bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of the hydrated rat to assay diuretic and antidiuretic activity of drugs
Authors: DeFelice Albert , Harris Alex , Brousseau Armand
Published: January 2005

This study compared oral renal excretory effects of several agents in three rat strains with that reported in man to assess predictive value of this species in cardiorenal drug development. Sprague‐Dawley (SD), Wistar‐Kyoto (WK), and spontaneously hypertensive rats (SHR) were hydrated and 3 hr urine volume, Na+, and K+ were measured, Normotensive SD and WK rats responded similarly, i.e., hydrochlorothiazide (HCTZ) and aminophylline were diuretic, while hydralazine and milrinone caused Na+ retention. Accordingly the more economical SD rat was then compared with SHR. Aminophylline (3–30 mg/kg) and the more effective HCTZ (1–30 mg/kg) achieved dose‐related diuresis and kaliuresis in both strains, increasing Na+ excretion by a maximum of 5–14‐fold, whereas the vasodilators hydralazine (3–30 mg/kg) and milrinone (1–10 mg/kg) reduced Na+, K+ and volume dose‐relatedly with Na+ output being 5–50% of control values. Verapamil promoted Na+ excretion in both strains by 1.5‐ to 4‐fold at 30 mg/kg, but was antinatriuretic at 80 mg/kg. Conversely, nifedipine had qualitatively differents effects in SHR and SD rats. That is, it elicited diuresis in the SHR at 10mg/kg (Δ Na+ = +155%) and no change in urine volume or Na+ and K+ cutput at 30 mg/kg, where as the Ca++‐antagonist provoked dose‐related volume, Na+, and K+ retention in the normotensive rat with 3 hr output being ca. 15–22% of that of vehicle‐treated controls. Accordingly the SD rat predicted the renal effects typically seen clinically for all agents except milrinone (Cody et al.: Clinical Pharmacology and Therapeutics 39: 128–135, 1986), supporting use of the economical SD rat as a primary assay for effects on renal excretion with the SHR strain reserved for assessing Ca++‐channel blockers in the hypertensive state.
Comparative study of central and peripheral histamine‐H1 receptor binding in vitro and ex vivo of non‐sedating antihistamines and of noberastine, a new agent
Authors: Leysen Josée E. , Gommeren Walter , Janssen Paul F. M. , Janssen Paul A. J.
Published: January 2005

A new antihistamine, noberastine, and clinically used non‐sedating antihistamines, astemizole, mequitazine, terfenadine, loratadine, and cetirizine were investigated for in vitro and ex vivo binding to histamine‐H1 receptors in guinea‐pig cerebellums and lungs. In vitro, all the drugs dissociated slowly from histamine‐H1 receptors (half‐times ≥ 100 min), Ki,app‐values decreased with longer incubation times and for potent lipophilic agents (astemizole, mequitazine, and terfenadine) Ki,app‐values were lower with more dilute tissue suspensions. Because of the slow dissociation, true binding equilibrium cannot be attained during limited incubation times and because of the apparently high tissue adsorption for some of the drugs, the actual free drug concentration in solution is unknown. Therefore measured binding parameters are apparent; true equilibrium binding constants cannot be estimated. Noberastine showed the lowest Ki,app‐value in various assay conditions (0.55–0.15 nM). In optimized assay conditions astemizole and mequitazine were nearly as potent (Ki,app‐values 0.2 and 0.29 nM). Terfenadine, cetirizine, and loratidine bound with 30‐, 80‐ and 100‐times lower affinity. The in vitro receptor binding and neurotransmitter inhibition profile of these compounds revealed that they all primarily bound to histamine‐H1 receptors. The occupation of lung and cerebellar histamine‐H1 receptors was investigated after oral administration of different dosages of the drugs and at various times after drug administration using ex vivo binding techniques. Noberastine and astemizole were the most potent componds and showed complete differentiation between lung and cerebellar receptor occupation (with 0.63 mg.kg−1: 70% lung receptor occupancy, less than 10% cerebellar receptor occupancy). With mequitazine and terfenadine a 7‐times higher dose was required to reach the same effect. Astemizole was extremely long acting, noberastine, mequitazine and terfenadine were short acting. Loratidine and cetirizine differentiated very poorly or not at all between lung and cerebellar receptor occupation (at 2.5 mg.kg−1: 70% and 60% lung receptor occupation, 50% and 70% cerebellar receptor occupation). The physicochemical properties of the drugs were considered in the discussion of the data. It appeared that penetration into the brain is not directly related to lipophilicity. The study allowed a quantitative comparison of the receptor binding properties of the drugs. Noberastine, as a shorter acting agent, and astemizole, as a long acting agent, appeared to be the compounds of choice as non‐sedating antihistamines.
Reversal of stress‐induced arousal in sleeping rats by some imidazopyrimidine benzodiazepine receptor ligands
Authors: James Vernon , Gardner Colin R.
Published: January 2005

Five selected imidazopyrimidine ligands for benzodiazepine receptors which show nonsedative anxiolytic behavioral profiles, were tested for their ability to reverse arousal induced by intermittent footshock stress in sleeping rats. RU32698, RU32759, RU33203, and RU33543 showed dose‐related inhibition of stress‐induced arousal in the dose range 2–10 mg/kg orally, as did chlordiazepoxide. After 14 daily doses there was little or no decrease in the magnitude of this effect with RU32759 and RU32698, respectively. In contrast, RU32514 only weakly reversed stress‐induced arousal at 10 mg/kg, a dose which is maximally active in a conflict procedure in rats. It is suggested that RU32514 possesses only weak agonist activity at benzodiazepine receptors and this is insufficient for it to be effective in this test. RU32698 and RU32759 show potential for development as non‐sedative anxiolytics and the sub‐acute dosing experiment suggests that they may not show marked tolerance.
Animal pharmacokinetics of selected imidazopyrimidine ligands for benzodiazepine receptors
Authors: Ager Ian R. , Doyle Anne B. , Hairsine Peter W. , McDonald Keith P. , Miller Peter , Parker Fred L.
Published: January 2005

