/min) caused a slight increase in left renal blood flow (P > 0.05), without affecting MAP, HR, TPR, or CO. Left kidney urine flow and sodium excretion also increased during intra‐renal POB infusion. Potassium excretion was unchanged and GFR decreased slightly. When POB (1 mg/kg) was infused systemically during anesthesia, MAP decreased to 82 ± 6 mmHg (P < 0.05). This was due to a 34% and 14% decrease in TPR and CO, respectively (P < 0.05). Whole animal urine flow, sodium excretion, and GFR all decreased significantly with systemic POB. These findings suggest that alpha‐adrenergic activity plays a role in the maintenance MAP and the determination of renal function in DOCA hypertensive swine.
Effects of antidepressants on isolated, electrically stimulated rat epididymal fat pads
Authors: Light Kim E. , Maickel Roger P.
Published: January 2005

The isolated, electrically stimulated rat epididymal fat pad in vitro was tested under various conditions as a model for neuronally induced lipolysis. A 24‐hr fast, or a preincubation without electrical stimulation, decreased spontaneous lipolysis as measured by glycerol release; however, only slight alterations were seen in the response of the pads during a 40‐min period of electrical stimulation. Spontaneous (nonstimulated) lipolysis was reduced by pretreatment with alpha‐methyl‐paratyrosine‐methylester and increased by pretreatment with reserpine; both of these treatments abolished the response to stimulation. The effects of addition of a variety of agents to the incubation medium confirm the role of a sympathetic nervous‐cyclic 3′,5′‐adenosine‐monphosphate mediated response system.
Studies on the efficacy and depressant potential of muscle relaxants in mice
Authors: Novack Gary D.
Published: January 2005

The present study was undertaken to confirm and extend previous observations on the use of morphine‐induced Straub tail and rotarod performance in mice as a means of assessing the efficacy of a compound as a muscle relaxant and its potential for depressant side‐effects, respectively. The ratio of the rotarod to Straub tail ED50s was calculated as an index of specificity. Our results generally confirmed previous reports in the case of diazepam, chlordiazepoxide and dantrolene. Additionally, the recently introduced muscle relaxants, cyclobenzaprine, baclofen, and DS 103‐282 were found effective in blocking Straub tail and their reported clinical specificity was reflected by the specificity observed in the mouse tests. DS 103–282 was found to be the most potent and specific. It is concluded that muscle relaxants with specificity ratios significantly greater than 1.0 appear to have comparatively few depressant effects at therapeutic doses. The relatively simple methods used in the present study appear to be useful in the initial assessment of compounds as potential muscle relaxants.
The effects of depolarizing agents and neuropeptides on dopamine release from striatal synaptosomes
Authors: VonVoigtlander Philip F. , Losey Elizabeth G.
Published: January 2005

Synaptosomes (isolated nerve endings) from rat corpus striatum responded to several depolarizing agents by releasing dopamine. Among these agents were KCl, glutamic acid, ouabain, and veratrine. Substance P hexapeptide (SP6) also caused dopamine release, but the magnitude of this effect was small and variable. A number of other neuropeptides (cholecystokinin 1–8, des‐Tyr‐γ‐endorphin, Leu5‐β‐endorphin and substance P) did not alter dopamine release. SP6‐induced dopamine release may result from substance P receptor‐induced depolarization; however, the lack of robustness of the response in this preparation makes it unsuitable for studying agonists and antagonists of substance P.
The effects of lidocaine and hexamethonium on prostaglandin F2α‐ and histamine‐induced bronchoconstriction in normal and ASCARIS‐sensitive dogs
Authors: Malo Peter E. , Wasserman Martin A. , Griffin Robert L.
Published: January 2005

The effects of local deposition of the topical anesthetic, lidocaine, and ganglionic blockade by hexamethonium were investigated in canine models of pharmacologic‐ and antigen‐induced bronchoconstriction. Control bronchopulmonary provocations, i.e., increases in pulmonary resistance (RL) and decreases in dynamic lung compliance (CDYN), were accomplished by aerosols of prostaglandin F2α (PGF2α) and histamine (HIST) in normal, pentobarbital‐anesthetized beagles. Pretreatment with an aerosol of lidocaine (2%, 30 breaths) significantly inhibited PGF2α‐ and HIST‐induced changes in RL by 43.9 ± 6.5% and 58.0 ± 10.9%, respectively, and significantly reduced CDYN changes due to an aerosol challenge with HIST by 43.6 ± 9.2%. An i.v. infusion of hexamethonium (10 mg/kg) significantly inhibited PGF2α‐ induced changes in RL (36.5 ± 10.4%), while inhibiting changes in both RL and CDYN produced by HIST (57.8 ± 7.5% and 63.1 ± 6.5%, respectively). In Ascaris‐sensitive animals, neither lidocaine nor hexamethonium had any statistically significant effect on the bronchopulmonary responses to antigen challenge. These results suggest that a portion of the bronchoconstrictive response to PGF2α and HIST in dogs may involve an indirect, vagal‐mediated reflex, which is sensitive to lidocaine at the afferent cholinergic pathway and to hexamethonium at the ganglion. In antigen‐induced bronchoconstriction, these reflex pathways may be of lesser importance.
Lithium and central monoamine neurotransmitter systems
Authors: Ahluwalia Pardeep , Singhal Radhey L.
Published: January 2005

