bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vascular and platelet pharmacology of 2‐camphanone, a new drug for the treatment of hemorrhoids
Authors: Wang Mintao , Xie Jianming , Greenberg Stanley S. , Longnecker Gesina 
Published: January 2005

Abstract2‐Camphanone (Alphanon ®) is under clinical evaluation for the treatment of hemorrhoids. This study examined the effect of 2‐camphanone on three parameters affecting hemorrhoidal distention: portal venous blood flow, vascular smooth muscle tone, and aggregation of human platelets. Mongrel dogs (10–18 kg) of either sex were anesthetized with pentobarbital sodium (35 mg/kg, i.v.) and instrumented for doppler measurment of portal vein and and fermoral artery blood flow velocity using a closed‐chest, spontaneusly breathing preparation. Intravenous. (i.v.) administration of 2‐camphanone (0.01, 0.03, 0.1, 0.3, and 0.6 mg/kg) or transdermal administration of 6 mg of 2‐camphanone selectively increased portal venous blood flow velocity by 13–31% above pre‐drug control values. 2‐Camphanone (0.1 to 100 μM) produced endothelium‐dependent relaxation of canine portal‐mesenteric (MV) and portal veins (PV), but not mesenteric arteries (MA), pre‐contracted with an EC50 concentration of norepinephrine (NE). 2‐Camphanone also inhibited acetylcholine‐induced contraction of MV but did not affect the contraction of the MV to NE, nerve stimulation, or KCl. The inhibitory effect of 2‐camphanone was not stereo‐sepcific but resided in both the (+) and (−)isomers. 2‐camphanone (up to 1 mM) did not affect platelet aggregation produced by ADP, collagen, or arachidonic acid, but inhibited epinephrine‐induced aggregation. The results show that 2‐camphanone increases portal venous blood flow velocity. 2‐Camphanone is effective by the i.v. and transdermal routes of administration. The effect may be mediated by substances released from the venous endothelium. Speculatively, this may reflect a free radical scavenging or anti‐oxidant effect of 2‐camphanone. This may be aided, in part, by camphanone‐induced inhibition of epinephrine‐mediated release of plateletderived venous stimulants during the stressful hemorrhoidal episodes.
Novel effects of memantine in antagonizing acute aldicarb toxicity: Mechanistic and applied considerations
Authors: Gupta Ramesh C. , Kadel Wade L. 
Published: January 2005

AbstractAdministration of a single sublethal dose of aldicarb (0.4 mg/kg, i.p.) to male Sprague‐Dawley rats produced the onset of hypercholinergic signs within 3–5 min. With increasing intensity the most severe signs, predominantly involving the peripheral nervous system (muscle fasciculations and convulsions), were evident within 15–30 min and lasted for about 90 min. Rats dosed with 0.1 mg/kg, i.p. did not develop intoxication while those dosed with 0.2 mg/kg, i.p. exhibited signs of moderate toxicity. A dosage of 0.6 mg/kg was found to be the minimal lethal dose (MLD). The inhibition of acetylcholinesterase (AChE) and carboxylesterase (CarbE) was dose‐depedent. Significant (P<0.01) inhibition in the activities of AChE and CarbE occured as early as within 15 min, and the maximal effect within 30 min. Time course of CarbE activity revealed marked inhibition in different neuronal and nonenuronal tissues, suggesting tremedous nonspecific binding of aldicarb. Prophylaxis with memantine HCl (18 mg/kg, i.p.) and atropine sulfate (16 mg/kg, i.p.) 30 min and 15 min, respectively, prior to aldicarb (0.4 mg/kg), provided compelte protection. Therapeutic administration of these two antidotes in combination also completely reversed the clinical signs of intoxication. It is suggested that memantine antagonized the aldicarb acute toxicity by protection/reactivation of activities of AChE and CarbE and reversible blockade of hyperneuromuscular transmission, in addition to muscarinic ACh receptor blockade by atropine.
Pharmacological characterization of the Raji lymphoblast platelet‐activating factor receptor
Authors: Travers Jeffrey B. , Li Qian , Fertel Richard H. 
Published: January 2005

AbstractPrevious studies in our laboratory have described the presence of high‐affinity plateletactivating factor (PAF) binding sites on the B lymphoblast cell line, Raji. In the present study, PAF receptor antagonists were used to examine the specificity of [3H]PAF binding and PAF‐induced intracellular calcium mobilization in this human lymphocyte cell line. In binding studies conducted at 4°C, PAF receptor antagonists competed with [3H]PAF for binding to Raji lymphocytes with the following rank order of potency: Ro 19‐3704 ∼ CV‐6209 > CV‐3988 > BN52021 > alprazolam. This order of potency is similar to those described for binding studies in platelets and neutrophils. The PAF receptor antagonists CV‐6209 and alprazolam inhibited the PAF‐induced calcium changes and PAF binding with similar potencies, indicating that the high‐affinity PAF binding sites are functional receptors coupled to calcium mobilization. The calcium channel antagonists verapamil, diltizem, and nimodipine inhibited Raji lymphoblast PAF binding with similar potencies, but had no effect on PAF‐induced intracellular calcium changes, suggesting the possibility that these compounds are not true competitive antagonists. These studies provide evidence that the Raji lymphoblast PAF receptor is pharmacologically similar to PAF receptors found on platelets and neutrophils, and thus could be of use as a model system to study the PAF receptor.
Stimulation of phosphoinositide hydrolysis by ibotenic acid in cerebellar neurons via two glutamate receptor subtypes
Authors: Raulli Robert , Wroblewski Jarda T. 
Published: January 2005