The kinetics of imidazopyrimidines selected for development were investigated in the rat, dog, and cynomolgus monkey using high pressure liquid chromatography (HPLC) measurements of levels. These data were compared with levels estimated by benzodiazepine radioreceptor binding assays and with the in vivo binding of the compounds to these receptors in the brain. RU 32698, RU 33203, and RU 33543 were found in relatively high peak levels in the plasma of rats (1–6 μg/ml at 10 min‐1 hr after 10–100 mg/kg orally [p.o.]), dogs (4–12 μg/ml at 2 hr after 20 mg/kg p.o.), and monkeys (0.4–10 μg/ml after 150–500 mg/kg p.o.). HPLC analysis showed one further prominent peak for either RU 33203 or RU 33543 which had similar characteristics in all three species and may represent a common route of metabolism. In the rat these putative metabolites were at low levels in the brain when compared with parent levels. Nuclear magnetic resonance (NMR) and mass spectra of these isolated metabolites identified them as the hydroxymethyl derivatives on the oxadiazole ring. The synthesised metabolites showed two to six times less affinity for 3H‐flunitrazepam‐labelled benzodiazepine receptors, and the RU 33203 metabolite, RU 34149, did not displace in vivo benzodiazepine receptor binding after administration to mice, despite high plasma levels. This, coupled with little activity in several in vivo pharmacological models, suggests that this metabolite only poorly crosses the blood brain barrier. A pharmacological effect in the stress‐induced ultrasounds model is consistent with this view as the rat pups used have a poor blood brain barrier. Daily dosing of low, pharmacologically effective doses of all three compounds (25 or 30 mg/kg p.o.) in rats showed little change in the plasma levels of parents after the 14th dose. There were slight increases in the levels of the metabolites of RU 33203 and RU 33543. Higher doses showed some decrease of parent levels on day 14 but a clear increase in the metabolite levels, particularly with RU 33543, suggesting enhanced metabolism on repeated dosing. No marked differences in overall plasma level time courses of parent or metabolites were observed when comparing the first or last (28–30 days) daily dose in monkeys (150–500 mg/kg p.o.).
Characterization of central H2 receptors mediating cardiovascular activity by means of three histamine H2 receptor antagonists: MK‐208, BMY‐25368, and cimetidine in the rat
Authors: Poulakos Jennifer J. , Gerges Elizabeth N. , Gertner Sheldon B.
Published: January 2005

Stimulation of central histamine H1 and or H2 receptors with histaminergic drugs results in a dose‐related pressor response and bradycardia in conscious, freely‐moving rats. Two recently developed peripheral histamine H2 antagonists, MK‐208 and BMY‐26368, as well as cimetidine, were evaluated with respect to their ability to block the cardiovascular actions of central histamine H2 receptors. These drugs do not readily cross the blood brain barrier, therefore, they were administered intracerebroventricularly (i.c.v.). The ability of these agents to attenuate the cardiovascular effects of the H2 agonist impromidine was studied in conscious, freely‐moving rats. Blood pressure and heart rate were monitored directly via indwelling carotid catheters, and drugs were administered i.c.v. through permanently implanted cannulae. All of the H2 antagonists tested induced a transient hypertensive response that lasted approximately 15 min. MK‐208 (30 μg) partially blocked the central cardiovascular actions of impromidine. Unlike other histaminergic agents, MK‐208 produced a tachycardia and a profound hyperactivity which slowly developed into seizures. BMY‐25368 and cimetidine failed to antagonize the cardiovascular actions of impromidine. These results demonstrate that cimetidine and BMY‐25368, established peripheral H2 antagonists, did not block central H2 receptors, suggesting that central and peripheral H2 receptors may be pharmacologically distinct.
Psychopharmacological effects of an imino‐thiazolidine derivative antidepressant candidate, EGYT‐4201
Authors: Gyertyán István , Petöcz Lujza , Gacsályi István , Fekete Márton I. K. , Tekes Kornélia , Kápolnai László
Published: January 2005

The imino‐thiazolidine derivative EGYT‐4201 exhibited marked activity in pharmacological tests characteristic for antidepressants. In the behavioral despair model and in antagonizing the effect of tetrabenazine its efficacy was considerably higher than that of several tricyclic and second generation antidepressant drugs. The compound also proved to be active in inhibiting the hypothermic effect of apomorphine. It potentiated the lethal effect of yohimbine, the hypermotility provoked by L‐dopa, and the stereotypy induced by D‐amphetamine. In contrast to amitriptyline and nomifensine, EGYT‐4201 showed neither sedative nor stimulant actions on spontaneous and conditioned behavior. The compound, similar to amitriptyline and viloxazine, exerted a moderate anticonvulsive effect against pentylenetetrazole, bicuculline, and picrotoxin. EGYT‐4201 did not exhibit significant anticholinergic activity on physostigmine induced lethality, oxotremorine evoked tremor, and isolated guinea pig ileum. In acute toxicity studies it proved to be more favourable than the reference compounds. EGYT‐4201 did not inhibit the enzymatic activity of the monoamino‐oxidase (MAO) enzyme, nor did it block the uptake of monoamines. The molecule was found to be inactive in binding studies of noradrenergic, dopaminergic, and serotonergic receptor types.
In vitro and in vivo studies on the effects of the alpha‐adrenoceptor blocker IP/66 (1‐(2‐ethoxy‐2‐(3′ ‐pyridyl)ethyl)‐4‐(2′‐methoxy‐phenyl)piperazine) on urethral tone in rats
Authors: Manzini Stefano , Perretti Francesca , Boni Paola , Barbanti Gabriele , Turini Damiano , Maggi Carlo Alberto
Published: January 2005