Lithium salts have been in use in psychiatric medicine for the past three decades, but their mechanism of action is still unknown. Studies using a model of mania to delineate the means by which they exert their therapeutic effect have been hampered by the lack of a suitable animal analogue, although attempts have been made to induce a “manic” state in rodents. For this reason, most investigations of the neurochemical basis of lithium action have used normal animals, and have focused primarily on the monoaminergic neurotransmitters, mainly because of the predominant theory of affective disorders (the “biogenic amine hypothesis”). Data indicate that these neurotransmitter substances are affected by lithium administration, although the findings are not always consistent and it is therefore difficult to determine exactly their role in the antimanic effect of lithium and the pathogenesis of the bipolar affective disorder. While animal studies have confirmed the existence of a “withdrawal” phenomenon, the involvement of biogenic amines or of central Y‐aminobutyric acid (GABA)minergic system in the rapid recurrence of psychotic symptoms soon after cessation of lithium therapy is still equivocal.
Psychotropic actions of BW 234U in the treatment of inpatient schizophrenics: A dose‐range study
Authors: Guy W. , Manov G. , Wilson W. H. , Ban T. A. , Fjetland O. K. , Manberg P. J. , Dren A. T.
Published: January 2005

In a 28‐day, dose‐range study, 11 chronic schizophrenic inpatients newly admitted to the hospital with acute exacerbations were administered a new antipsychotic, BW 234U, in daily doses ranging from 100 to 400 mg/day on a fixed/flexible schedule to determine therapeutic dose range, safety, and psychotropic activity with special regard to possible antiaggressive action. The results of weekly assessments with standard psychiatric rating instruments indicate that BW 234U has dual psychotropic action—an antipsychotic and an activating effect—that may have potential value in the treatment of depressive illness. The drug appears to be relatively free from neurologic, cardiovascular, anticholinergic, and CNS‐depressant side effects.
An improved model for assessment of positive inotropic activity in vitro
Authors: Anderson William G.
Published: January 2005

Responses of guinea pig paced left atria to positive inotropic agents that probably act by different mechanisms were compared at two different calcium concentrations in vitro (1.25 and 2.50 mM). Consistently good results were obtained with isoproterenol, ouabain, amrinone, and 3‐isobutyl‐1‐methylxanthine only at the lower calcium concentration, which resulted in a greater percentage of responsive preparations, greater response discrimination, lower incidence of spontaneous and drug‐induced arrhythmias, and therefore a better quantitative assessment of concentration‐response relationships. Satisfactory responses were also obtained with the indirect‐acting agent tyramine and with the new agent, vardax. An excellent correlation between the magnitude of tension developed and the maximum rate of tension development was obtained for various inotropic stimuli. The partial beta agonists, prenalterol and dichloroisoproterenol, gave relatively poor responses under both sets of experimental conditions. It is concluded that the use of a low calcium concentration in the bathing medium enhances responsiveness to a variety of inotropic agents acting by different mechanisms, providing a useful and more reliable model for testing in vitro. It is suggested that a low external calcium concentration results in a smaller predrug sarcolemmal calcium flux, which may be markedly enhanced by inotropic agents.
Acute cardiovascular effects of bepridil in anesthetized mongrel dogs
Authors: Jandhyala Bhagavan S. , Steenberg Marie L. , Buckley Joseph P.
Published: January 2005

The cardiovascular effects of bepridil, a calcium antagonist, were investigated in pentobarbital‐anesthetized dogs. The intravenous administration of bepridil, 5 mg/kg, produced significant reductions in heart rate, cardiac output, and cardiac contractility. There was an initial transient marked increase in coronary blood flow and a significant increase in oxygen consumption which was followed by a decrease in oxygen consumption 5 min after administration of bepridil. The progressive and significant reductions in heart rate, cardiac contractility, cardiac output, and left ventricular minute work could be responsible for the secondary reduction in oxygen consumption. Coronary hemodynamic effects appeared to be independent of other cardiac effects since there appears to be no temporal correlation between these two phenomena. The coronary vasodilator property of bepridil was specific since there was an initial decrease in renal, femoral, and mesenteric blood flows.
The antihypertensive effect of a selective central muscarinic cholinergic antagonist: N‐(4‐diethylamino‐2‐butynyl)‐succinimide
Authors: Coram Willie Mae , Brezenoff Henry E.
Published: January 2005

N‐(4‐Diethylamino‐2‐butynyl)‐succinimide (DKJ‐21), a cholinergic antagonist selective for muscarinic receptors in the central nervous system, has an antihypertensive effect in conscious spontaneously hypertensive rats (SHR) but not in normotensive Wistar‐Kyoto (WKY) control rats. Intravenous doses over a range of 3.1 to 25.0 mg/kg produced a dose‐dependent decrease in systolic blood pressure. This effect was still apparent 24 hr after drug administration, but blood pressure returned to predrug levels by 48 hr after injection of DKJ‐21. In a dose–response study, the maximum antihypertensive response in a group receiving 25.0 mg/kg was 43 ± 8 mm Hg. Marked variability of the maximum response was observed in all age groups and with all doses. Decreases in blood pressure up to 75 mm Hg were obtained in individual animals. The magnitude of the antihypertensive effect is not age related since 10‐, 15‐, 22‐, and 36‐week‐old SHR responded to the same degree after injection of 25 mg/kg DKJ‐21. Smaller doses (50 μg) of DKJ‐21 decreased blood pressure when administered into the lateral cerebral ventricle of SHR. Vascular responses to norepinephrine, acetylcholine, dimethylphenylpiperazinium, angiotensin I, and tyramine were not inhibited by i.v. injection of DKJ‐21; however, the centrally mediated pressor response to physostigmine was reduced by 60%.
Antagonism of discriminative stimuli produced by anxiogenic drugs as a novel approach to bioassay anxiolytics
Authors: Lal Harbans , Fielding Stuart
Published: January 2005

Antagonism of selected agonist‐type drugs is an approach commonly employed to identify new drug activity. In the search for new anxiolytics, drug antagonism has not been a drug development tool in the past because of the lack of a suitable anxiogenic agonist for routine use. Recently, a number of anxiogenic drugs have been described. Pentylenetetrazol is one of those drugs. This review provides a critical examination of pentylenetetrazol with regard to its suitability as an agonist of anxiety that may be used routinely to predict and bioassay anxiolytic activity of novel molecules. In addition, drug discrimination is presented as a novel tool to measure objectively a specific animal activity which shows the same pharmacological properties as the subjectively perceived symptom of anxiety in human subjects. It is believed that the antagonism of an interoceptive discriminative stimulus produced by pentylenetetrazol may be a reliable and sensitive procedure to identify anxiolytic drugs of the future.
Vascular serotonin receptors and blood pressure regulation
Authors: Cohen Marlene L.
Published: January 2005

In most vascular beds, receptors mediating contraction to serotonin are of the 5HT2 type (defined by [3H]‐spiperone binding in brain tissue). Research on vascular serotonin receptors has been prompted by the development of ketanserin, a potent 5HT2‐receptor antagonist. Recent data suggest that ketanserin also possesses α‐receptor antagonist activity and that this property accounts for its antihypertensive activity in spontaneously hypertensive rats (SHR). The multiple blocking activities of ketanserin have prompted a search for more selective 5HT2‐receptor antagonists to elucidate the role of vascular serotonin receptors in blood pressure regulation. Consequently, 1‐(1‐naphthyl)piperazine (1‐NP) and LY53857, an ergoline derivative, have been identified as potent and highly selective 5HT2‐receptor antagonists in vascular tissue. 1‐(1‐napthyl)piperazine and LY53857 show approximately 2,000‐ and 300,000‐fold greater affinity, respectively, for 5HT2‐receptors than for α‐receptors compared to a 60‐fold selectivity of ketanserin. However, neither 1‐NP nor LY53857 lowered blood pressure in the SHR in doses that markedly shifted the pressor response to serotonin but did not antagonize α‐adrenergic receptors. Furthermore, blood pressure reduction in the SHR correlated poorly with the ability of several “5HT2‐receptor antagonists” to bind to 5HT2‐receptors and correlated extremely well with the binding of these agents to α‐receptors. Thus, in SHR, 1) antihypertensive activity of ketanserin occurred in doses that block α‐receptors and not at lower doses that block serotonin receptors, 2) more specific serotonin antagonists that did not block α‐receptors in vivo did not lower blood pressure, and 3) the reduction in blood pressure produced by a series of serotonin receptor antagonists correlated with their ability to block α‐receptors but not 5HT2‐receptors.
The state of the art of the science of drug discovery—an opinion
Authors: Maxwell R. A.
Published: January 2005

The discovery of drugs (and their subsequent development) is a difficult subspeciality in pharmacology that, in conjunction with clinical medicine, generates the vitality underlying the entire pharmacologic‐therapeutic enterprise. The drug discovery process is unique among biomedical sciences in that it takes place almost solely in industrial research institutions rather than in nonindustrial institutions—i.e., academic and government laboratories. The conventional view of drug discovery is that, since it is mission‐oriented and pharmacological, it is derivative on the basic pharmacological research carried out in nonindustrial research institutions. It is argued by the author that this model is oversimplistic and is not applicable to pharmaceutical research: It is very frequently the case that drugs are developed first and thus precede “basic” knowledge and in fact are the source of new academic findings, especially in pharmacology. In addition, new drugs are useful tools in physiology and biochemistry. Thus, the discovery of an innovative drug is per se a basic contribution. A more reasonable model of the relationship between drug discovery (and development) and nonindustrial research—physiological, biochemical, and pharmacological—is that of symbiosis with each segment nurturing the other to mutual benefit.