IP/66 (1‐(2‐ethoxy‐2‐(3′‐pyridyl)ethyl)‐4‐(2′‐methoxy‐phenyl))piperazine is a newly synthetized and stereoselective alpha‐adrenoceptor blocking drug. This compound exhibits preferential blocking activity in postjunctional as compared to prejunctional alpha‐adrenergic responses. Furthermore, IP/66 inhibits phenylephrine‐induced motor response in human and rat prostatic tissue and phenylephrine‐, DMPP‐ and EFS‐induced motor responses in rat urethral tissues, being equieffective or even more potent than prazosin. Like prazosin, intravenous administration of IP/66, at doses at which no hypotensive effect is observed, induces a marked inhibition of phenylephrine or DMPP‐induced increase in urethral perfusion pressure, in anaesthetized pithed rats. Finally, IP/66 administration exerts beneficial effects in animals with surgically‐ or pharmacologically‐induced urethral outflow obstruction. As a whole, the pharmacodynamic profile of IP/66 is promising and this drug might be proposed for clinical setting evaluating its efficacy for the treatment of lower urinary tract dysfunctions.
Prepulse inhibition as a screening test for potential antipsychotics
Authors: Rigdon Greg C. , Viik Kaido
Published: January 2005

Startle response amplitude is greatly reduced by a low intensity pulse presented 100 msec prior to the startle stimulus. The magnitude of this prepulse inhibition (PPI) is reduced in schizophrenic patients. In rats, apomorphine disrupts PPI; haloperidol antagonizes apomorphine's effects. We tested the antipsychotic drugs haloperidol, chlorpromazine, clozapine, and risperidone, and the non‐antipsychotic psychopharmacological agents diazepam, buspirone, and imipramine for their ability to antagonize apomorphine's effects on PPI of the acoustic startle reflex. Haloperidol, chlorpromazine, and risperidone antagonized apomorphine's blockade of PPI. Clozapine antagonized apomorphine's effect only at a dose that decreased startle amplitude by 82%. Imipramine and diazepam did not antagonize apomorphine's effect at behaviorally relevant doses. Buspirone weakly antagonized apomorphine blockade of PPI, but, like apomorphine, disrupted PPI when given alone. These results suggest that this PPI test may provide a useful screening procedure for compounds wtih antipsychotic activity. However, the lack of a robust clozapine effect needs to be investigated.
Medication property effects on expectations of action
Authors: Buckalew L. W. , Ross Sherman
Published: January 2005

This paper applied a psychological perspective, initiated from placebo research, on medication physical properties and related perceptions, expectations, and preferences. The purpose was to identify expectations of drug indications related to medication color and to identify any preferences for oral medication form. A census‐based (age, race, gender) sample of 102, screened for color vision, classified 29 different colored capsules as to physiological system(s) expected to be influenced. Medication form preferences were verbally obtained. Nonrandom distributions were found for 18 capsules, with 10 related to specific physiological indications to include “Unknown.” Capsules were clearly favored over pills and caplets. Age, gender, and race effects were minimal in sortings and preferences. Related research on perceptions of medications was reviewed and integrated with present data. Findings should have implications for drug development, drug effectiveness, and patient compliance. A theoretical framework was offered for understanding possible effects of preparation perceptual properties.
Heptaminol hydrochloride (hept‐a‐Myl®) facilitates a light‐dark discrimination task in a Y‐maze using electrical self‐stimulation as reinforcement
Authors: Cazala P. , Durantou F. , Pourrias B.
Published: January 2005

The effects of intraperitoneal injections of heptaminol hydrochloride (hept‐a‐myl®) on a light‐dark discrimination task in a Y‐maze using intracranial self‐stimulation (ICSS) in the lateral hypothalamus (LH) as reinforcement were studied in BALB/c mice. At the two doses injected (34.6 and 60 mg/kg) heptaminol facilitated the discrimination between the arm reinforced by LH stimulation and the neutral arm, during the acquisition and reversal phases of the task. However, mice injected with the dose of 34.6 mg/kg performed the best discrimination performance (i.e., made the lowest number of discrimination errors). Moreover, heptaminol greatly decreased the latency to initiate LH stimulation, whereas the latency to terminate it was not modified.

These results suggest that heptaminol (1) can be considered as a cognitive enhancing agent which is able to improve the discrimination performance whatever the complexity of the learning task and (2) modulates the activity of certain neuronal mechanisms involved in ICSS regulation.
Evidence for a unique interaction of loreclezole with the GABA receptor complex
Authors: Vaught Jeffry L. , Wauquier AlBert
Published: January 2005

The interaction of loreclezole (a structurally novel non‐benzodiazepine anticonvulsant), diazepam, phenobarbital sodium, and ethosuximide with the benzodiazepine antagonists β‐CCE, Ro 15‐1788, and CGS 8216 and the purine antagonist aminophylline were examined in the rat i.v. metrazol seizure test. The anticonvulsant activity of loreclezole was inhibited by β‐CCE and CGS 8216 but not by Ro 15‐1788 or aminophylline. The inhibition produced by CGS 8216 was dose dependent (ID50 = 0.04 mg/kg i.p. CGS 8216) and surmountable. When the interactions of the various antagonists with loreclezole were compared to those of diazepam, phenobarbital sodium, and ethosuximide, a clear differentiation of activity was evident. β‐CCE blocked the anticonvulsant activity of all four compounds whereas Ro 15‐1788 blocked only the anticonvulsant effects of diazepam. CGS 8216 blocked the anticonvulsant effects of diazepam and loreclezole in a similar manner while being much less effective against the anticonvulsant effects of ethosuximide and ineffective against phenobarbital sodium. Aminophylline blocked the anticonvulsant effects of only ethosuximide. Based on these data and the anticonvulsant profile of loreclezole, we suggest that loreclezole represents a new class of agents which modulate GABAergic transmission via a unique interaction with the GABA receptor complex.
Marine products as a source of antiviral drug leads
Authors: Che Chun‐Tao
Published: January 2005