The problems of pharmacologists involved in drug development are more complex than those of nonindustrial pharmacologists in that the end points of their work—successful clinical trial and marketing—demand more than an interesting pharmacological action; the action must be of therapeutic significance and be resident in a molecule which has been determined to be nontoxic, bioavailable, patentable, and commercially viable. The differences in goals between academic (non‐mission‐oriented) and industrial (mission‐oriented) pharmacological research and the consequent demands in the latter for specified kinds of results often leads to differing patterns of research and research judgments that can be a source of misunderstandings and confusion between industrial and nonindustrial pharmacologists.
Cholinergic hypothesis of human memory: Review of basic and clinical studies
Authors: Sitaram Natraj
Published: January 2005

Recent neurochemical data from autopsy and biopsy studies of Alzheimer patients lends strong support for a selective impairment of cholinergic functioning. A number of pharmacological trials are described testing the effects of cholinergic agonists and antagonists on cognitive functions of both young normal volunteers as well as geriatric, demented patients. Paradigms included prelearning and postlearning pharmacological manipulations as well as testing the effect of a combination of a cholinergic precursor (lecithin) plus an anticholinesterase (tetrahydroaminoacridine). The results indicated great variability of responses among subjects, with mild‐to‐moderate enhancement of memory recall in specific subgroups of normal controls and demented patients. Further research should be aimed at developing reliable in vivo cholinergic markers and validation of these measures as response predictors of specific cholinergic treatments in patients with dementia.
Hormonal mediation of the memory disorder in depression
Authors: Reus Victor I.
Published: January 2005

Many patients with major depression show deficits in information processing to a degree that parallels the severity of the mood disorder. Parallel findings of alteration in hormonal systems known to modulate memory functions suggest that the biological and cognitive changes described may be functionally linked. A specific goal for norepinephrine and the limbic hypothalamic‐pituitary‐adrenal axis is hypothesized and related to specific components of the alteration in information processing. The cognitive and mood effects of stimulant compounds in normal and depressed patient populations and parallels between the biologic and cognitive changes seen in normal aging and those observed in depression are considered.
Nootropic drugs: Animal models for studying effects on cognition
Authors: Schindler U. , Rush D. K. , Fielding S.
Published: January 2005

The term “nootropic” refers to compounds that act on cognitive functions. These drugs should facilitate learning and memory and prevent impairment of cognitive functions induced by diseases and brain insults. In animal models of impaired cognitive functions, the effects of several nootropic substances were investigated. Learning and retention in passive avoidance, and positive reinforcement paradigms were disrupted by hypoxia, cerebral ischemia and amnesia‐inducing agents. Piracetam and several other novel nootropic compounds were shown to improve performance in these animal models. These results indicate that experimentally induced cognitive dysfunction in animals can be attenuated with drug treatment.
Comparative activity of antihypertensive drugs as determined by the indirect measurement of blood pressure
Authors: Yaden Senka , Palmer Ralph T. , Elko Edward E. , Lal Harbans
Published: January 2005

Many protocols for studying blood pressure over a long period of time in the same animal involve direct measurement via arterial cannulation. Chronic cannulations are not only stressful but also cause a high rate of mortality. In rats, the most common procedure other than permanent catheterization consists of transitory occlusion and reinstatement of blood flow in the tail to record systolic blood pressure. In this technique, animals are warmed individually to increase blood flow, which often results in stress to the animal and high variability in the results. Recently, an automated version of testing equipment for indirect measurement of blood pressure has become available. Utilizing this system, a number of atithypertensive drugs were tested in spontaneously hypertensive rats in order to (1) determine the sensitivity and reliability of measurements made by the automated system and (2) evaluate relative potency and efficacy of antihypertensive drug therapy. The ED50 and confidence limits were determined for the following antihypertensive drugs: clonidine, guanabenz, para‐aminoclonidine, hydralazine, minoxidil, prazosin, and aceperone. Systolic blood pressure was measured by means of tail cuffs with built‐in photoelectric sensors in 12 rats concurrently. It is concluded that the use of the automated equipment provides reliable and reproducible measurement of blood pressure and permits testing of the effects of antihypertensive drugs repeatedly in a larger number of rats.
Inhibition of ultrasonic distress vocalizations in rat pups by chlordiazepoxide and diazepam
Authors: Gardner C. R.
Published: January 2005

Wistar rat pups emit ultrasonic distress cries when placed on a cold plate or when held by the tail. More sounds were induced by tail holding than by placing on the cold plate, but in both cases the number emitted was relatively constant from 7 to 13 days of age. Chlordiazepoxide and diazepam inhibited the sounds, and their activity was only associated with sedation and muscle relaxation at higher doses. The muscle relaxant mephenesin had little effect. Prazosin induced sedation and hypothermia and inhibited sounds induced by tail holding more than those on the cold plate. Clonidine induced hypothermia and weak sedation and increased sound emission weakly for the tail holding response but markedly for responses on the plate. This separation of responses may result from potentiation of responses on the plate by drug‐induced hypothermia. Although sedative effects result in decreased ultrasounds, the benzodiazepines continue to reduce sounds at doses showing little or no sedation. It is suggested that the benzodiazepines may reduce the sound via their anxiolytic action.
Receptor specificity of the 5HT2 receptor antagonist, LY53857
Authors: Cohen Marlene L. , Colbert Walter , Wittenauer Laura A.
Published: January 2005

LY53857 is a potent antagonist at vascular 5HT2 receptors that lacks prominent α1 or dopamine antagonist activity. The present report investigates the interaction of LY53857 with other receptor mechanisms. LY53857 showed no agonist activity in the guinea pig trachea, guinea pig atria, guinea pig ileum, or rat vas deferens. Furthermore, LY53857 did not antagonize histamine (H1) or β2 receptors in the guinea pig trachea, β1 in the guinea pig atria, muscarinic, or angiotensin I receptors in the guinea pig ileum. However, LY53857 did block α2 receptors (−log KB = 6.51) as determined by antagonism of the inhibitory effects of the selective β2 agonist, UK‐14,304, on the twitch response in the guinea pig ileum. LY53857 antagonized β2 receptors at concentrations approximately 6000‐fold higher than necessary to block 5HT2 receptors (−log KB = 10.3). Taken in concert, these data support the contention that LY53857 is a highly selective antagonist of 5HT2 receptors, and that LY53857 is a useful tool with which to probe 5HT2 receptors and serotonergic mechanisms.
A preliminary investigation of “albert 285” (HWA 285) on psychomotor performance, mood, and memory
Authors: Hindmarch Ian , Subhan Zahed
Published: January 2005

Eight healthy female volunteers received 150, 300, and 450 mg of HWA 285 and placebo according to a randomized, double‐blind crossover design. The subjects completed a battery of psychological tests including critical flicker fusion (CFF), choice reaction time (CRT), subjective ratings of drug effects (LARS), and a Sternberg memory scanning test (SMST) 1 and 2 hr following treatment. No statistically significant changes from placebo were observed on CFF, CRT, or subjective ratings of drug effects. However, memory as assessed using the Sternberg technique was significantly improved with respect to placebo 1 hr following treatment with HWA 285 at 150, 300, and 450 mg dose levels. The action of the drug was found to be specific in its effects on the central serial comparison stage of the information processing model.
Open label evaluation of the novel antipsychotic compound BW234U in chronic schizophrenics
Authors: Schwarcz Glenn , Halaris Angelos , Dren Anthony , Manberg Paul
Published: January 2005

In a 28‐day open label study, 15 inpatients with chronic schizophrenia in relapse were treated with BW234U. Approximately half of the patients showed marked improvement. Four patients showed no change and three dropped out. Thought disturbance improved markedly. The compound was tolerated very well.
Safety and efficacy of bupropion, a novel antidepressant
Authors: Dufresne Robert L. , Becker Robert E. , Bltzer Robert , Wagner Richard L. , Lal Harbans
Published: January 2005

Bupropion, a pharmacologically unique antidepressant, was found to be both safe and effective in an open clinical trial in 16 depressed inpatients. Subjects were given either bupropion in doses ranging from 300 to 750 mg daily or the positive control amitriptyline in doses ranging from 75–300 mg daily. Patients were dosed following an ascending dosage regimen for a minimum of 2 and up to 10 weeks. Clinical assessment of antidepressant efficay was made prior to, during, and on the last day of drug therapy through the use of the Hamilton depression scale, the Zung self‐rating depression scale, and the clinical global impressions rating scale. Patients were assessed for adverse reactions on relevant observational, medical, and clinical laboratory tests prior to and throughout the study. Patients improved significantly from baseline on the efficacy rating scales in a manner similar to the positive control, though the small size of the positive control group lessened the chance of occurrence of statistically significant differences between groups. The main adverse reactions reported by bupropion‐treated patients were agitation or excitement, insomnia, and a mild tremor. Dry mouth and orthostatic hypotension occurred most often in amitriptyline‐treated patients.
A novel, orally effective hypoglycemic agent, SaRI 59–801, in laboratory animals
Authors: Ho Robert S. , Wiseberg Jack J. , Brand Leonard J. , Nadelson Jeffrey , Boyajy Louis D.
Published: January 2005

SaRl 59‐801 (59‐801) (α‐[dimethylaminomethyl]‐2‐[3‐ethyl‐5‐methyl‐4‐isoxazolyl]‐1H‐indole‐3‐methanol), is a novel, orally effective hypoglycemic compound which appears to act largely, if not entirely, by stimulation of insulin release. The compound is structurally unrelated to sulfonylurea derivatives. The 2‐hr hypoglycemic ED25 in fasting mice was 110 mg/kg; the plasma insulin levels were increased, with an ED50 of 47 mg/kg. Significant hypoglycemic activity was observed 2 hr after oral administration of 59‐801 to fasting rats (ED25 = 86 mg/kg), while plasma insulin was elevated by 62% at 100 mg/kg. 59‐801 caused an insignificant decrease in plasma lactic acid levels. The hyperglycemic response 30 min after an oral starch load was inhibited by 1‐hr pretreatment with 59‐801 (ED50 = 37 mg/kg). No tolerance to the hypoglycemic effect was observed after 28 days of dosing in rats. In monkeys, the agent also produced hypoglycemia with a minimum effective dose of 10 mg/kg and an ED25 of 33 mg/kg for a period of 6 hr after oral administration. In genetically diabetic (db+/db+) mice, 59‐801 was more potent in producing hypoglycemia (ED25 = 47 mg/kg) than their lean littermates (ED25 = 131 mg/kg). In alloxan‐diabetic rats or streptozotocin‐diabetic mice, this agent was inactive at 200 mg/kg, but at 400 mg/kg, it caused reduction of blood glucose levels of 29–39 and 21%, respectively, possibly the result of stimulation of residual β‐cell function. Thus far, stimulation of insulin release is the only mechanism found to explain the acute hypoglycemic activity of 59‐801.
The serotonin‐S2 Receptor: A receptor‐transducer coupling model to explain insurmountable antagonist effects
Authors: De Courcelles Didier de Chaffoy , Leysen Josée E. , Roevens Peter , van Belle Herman
Published: January 2005