A survey is presented of the occurrence of organic compounds from aquatic organisms that have been reported to have antiviral activities. Studies of the chemical structures and antiviral properties of unusual metabolic products of aquatic life have demonstrated that marine organisms offer excellent prospects in the search for antiviral drugs.
Effects of Ginkgolide B and Ginkgo biloba extract on local cerebral glucose utilization in the awake adult rat
Authors: Lamour Yvon , Holloway Harold W. , Rapoport Stanley I. , Soncrant Timothy T.
Published: January 2005

The effects of the extract of the leaves of Ginkgo biloba and of one of its major components, Ginkgolide B, on local cerebral glucose utilization (LCGU) have been studied in the awake adult rat. Ginkgolide B (10 mg/kg i.p.) had no significant effect on LCGU in 38 brain regions studied. In contrast, the Ginkgo biloba extract (150 mg/kg i.p. in 3 divided doses) produced significant and widespread decreases in LCGU in 21 brain regions (range 3–26% reduction). These results demonstrate that Ginkgo biloba is able to reduce brain glucose utilization, but that the substance responsible for this effect may not be Ginkgolide B.
Effect of fentanyl on the electrophysiological recovery following incomplete global cerebral ischemia
Authors: Vasthare Usha S. , Rubin Sharon , Riina Howard A. , Rosenwasser Robert H. , Carlsson Christer , Tuma Ronald F.
Published: January 2005

The effects of two commonly used doses of the opioid fentanyl (50 and 100 μg/kg) on the electrophysiological outcome following global cerebral ischemia were studied in rats. The somatosensory evoked responses (SSER) and EEG activity were utilized to assess neurophysiological outcome. Prior to ischemia, there was no difference in the latency of the cortical peak of the SSER between groups. During the ischemic period, SSER and EEG activity were abolished in both groups. During the reperfusion period, however, the cortical peak of the SSER returned within 30 min in the animals anesthetized with 50 μg/kg of fentanyl, whereas in the animals anesthetized with 100 μg/kg fentanyl the cortical peak did not return by 60 min. This suggests that the animals anesthetized with a high dose of fentanyl are more susceptible to ischemic damage and that a high dose of fentanyl may exacerbate neurological damage following an ischemic insult to the brain.
Subcortical arteriosclerotic encephalopathy (Binswanger's disease): Clinical observations and therapeutic implications
Authors: Bogucki Andrzej , Prusiński Antoni , Szymańska Róźa , Lorenc Józefa
Published: January 2005

Subcortical arteriosclerotic encephalopathy (SAE), or Binswanger's disease, is one of the forms of vascular dementia. In SAE arteriosclerotic changes affect subcortical arteries and arteroles. Atherosclerosis of large cerebral arteries is common among SAE patients. As dyslipoproteinemias are risk factors for atherosclerosis we studied blood lipids and lipoproteins in patients with clinical diagnosis of SAE. In 11 patients diagnosis of the disease was established on the basis of CT scans and clinical course consistent with SAE. In the studied group a tendency to increased total cholesterol and apolipoprotein B and to decreased HDL cholesterol (HDL‐CH) were found. The levels of LDL cholesterol (LDL‐CH) and the CH/HDL‐CH and HDL phospholipides/HDL‐CH ratios were significantly higher in SAE patients when compared to controls.
Cyclo(leu‐gly) reverses the permanent dopamine receptor up‐regulation induced by ovariectomy
Authors: Fields Jeremy Z. , Wichlinski Lawrence J. , Ritzmann Ronald F. , Drucker George E. , Gordon John H.
Published: January 2005

Several neuropsychiatric diseases, including tardive dyskinesia and schizophrenia, are thought to involve increased neurotransmission at dopaminergic synapses. Although many animal models of this dopaminergic hyperactivity have been studied, the ovariectomized (OVX) rat model, which we recently developed, appears to be unique. The brain D2 DA receptor up‐regulation (increases in receptor number) and the behavioral hypersensitivity to dopamine (DA) agonists that develop in this model after a few months appear to be permanent. Using this model, it is now possible to screen for agents that can reverse a permanent dopaminergic supersensitivity. In this report, we document such a reversal by cyclo(leu‐gly) (CLG), a dopaminergic neuromodulator, in the OVX model. Female Fisher rats were ovariectomized and allowed to recover for 3 months. Following a challenge dose of apomorphine (0.45 mg/kg, i.p.) OVX rats showed significantly more stereotypic sniffing (+ 175%) than sham controls. Following lower doses of APO (125 and 150 μ/kg, i.p.), OVX rats showed significantly more locomotor activity (+ 105 and + 365%). CLG (4 daily doses, 8 mg/kg, s.c.) reversed these hypersensitive responses. In parallel, OVX rats showed a significant increase (+ 35%) in [3H]‐spiroperidol binding (Bmax) in corpus striatum relative to sham rats; this dopamine receptor up‐regulation was also reversed by CLG. We conclude (1) that the long‐term OVX rat is useful for modelling the permanent or irreversible aspect of supersensitivity to DA; and (2) CLG may be useful in the treatment of dopaminergic diseases.
Histamine‐induced wheal, flare, and pruritus: Inhibition by cetirizine, terfenadine, and placebo
Authors: Coulie P. J. , Ghys L. , Rihoux J. P.
Published: January 2005