Five serotonin‐S2 antagonists, ketanserin, pipamperone, methysergide, ritanserin, and LSD, were tested for their ability to inhibit signal transduction coupled to the serotonin‐S2 receptor by measuring the serotonin‐induced [32P] phosphatidic acid formation. The five drugs inhibited the response in a non‐competitive manner. Since drugs such as ketanserin and pipamperone were found to dissociate rapidly from serotonin‐S2 receptor sites in binding studies, slowly reversible binding can hardly explain the apparent non‐competitive inhibition of the biochemical effect. The authors, therefore, propose a new model of interaction between the serotonin‐S2 receptor macromolecule and the signal transducing system that is compatible with the present and previous experimental observations.
Non‐antidopaminergic, non‐cholinergic stimulation of gastric emptying with cisapride (R 51 619) in rats
Authors: Megens Anton A. H. P. , Canters Luc L. J. , Artois Kamiel S. K. , Smeyers Frans , Keersmaekers Roger C. A. , Awouters Frans
Published: January 2005

The gastrokinetic activity of cisapride, bethanechol, domperidone, and metoclopramide was tested in rats and compared with the direct cholinergic activity (induction of salivation and lacrimation in rats) and peripheral and central antidopamine activity (antagonism of apomorphine‐induced emesis in dogs and abnormal behaviour in rats, respectively) of the compounds.

Cisapride showed a high dissociation between gastrokinetic activity (0.31 mg/kg) on the one hand, and direct cholinergic activity (ED50: ≥ 40 mg/kg) and peripheral and central antidopamine activity (ED50s: 3.3 and 18.6 mg/kg), on the other hand. In contrast, metoclopramide combined antidopamine effects (ED50s: 0.28 and 0.76 mg/kg for peripheral and central activity) and bethanechol direct cholinergic effects (ED50s: 2.7 and 3.6 mg/kg for lacrimation and salivation) with their gastrokinetic activity, which was obtained with bethanechol at 0.63 mg/kg and with metoclopramide at 1.25 mg/kg. Domperidone was found to be a potent and selective antagonist of peripheral dopamine receptors (ED50: 0.0071 mg/kg) but failed to stimulate gastric emptying (ED50: ≥ 10 mg/kg).

The present data confirm cisapride as a potent gastrokinetic compound devoid of antidopaminergic or direct cholinergic properties.
A comparative study on the in vitro metabolism of cisapride using subcellular liver fractions of dog, rabbit, and male and female rats
Authors: Lavrijsen Karel L. M. , Meuldermans Willem , Knaeps Fons A. G. , Lauwers William , Heykants Jozef
Published: January 2005

Cisapride‐3H, labeled at the fluorophenyl moiety or at the piperidine ring, was incubated with the supernatant and microsomal fractions of various animal livers and an NADPH‐generating system. The major metabolites were identified by co‐chromatography with high performance liquid chromatography (HPLC) and by mass spectrometry. A mass balance of the major metabolites in incubates was made up by radio‐HPLC. The rate of metabolism of the drug decreased in the following order: rabbit ≥ male rat ≥ dog ≥ female rat. The major in vitro metabolic pathways in the animal species were rather similar. Main biotransformation routes were oxidative N‐dealkylation at the piperidine nitrogen and aromatic hydroxylation occurring either at the fluorophenyl or at the benzamide moiety. Hydroxylation was relatively more abundant in female compared to male rats, whereas oxidative O‐dealkylation was important in incubates with rabbit subcellular fractions only. Furthermore, the formation of at least four sulfate conjugates could be demonstrated. Metabolism experiments with phenobarbital‐induced or 3‐methylcholanthrene‐induced microsomes indicated that phenobarbital inducible cytochrome P‐450 isoenzyme(s) are involved in the in vitro metabolism of cisapride.
An efficient method to evaluate protective drugs against regional ischemia of the heart
Authors: Vandeplassche Godelieve , Wouters Luc , Hermans Carlo , Xhonneux Raymond , Borgers Marcel , Flameng Willem
Published: January 2005

The variables related to infarct size were examined in order to develop an efficient procedure for the assessment of cardioprotective action in the dog. In the open chest model the left anterior descending coronary artery was ligated for 90 or 240 min. Regional myocardial blood flow was measured by tracer microspheres and infarct size was studied using triphenyltetrazoliumchloride. Infarct size was measured in relation to perfusion area, collateral flow, and rate pressure product. Using perfusion area as an independent variable, only 61% of the variance in infarct size could be explained. Including collateral flow also, this percentage increased to 80. Using perfusion area and collateral flow, infarct size could be predicted accurately. The usefulness of this procedure is demonstrated by data obtained with test compound R 51 430.
Rimcazole (BW 234U), a novel antipsychotic agent whose mechanism of action cannot be explained by a direct blockade of postsynaptic dopaminergic receptors in brain
Authors: Ferris R.M. , White H.L. , Tang F.L.M. , Russell A. , Harfenist M.
Published: January 2005