Twelve adult volunteers were enrolled in a four‐session, double‐blind, crossover, randomized study. On each session, two capsules were administered in the morning and contained the pulverised products of either placebo (P) + P, terfenadine (T) 60 (mg) +P, T 60 + T 60, or cetirizine (C) 10 + P. On the evening of each experimental day, two capsules were taken at 0800 pm either as P + P or as T 60 + P or as P + P, or as P + P. We thus have four groups called, respectively, placebo, terfenadine 60 bid, terfenadine 120, and cetirizine 10. Pricks (100 mg/ml histamine) were performed before drug intake and 5, 12, 17, and 24 hr after drug intake. Ten minutes after each prick, wheal areas were underlined and transfered onto a transparency to be measured later. One volunteer gave up the trial due to the appearance of a serious disease not related to the trial. Regarding initial wheals, cetirizine 10, terfenadine 60 bid, and terfenadine 120 significantly (P < 0.01) reduced the wheal at H5, H12, H17, and H24 (except NS at H17 for T120). At H5, H12, and H17, cetirizine 10, terfenadine 60 bid, and terfenadine 120 were significantly more potent than P (P < 0.03). At H24, only cetirizine 10 and terfenadine 60 bid were significantly more potent than placebo. Pairwise global comparison shows a significant difference (P = 0.03) in favour of cetirizine regarding terfenadine 120. Side effects under active drugs were not different from those under placebo.
Angiostatic cortexone‐heparin combination treatment suppresses chronic granulomatous inflammation in mice
Authors: Dunn Colin J. , Galinet Louise A.
Published: January 2005

Combined steroid‐heparin therapy has been shown to inhibit angiogenesis and tumor growth. We therefore decided to test the antiinflammatory activity of this combination therapy using “cotton pellet” and “delayed‐type hypersensitivity” granuloma reactions, which display a high degree of angiogenesis. Subcutaneous injection of cortexone (deoxycorticosterone) caused significant suppression of both granulomatous reactions only when administered to mice receiving heparin ad libitum in the drinking water. Significant reduction in inflammatory leukocyte infiltration and angiogenesis was also observed histologically compared with controls. Coretexone or heparin alone failed to alter the granulomatous responses. Hematomas were observed only in the cortexone‐heparin combination therapy group at the cortexone subcutaneous injection site suggesting a possible effect on endothelial cell integrity; blood coagulation times remained unaltered, and no evidence of hemorrhage was observed at autopsy. Modest loss in thymic weight occurred only in mice receiving cortexone (100 mg/kg/day s.c.), regardless of concomittant heparin treatment. We conclude that combination cortexone‐heparin treatment causes significant inhibition of chronic granulomatous inflammation, which is independent of glucocorticoid or coagulation mechanisms. Further investigation is required to determine whether this effect is accomplished via inhibition of macrophage function, endothelial cell proliferation, or interference with tissue matrix metabolism.
Cyclosporine uptake by cultured human proximal tubule cells
Authors: Kahng Myong Won , Lee Jung Young , Trifillis Anna L.
Published: January 2005

Characteristics of cyclosporine A (CsA) uptake in cultured normal human proximal tubule cells (PTC) have been studied. The uptake was very rapid, concentration dependent, and reached a steady state level within 10 min. Kinetic analysis yielded an apparent Km of 5.0 μM and Vmax of 66.7 pmoles/min μg DNA. Verapamil, a calcium channel blocker, at 0.1, 0.5, and 1.0 mM had no inhibitory effect on CsA uptake. Subcellular distribution of CsA following 1, 2, 5, and 10 min incubation of PTC suspension was determined by digitonin differential solubilization. The cytosol fraction contained 26% and the nuclear fraction contained 74% of CsA at all time periods studied. These studies demonstrate that in normal human renal PTC, uptake of CsA is rapid and saturable. Most of the CsA, once taken up by the human PTC, is concentrated in the nucleus.
Co‐mitogenic assay for assessing the effects of aflatoxin B1 on interleukin‐1 production in bovine macrophages
Authors: Walsh Catherine J. , Bodine Ashby B. , Scott Thomas R.
Published: January 2005

Previous research has shown that aflatoxin B1 (AFB1) markedly decreases the uptake of tritiated thymidine in bovine peripheral lymphocytes. Currently, the immunosuppressive activities of aflatoxin B1 are being investigated further using bovine macrophages as a model cell type. Polystyrene‐adhered macrophages demonstrated a 50% reduction in up‐take of tritiated thymidine at 10 μg/mL aflatoxin B1. The distribution of 3H‐AFB1 in bovine macrophages was investigated to study mechanisms by which AFB1 may be exerting immunosuppressive effects. Only 12.96% of the incorporated 3H‐AFB1 was taken into nuclear DNA, whereas 80.13% remained in the cytosolic fraction. A co‐mitogenic assay was developed to ascertain the correlation between reduced tritiated thymidine uptake, binding of 3H‐AFB1 to nuclear DNA, and interleukin‐1 (IL‐1) production and/or activity. Conditioned media containing interleukin‐1 activity was prepared by culturing macrophages for 24 hr with 2.5 μg/mL lipopolysaccharide, 45 ng/mL phorbol myristate acetate, with or without 10 μg/mL aflatoxin B1. The conditioned media was used in a co‐mitogenic assay with calf thymocytes as target cells. In this assay, the response of calf thymocytes to conditioned media from AFB1‐treated cells did not differ from the response to control conditioned media. In addition, AFB1 added to thymocyte cultures co‐stimulated with conditioned media and concanavalin A (ConA) greatly diminished the thymocyte response to co‐stimulation. The data support the conclusions that the immunosuppressive effects of AFB1 on the bovine macrophage and T lymphocyte may not be directly related via impaired IL‐1 production. The blinding of AFB1 to macrophage DNA was not sufficient to produce any detectable effect on interleukin‐1 production by bovine macrophages.
Effects of a low‐doses treatment with cuprum on neostigmine digestive action in female mice
Authors: Santini R. , Tessier M. , Belon P.
Published: January 2005

A low‐doses treatment with cuprum 4CH, 24 and 5 hr before neostigmine (50 μg/kg/IP) administration, has been done in the female mouse. This treatment significanlty reduces (Kruskal‐Wallis—P < 0.02) the facilitating action of neostigmine on intestinal transit. Cuprum 4CH treatment administered alone has no significant effect on transit.
Functional link between myocardial α1‐ and β1‐adrenoceptors in neonatal rabbits
Authors: Varma Daya R.
Published: January 2005