Rimcazole is a novel antipsychotic agent free of extrapyramidal side effects as judged by its profile in animal behavioral models and by results of early clinical trials in acute schizophrenic patients. The present study shows that rimcazole is different biochemically from the typical and atypical neuroleptics. Concentrations of 10−5 to 10−4 M are necessary to achieve even weak effects on dopamine‐stimulated adenylate cyclase activity (D1 receptors), [3H]dopamine binding in mesolimbic and striatal areas of rat brain. Rimcazole's extremely weak potency as a D2 receptor blocker in brain was readily apparent when compared to several other neuroleptics: It was 160 times weaker than sulpiride, the least potent striatal D2 receptor blocker studied, and 10,000 times weaker than haloperidol, the most potent. Rimcazole had no effect on many of the enzymes involved in catecholamine synthesis and metabolism in vitro, did not effect the synthesis of [3H]dopamine from [3H]tyrosine in vivo, and did not alter the effects of a dopaminergic agonist and a dopaminergic antagonist on [3H]dopamine synthesis in vivo. It was moderately potent as an inhibitor of serotonin (5‐HT2) receptors but had only weak effects on muscarinic cholinergic, α1–, α2 –, β –adrenergic, benzodiazepine, GABA, adenosine (A1 and A2), glycine, serotonin (5‐HT1), imipramine, neurotensin, and phencyclidine receptors and calcium channels in binding assays. It was a moderately potent, competitive inhibitor of dopamine uptake in vitro and had no pharmacologically relevant effects on the spontaneous release of biogenic amines from isolated nerve endings. These data suggest that if rimcazole is shown to be a clinically effective antipsychotic agent, it will be the first antipsychotic whose mechanism of action cannot be explained by a direct blockade of postsynaptic dopaminergic (D2) receptors in brain.
Double‐blind dose determination study of a new antidepressant—sertraline
Authors: Guy William , Manov Gregory , Wilson William H.
Published: January 2005

As part of a multicenter dose determination study designed to evaluate the safety and therapeutic activity of four fixed dose levels of sertraline—a new antidepressant with biochemical characteristics different from tricyclics—17 patients with diagnoses of major depressive disorder were treated with active medication under double‐blind conditions for 4 weeks following a 1‐week washout period. Patients receiving the two higher dose levels of sertraline exhibited almost no symptomatic improvement and manifested more adverse events that patients receiving the two lower dose levels. No statistically significant differences between the low‐dose groups and the placebo group were found. Thus, the efficacy of sertraline could not be demonstrated under these design constraints, although differential dose level effects were indicated. Dosage levels up to 100 mg/day would appear to be more clinically appropriate than higher dosage levels.
Diuretic effects of a novel uricosuric antihypertensive S‐8666 in rats, mice, monkeys, and dogs: Comparison with furosemide and trichlormethiazide
Authors: Nakamura Masuhisa , Shimizu Toshikatsu , Miyata Kenji , Kawabata Tomoji , Harada Hiroshi
Published: January 2005

Oral dose‐response relationships of S‐8666 to Na excretion were established in male and female Sprague‐Dawley rats (3–100 mg/kg), male and female ddy mice (3–300 mg/kg), female cynomolgus monkeys (2–50 mg/kg), and female beagle dogs (3–100 mg/kg). The natriuretic potency of S‐8666 was almost comparable to that of furosemide in rats but was lower in mice, monkeys, and dogs. The maximal effects were similar for S‐8666 and furosemide, which had higher ceiling values than trichlormethiazide (TCM) in rats, mice, monkeys, and dogs. Thus, S‐8666 seems to have a “loop diuretic” property like furosemide. After oral administration of S‐8666 to rats (20–100 mg/kg), the onset of natriuresis was rapid, with the peak effect occurring within 1–2 hr. TCM showed a longer lasting pattern of natriuresis than S‐8666 and furosemide. With intravenous administration (1–10 mg/kg) to rats, the t1/2 for natriuresis was 16–20 min for S‐8666 and furosemide in rats. S‐8666 showed enantioselectivity; its (S)‐(–)‐form was natriuretic, whereas the (R)‐(+)‐form was inactive. These results indicate that S‐8666 is a diuretic with a high ceiling property that has a lower potency than TCM and a longer lasting effect than furosemide.
N‐alkyl‐substituted aryl‐piperazine drugs: Relationship between affinity for serotonin receptors and inhibition of aggression
Authors: McMillen Brian A. , Davanzo Elizabeth A. , Scott Sara M. , Song Arleen H.
Published: January 2005

Buspirone is the first of several N‐alkyl‐substituted aryl‐piperazine‐containing drugs to be approved for use as an anxiolytic agent. These drugs do not interact with the benzodiazepine‐GABA receptor complex and therefore do not share the sedating and anticonvulsant effects of benzodiazepines. Buspirone and its analogs, gepirone and ipsapirone, act as agonists both pre‐ and postsynaptically at 5HTla receptor sites. A series of piperazine‐containing drugs was tested for their affinity at the 5HTla (postsynaptic) binding sites in hippocampus and compared with their ability to inhibit isolation‐induced aggression by mice. The potent 5HTla agonist, 8‐OH‐DPAT, was the most potent drug in both tests: IC50 = 1 nM, and ED50 = 2.4 μmol/kg for inhibition of [3H]‐5HT binding and aggression, respectively. There was a good correlation between ability to inhibit aggression and ability to inhibit [3H]‐5HT binding to hippocampal membranes. Fluprazine (DU 27716) was the major exception, but results with SKF 525‐A pretreatment to inhibit drug oxidation suggest that both fluprazine and metabolites have antiaggressive activity. Like other aryl‐piperazine drugs, fluprazine is potentiated by coadministration of a postsynaptic 5HT receptor antagonist, methysergide. Since antagonists of postsynaptic 5HT receptors potentiate gepirone and 8‐OH‐DPAT inhibition of aggression, these data suggest that affinity for 5HTla receptors at presynaptic autoreceptor sites is critical for the antiaggressive activity of these drugs and possibly for their anxiolytic effects.
Cognitive functions affected by scopolamine in alzheimer's disease and normal aging
Authors: Jacob Huff F. , Mickel Susan F. , Corkin Suzanne , Growdon John H.
Published: January 2005

We gave scopolamine to patients with Alzheimer's disease (AD) and age‐matched control subjects in order to identify which cognitive functions are affected by blocking muscarinic receptors for acetylcholine (ACh). Both subject groups showed dose‐related impairments in verbal learning, and patients with AD exhibited enhanced vulnerability to effects of scopolamine on attentional vigilance. In the same dose range, scopolamine did not alter retrieval from long‐term lexical‐semantic memory or performance on a test of visual discrimination, suggesting that cholinergic neurotransmission is not critical for these cognitive functions. The importance of cholinergic transmission in learning and attention is confirmed by this study, and the results indicate that both these abilities should be measured in investigations of potential cholinergic treatments for AD.
Clonidine disrupts aged‐monkey delayed response performance
Authors: Davis Robert E. , Callahan Michael J. , Downs David A.
Published: January 2005

Clonidine (0.03–0.06 mg/kg), in a dose‐ and delay‐dependent manner impaired the ability of aged rhesus monkeys to perform a microcomputer‐controlled delayed response test similar to that used previously by Bartus et al. (J. Gerontol. 33:858–871, 1978). These doses of clonidine produced overt sedation, increased response latencies and decreased the percentage of correct responses. Continued disruption of delayed response performance was seen during 11 days of repeated daily clonidine (0.04 mg/kg) administration. Performance immediately returned to preexisting baseline levels on the day following cessation of this repeated drug regimen. In addition, repeated clonidine administration did not alter responsivity to acutely administered clonidine, suggesting that tolerance did not develop rapidly to the disruptive effects of this agent. These data indicate that clonidine impairs delayed response performance in aged rhesus monkeys under these testing conditions.
Pharmacological effects of MDL 11,939: A selective, centrally acting antagonist of 5‐HT2 receptors
Authors: Dudley Mark W. , Wiech Norbert L. , Miller Francis P. , Carr Albert A. , Cheng Hsien C. , Roebel Lawrence E. , Doherty Niall S. , Yamamura Henry I. , Ursillo Richard C. , Palfreyman Michael G.
Published: January 2005

MDL 11,939 (α‐phenyl‐1‐(2‐phenylethyl)‐4‐piperidine methanol) has been shown, through in vitro studies utilizing radioligand binding and isolated tissues as well as through in vivo tests of central and peripheral serotonergic activity, to be a potent, selective antagonist at 5‐hydroxytryptamine receptors of the 5‐HT2 subtype. In particular, MDL 11,939 shows low affinity for the 5‐HT1 and 5‐HT3 subtypes of the serotonin receptor and displays low or negligible affinity for alpha adrenergic, dopaminergic, cholinergic, histamininergic, and opiate receptors. Because the 5‐HT2 subtype of the serotonin receptor has been implicated in the control of both the central nervous and vascular systems of experimental animals, it is likely that a compound with the potency and specificity of MDL 11,939 has interesting therapeutic potential.
Structure and function of the stratum corneum permeability barrier
Authors: Elias Peter M.
Published: January 2005

The main function of the epidermis is to generate an impermeable outer layer, the stratum corneum. The stratum corneum can be considered morphologically and functionally to represent a two‐compartment system composed of: (1) anucleate corneocytes (the bricks), largely composed of fibrous protein networks; and (2) the intercellular matrix (the mortar), predominantly composed of neutral lipid. Whereas much prior and current work on the stratum corneum has focused on the protein biochemistry leading to the formation of the keratinized corneocyte (“keratinization”), this paper is concerned with the formation, composition, and function of the intercellular matrix of the stratum corneum. For those interested in permeability barrier function, percutaneous transport, and the cutaneous reservoir, as well as most inherited disorders of cornification, it is critical to understand the “mortar,” for it is this domain that logically regulates all of these important phenomena.
Placebo‐controlled, double‐blind, crossover study to investigate the hypoxia‐protective effect of vinpocetine by psychophysiological methodology in healthy volunteers
Authors: Schaffler K.
Published: January 2005

Vinpocetine positively influences cerebral vascular resistance (> CBF), as well as O2‐extraction (> A/V‐O2‐difference) and the brain's glucose and neurotransmitter turnover, as has been shown in other experimental and clincal studies. Therefore, a hypoxia‐protective effect of vinpocetine should be expected in an experimental simulatory approach using hypoxic hypoxidosis.