Ontogeny of inotropic responses of the left atria and chronotropic responses of the right atria of rabbits was studied in vitro. The maximal inotropic effect (efficacy) of isoproterenol on atria from neonatal (1.5 weeks old) rabbits was significantly less than that of norepinephrine and epinephrine. The inotropic efficacy of isoproterenol increased with age and reached adult levels at 6 weeks. There was no difference in the potency and efficacy of inotropic effects of epinephrine and norepinephrine on neonatal and adult (∼40 weeks old) rabbit atria. At threshold concentrations, phenylephrine synergistically potentiated the inotropic effects of isoproterenol on atria from neonatal but not on atria from adult rabbits. The potentiation of the inotropic effects of isoproterenol by phenylephrine on neonatal rabbit atria was abolished by prazosin. There was no difference in the chronotropic effects of isoproterenol on atria from neonatal and adult rabbits. It is speculated that α1‐ and β1‐myocardial adrenoceptors are functionally linked in early life and a full expression of inotropic responses requires a concomitant activation of both receptor types.
Comparative effects of linogliride fumarate and tolbutamide sodium on insulin secretion and glucose utilization in rat pancreatic islets
Authors: Tuman Robert W. , Morris David M. , Bryan Debra J. , Wallace Nathanial H. , Voina Sandra J. , Bowden Charles R. , Tutwiler Gene F.
Published: January 2005

The effects of linogliride fumarate (0.1 mmol/liter) and tolbutamide sodium (0.5 mmol/liter) on insulin secretion and glucose utilzation were directly compared in isolated perifused rat islets. Both compounds potentiated glucose‐primed (5.5 mmol/liter) insulin release. The insulin secretory response at the concentration chosen was qualitatively different for the two agents. In the presence of glucose, the insulin secretory effect of tolbutamide was biphasic, whereas linoglirde predominantly increased second‐phase insulin secretion. In the absence of exogenous glucos, tolbutamide stimulated first‐phase insulin release wherease linogliride was ineffective without glucose in the perifusion medium. Neither linogliride (0.1 mmol/liter) nor tolbutamide (0.5 mmol/liter) stimulated islet cell glucose usage as measured by conversion of [5−3H]‐glucose to 3H2O. The insulin secretagogue effect of linogliride was completely abolished when islet cell glucose usage was partially blocked (22% reduction) by mannoheptulose (MH) (10 mmol/liter). When glucose usage was significantly inhibited (55%) by 2‐deoxyglucose (2DG) (10 mmol/liter), linogliride‐stimulated insulin secretion was not significantly reduced. In contrast, tolbutamide‐stimulated first‐phase insulin release was not inhibited when glucose usage was reduced by either MH or 2‐DG, wherease secondphase insulin release was significantly inhibited. In summary, linogliride potentiates insulin secretion in isolated islets by a glucose‐dependent process, but with a kinetic profile and response to metabolic inhibitors different from that of tolbutamide.
L‐683,877: Pharmacological profile of a novel 5‐HT3 receptor antagonist
Authors: Tattersall David , Newberry Nigel , Beer Margaret S. , Rigby Mike , Gilbert Michael , Maguire Janet J. , Mudunkotuwa Nikki , Duchnowski Mark , McKnight Alexander T. , Swain Christopher J. , Kneen Clare , Dourish Colin T.
Published: January 2005

The 5‐HT3 receptor antagonist properties of the novel compound L‐683,877 (−) (2′‐(1‐methyl‐1H‐indol‐3‐yl)‐)spiro(1‐azabicyclo[2.2.2]octane‐3,5′(4′H)‐oxazole) have been characterised in vitro and in vivo. In radioligand binding studies, L‐683,877 displaced [3H]quaternized ICS 205–930 binding to membranes of rat cortex with a pKi of 8.71. L‐683,877 was essentially inactive (pKi<5) at 5‐HT1A, 5‐HT1B, 5‐HT1C, 5‐HT1D, 5‐HT2, and dopamine D1 and D2 binding sites. In the rat isolated vagus nerve and superior cervical ganglion (SCG) preparations, L‐683,877 antagonized 5‐HT3 agonist‐induced depolarizations with apparent pKB values of 9.30 and 8.25, respectively. Similarly L‐683,877 antagonized the positive chronotropic effects of 5‐HT in the isolated rabbit heart preparation (apparent pKB 10.10). In the anaesthetized rat, L‐683,877 (10–100 μg kg−1 i.v.) antagonized the Bezold Jarisch reflex evoked by 5‐HT; at a dose of 10 μg kg−1 i.v. L‐683,877 caused a twofold shift in the dose response curve. The retching and vomiting response induced in the ferret by cisplatin (10 mg kg−1 i.v.), was markedly attenuated by L‐683,877 (0.1 mg kg−1 i.v. and p.o.) and completely prevented by higher doses (10 mg kg−1 i.v. and p.o.). These data indicate that L‐683,877 is a potent and selective 5‐HT3 receptor antagonist.
Evaluation of the discriminative stimulus effects of venlafaxine, a potential antidepressant, in rhesus monkeys
Authors: Nader Michael A. , Woolverton William L.
Published: January 2005

The discriminative stimulus effects of the novel antidepressant venlafaxine were examined in rhesus monkeys. Separate groups of monkeys discriminated either 0.56 or 1.0 mg/kg (i.g.) d‐amphetamine (N = 3) or 10 mg/kg (i.g.) pentobarbital (N = 4) from saline, in a discrete‐trials shock avoidance/escape paradigm. In d‐amphetamine‐trained monkeys, 10–17 mg/kg venlafaxine occasioned only saline‐appropriate responding and had minimal effect on response latency in alll monkeys. The highest dose of venlafaxine tested (30 mg/kg) occasioned at least 95% d‐amphetamine‐lever responding in two of three monkeys. Following this dose, the average latency to respond after the onset of a trial increased substantially in both monkeys; in one monkey avoidance responding was disrupted and shocks were occasionally received. In the third monkey, 30 mg/kg venlafaxine occasioned only saline‐lever responding and had no effect on response latency. In pentobarbital‐trained monkeys, venlafaxine (3.0–30 mg/kg) occasioned primarily saline‐lever responding and these doses had minimal effects on response latency. In general, venlafaxine was more potent in d‐amphetamine‐trained monkeys than in pentobarbital‐trained monkeys in its effects on response latency. Drug discrimination procedures in animals have been shown to differentiate compunds in a manner that is consistent with their subjective effects. Thus, result from the present experiment suggest that venlafaxine may produce subjective effects similar to d‐amphetamine in some individuals, but only at high doses.
Natriuretic and diuretic effects of cicletanine in conscious, hydrated, normotensive rats
Authors: Buchholz R. Allan , Brousseau Armand , Silver Paul J.
Published: January 2005

The natriuretic and diuretic actions of cicletanine, a novel agent with vasorelaxant and antihypertensive properties, were examined in conscious, hydrated, normotensive rats. Cicletanine, the (+)‐ and (−)‐enantiomers of cicletanine, hydrochlorothiazide (HCTZ), or vehicle(s) were administered orally or intravenously (1, 3, 10, 30 mg base/kg) to water‐loaded (27 ml/kg) rats and 3 hr urine volume, Na+ and K+ were measured. Racemic cicletanine (3 mg/Kg, p.o.) caused a significant increase in urinary Na+(+174%) and K+ (+46%) excretion, unaccompanied by diuresis. Diuresis was detected only with larger oral doses of racemic cicletanine (10–30 mg/kg). Oral administration of a 1‐mg/kg dose of (+)‐cicletanine caused significant natriuresis that was not detected with either racemic or (−)‐cicletanine. The (+)‐enantiomer (3–30 mg/kg) produced natriuresis and diuresis quantitatively similar to that of racemic cicletanine. By contrast, (−)‐cicletanine induced only slight natriuresis, kaliuresis, and diuresis upon administration of the largest dose (30 mg/kg, p.o.). Intravenous administration of the racemate and enantiomers of cicletanine caused natriuretic/diuretic activity that was very similar to that seen with oral administration. The natriuresis caused by a 3‐mg/kg dose of racemic cicletanine was unaffected by indomethacin. However, indomethacin attenuated the natriuresis and eliminated the diuresis produced by the 10‐ and 30‐mg/kg doses of cicletanine. Indomethacin had no effect on the kaliuretic actions of cicletanine. Indomethacin blunted the natriuresis and eliminated the diuresis caused by all doses of HCTZ. In conclusion, the natriuretic, kaliuretic, and diuretic effects of racemic cicletanine in the conscious, hydrated, normotensive rat appear to be mediated primarily by the ( + )‐enantiomer. A dose‐dependent separation exists between the natriuretic and diuretic actions of cicletanine, with only natriuresis noted at smaller doses. The natriuresis caused by racemic cicletanine has both indomethacin‐resistant and indomethacin‐sensitive components, while cicletanine‐induced diuresis appears to be mediated exclusively by prostaglandins.
Novel low‐molecular‐weight superoxide dismutase mimic deferoxamine‐manganese improves survival following hemorrhagic and endotoxic shock
Authors: De Garavilla Lawrence , Chermak Timothy , Valentine Heather L. , Hanson Robert C.
Published: January 2005

The purpose of this study was to demonstrate the in vivo activity of the novel low‐molecular‐weight superoxide dismutase (SOD)‐mimic deferoxamine‐manganese (Def‐Mn) in models of circulatory shock. Two forms of Def‐Mn were examined: the pink‐complex (NPC 14550) and the green complex (NPC 15823). Hemorrhagic shock was induced in rats (40 mmHg, 60 min) followed by autotransfusion of shed blood, and endotoxic shock (LPS, 200 μg/10g BW) was induced in mice. Significant lethality (ca. 20% survival rate at 24 hr) was observed in each model. Following hemorrhagic shock, NPC 14550 (10 mg/kg) increased the 24‐hr survival rate to 48% (P=0.03), while NPC 15823 (10 mg/kg) did not significantly alter survival rate (30%, P > 0.05). Following endotoxin challenge, both NPC 14550 and NPC 15823 significantly improved the 24‐hr survival rate to 68% (P≤0.001) and 55% (P=0.002), respectively. Bovine erythrocyte SOD and polyethylene glycol‐SOD (Peg‐SOD) also afforded significant protection in these models and, as anticipated, SOD afforded transient protection, while Peg‐SOD provided significant protection for 24 hr and longer. Deferoxamine mesylate provided only transient protection. It is concluded that the SOD‐mimic Def‐Mn has beneficial effects following circulatory shock and, furthermore, these data provide additional evidence that the superoxide radical does play a role in these disorders.
Overview of the CNS pharmacology of BW 1370U87: A chemically novel, reversible, selective MAO‐A inhibitor with potential to be a new antidepressant drug
Authors: Cooper B. R. , White H. L. , Beek O. , Norton R. M. , Rigdon G. C. , Howard J. L. , Kraemer G. W. , Ferris R. M.
Published: January 2005

BW 1370U87 is a potent, reversible, selective inhibitor of rat and human brain MAO‐A with a competitive mechanism of action. The ED50 of BW 1370U87 for inhibition of MAO‐A in rat brain is 8 mg/kg after oral administration, and the duration of action exceeds 7 hr. The ED80 dose for inhibition of MAO‐A (20 mg/kg) elevates NE, DA, and 5‐HT levels in brains of rats without significantly potentiating the blood pressure effects of a 15 mg/kg oral dose of tyramine. This dose of tyramine, extrapolated to man, exceeds the amount that could be consumed at one time from dietary sources. No inhibition of MAO‐B has been observed with BW 1370U87 either in vitro or ex vivo. BW 1370U87 was effective in the 5‐hydroxytryptophan potentiation test over the dose range that produced MAO‐A inhibition in brain in both rats and mice, and it reduced swim stress induced immobility in the Porsolt test. The compound has positive effects on abnormal social behavior produced by early social deprivation in the rhesus monkey. BW 1370U87 had no adverse cardiovascular effects in dogs or rats. It also had no significant pharmacological effects on various isolated tissue preparations and did not cause changes in the neuronal transport or the receptor systems which mediate the antidepressant effects or side effects of the tricyclic antidepressants. An acute oral dose 100 times that which produced an 80% inhibition of brain MAO‐A exhibited no signs of toxicity. BW 137OU87 appears to be a safe reversible MAO‐A inhibitor with potential for treating depression, anxiety conditions, panic, phobias, obsessive compulsive behaviors, and borderline personality disorders.
BW 1370U87, a new monoamine oxidase‐A inhibitor: Effects on biogenic amine neurotransmitter and metabolite levels in rat brain
Authors: Jones‐Humble Stacey A. , Norton Ron M. , White Helen L. , Cooper Barrett R.
Published: January 2005

Monoamine oxidase (MAO) inhibitors increase brain concentrations of biogenic amines and decrease concentrations of the acidic metabolites of biogenic amines. It has been suggested that the magnitude of these effects is an indicator of MAO inhibition. Oral doses of BW 1370U87, moclobemide, and brofaromine were given to rats at doses previously shown to induce brain MAO‐A inhibition by at least 80%. The effects on brain biogenic amines and their metabolites were quantified 2 and 4 hr after oral dosing using HPLC with electrochemical detection. Moclobemide and BW 1370U87 induced larger increases in 5HT, NE, and DA and larger decreases in DOPAC, 5HIAA, and HVA than did brofaromine at the doses tested. At 8 hr post‐dose the effects of BW 1370U87 on 5HT, NE, DOPAC, and HVA were still significant (P≤0.05), and the time course was similar to that seen following moclobemide and brofaromine treatment. Only BW 1370U87 increased brain concentrations of biogenic amines at a dose that does not significantly potentiate pressor effects of orally administered tyramine.
Potentiation of the behavioral effects of 5‐hydroxytryptophan by BW 1370U87, a selective monoamine oxidase‐A inhibitor
Authors: Burchall Christopher J. , Soroko Francis E. , Rigdon Greg C.
Published: January 2005

BW 1370U87, a novel, selective, reversible monoamine oxidase‐A inhibitor, was tested in the 5‐HTP (5‐hydroxytryptophan) potentiation test in mice and rats to establish its activity following systemic administration, to determine its duration of action and to determine if its effects were reversible in vivo. The behavioral effects of a threshold dose of 5‐HTP were potentiated by BW 1370U87 in mice with ED50s of 3.4 mg/kg i.p. and 18.4 mg/kg p.o. 5‐HTP potentiation occurred in rats with an ED50 of 10.4 mg/kg p.o. BW 1370U87 (20 mg/kg) was active 9 hr, but not 16 hr following oral administration, consistent with reversible enzyme inhibition.
Metabolism of BW 1370U87 in rat, dog, and man
Authors: Harrelson Jane Croft , Johnson Thomas E. , White Helen L. , Welch Richard M.
Published: January 2005

BW 1370U87 is a potent, selective inhibitor of rat and human brain MAO‐A. The plasma concentrations of BW 1370U87 and its metabolites were determined in rat, dog, and man. After an oral dose, BW 1370U87 undergoes extensive first‐pass metabolism in all species studied. The 1‐(1,2, dihydroxyethyl) metabolite, BW 1003U88, was a major metabolite in rat, dog, and human plasma. The 1‐(1‐hydroxyethyl) metabolite, BW 183U88, was a major metabolite in dog plasma, whereas it was present in much lower concentrations in the rat and man. Both BW 1003U88 and BW 183U88 are active MAO‐A inhibitors although not as active as the parent compound. The inactive 1‐(2‐acetic acid) metabolite, BW 1552U88, was a major metabolite in rat plasma but a minor metabolite in the dog. Plasma concentration versus time profiles in both rat and man suggest that the metabolites undergo enterohepatic recycling. Although plasma concentrations of BW 1370U87 were relatively low compared to the metabolites, the concentrations detected in rat and man after a 50 mg/kg or 400 mg oral dose, respectively, exceeded the IC50 value measured in rat and human brain. Furthermore, the time course of MAO‐A inhibition appears to follow the plasma concentration versus time profile of BW 1370U87 in the rat. Preliminary experiments in rats indicate that BW 1370U87 and its metabolites distribute into brain and inhibit MAO‐A.
Effects of L‐alpha‐glycerylphosphorylcholine on the EEG power spectrum in the rat
Authors: Lacomba Corrado , Cagiano Raffaele , Maci Oronzo , Valerio Jaqueline , Cuomo Vincenzo
Published: January 2005

The effects of L‐alpha‐glycerylphosphorylcholine (alpha‐GPC), a putative acetylcholine precursor, on the EEG power spetrum in rats were investigated. The results show that the oral administration of alpha‐GPC (100–300–600 mg/kg) induced a significant decrease in absolute spectral energy in the delta frequency band. A significant increase in absolute spectral energy in the beta frequency band was elicited by alpha‐GPC at dose levels of 100 and 300 mg/kg, while the administration of a higher dose (600 mg/kg) of this compound resulted in the loss of response (bell‐shaped dose‐response curve). No significant changes in the EEG power spectrum were found in rats treated with phosphatidylcholine (PC).

The present data, suggesting that the electrocorticographic (ECoG) activation elicited by alpha‐GPC may be correlated with its stimulatory effect on brain acetylcholine release, further extend the pharmacological profile of this new cognition enhancer. © 1992 Wiley‐Liss, Inc.