AbstractIn primary cultures of cerebellar granule cells, ibotenate produced a dose‐dependent biphasic stimulation of phosphoinositide (PI) hydrolysis. The high‐affinity component of ibotnate action (EC50 = 100 nM) was characteristic of the metabolotropic glutamate receptor activation. The action of ibotenate, like that of quisqualate, was inhibited by pretreatment of granule cells with pertussis toxin, confirming the participation of a guanosine triphosphate (GTP)‐binding protein in ibotenate signal transduction. In contrast, the low‐affinity component of ibotenate‐stimulated PI hydrolysis (EC50 = 100 μM) exhibited the pharmacology of the N‐methyl‐D‐aspartate (NMDA) receptor. This action was inhibited by NMDA receptor antagonists 3‐(2‐carboxy‐piperazin‐4‐yl)propyl‐1‐phosphonic acid (CPP) and (+)5‐methyl‐10, 11‐dihydro‐5H‐dibenzocyclohepten‐5, 10‐imine maleate (MK‐801) and was potentiated by glycine. Moreover it was inhibited by 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX), acting as an antagonist at the positive modulatory site of the NMDA receptor. The low‐affinity component of ibotenate‐induced Pl hydrolysis correlated well with the ability of ibotenate to induced 45Ca2+ influx, confirming the action of ibotenate at the ionotropic NMDA receptor. Thus, in cerebellar granule cells, ibotenate appears to stimulate Pl hydrolysis by acting at two distinct glutamate receptor subtypes.
A comparison of the potency and specificity of the direct muscle relaxant activity of azumolene and dantrolene
Authors: Dhillon Daljit S. , Pong Schwe F. , Moorehead Thomas J. 
Published: January 2005

AbstractDantrolene is a unique directly acting skeletal muscle relaxant that is clinically useful in the treatment of chronic muscle spasticity and malignant hyperthermia. Azumolene is a new dantrolene‐like drug that has better aqueous solubility and that may also be of use in the treatment of acute muscle spasm. Potency of both compounds was determined in the anesthetized, curarized rat gastrocnemius (using different routes of administration) and the isolated chick biventer muscle preparations. The specificity of effects in vitro was evaluated by comparing effects in the chick biventer with those seen in the rat aortic strip. Route of administration governed potency for both drugs, with rank order i.v., i.p., and i.d. being the least potent. In vivo, dantrolene was approximately twice as potent as azumolene when administered by any of the routes tested. However, both drugs are equipotent in vitro. Reasons for the discrepancy between in vivo and in vitro potencies are discussed. The muscle relaxant effects of both azumolene and dantrolene are specific for skeletal muscle, being 10‐fold more potent in skeletal than in arterial smooth muscle. The reasons for this specificity are probably due to basic differences in the physiology of smooth and skeletal muscle. We conclude that the new agent, azumolene, is a specific, potent skeletal muscle relaxant with properties qualitatively similar to those of dantrolene.
Additive and superadditive vasodilating combinations of diltiazem and glyceryl trinitrate in isolated rabbit aorta
Authors: Freeman Keith A. , Bove Alfred A. , Tallarida Ronald J. 
Published: January 2005

AbstractThe combined use of two drugs with overtly similar action is a common therapeutic strategy. Combinations in doses that produce synergism are frequently sought. In this study, we examined the vasodilating action of diltiazem (DIL) and glyceryl trinitrate (GTN), tested in several fixed‐ratio combinations on an isolated preparation of the rabbit aorta. This pair of drugs, widely used clinically, exhibited significant superadditivity (synergism) in certain fixed‐ratio combinations tested, i.e., 30:1 and 100:1 of DIL:GTN (based on weight), and only simple additivity in other dose ratios, 1:15, 1:1, and 15:1. A demonstration of synergism requires that the total dose of the mixture needed to produce a level of effect be significantly less than the theoretically additive dose calculated; hence, statistical confidence limits of the additive value are needed. Testing of this nature has been limited for statistical reasons to drug combinations that produce parallel regressions of effect on log (dose). In this paper we illustrate the application of new statistical methodology that permits testing of drug combinations that produce nonparallel assays and report our experimental findings, which show that only certain fixed‐ratio combinations of DIL and GTN are superadditive (synergistic) in this test. Although vasodilation alone does not imply antianginal action, these findings may serve as a guide for further clinical testing.
Effects of the antidepressant compound nefazodone on central monoaminergic neuronal discharge in rats
Authors: Vandermaelen Cam P. , Braselton John P. 
Published: January 2005

AbstractThe effects of i.v. administration of the antidepressant compound nefazodone were assessed on the firing rates of spontaneously active noradrenergic neurons in the locus coeruleus (LC), serotonergic neurons in the dorsal raphe (DR), and dopaminergic neurons in the substantia nigra (SN) of chloral hydrate anesthetized male albino adult rats, utilizing extracellular single‐unit recording methods. Nefazodone, tested in doses of 0.1–10.0 mg/kg, had variable effects on LC neurons, but the predominant effect was a mild excitation of firing (ED25 = 1.953 mg/kg). This may in part be caused by the 5‐HT2 antagonist properties of the compound, since ritanserin also produced a mild excitation of LC neurons. By comparison, desipramine very reliably inhibited LC neurons (ED50 = 0.333 mg/kg, i.v.). For DR neurons, i.v. nefazodone (0.1–3.2 mg/kg) produced variable effects, with inhibition being the most common (63% of cases tested). The ED25 for inhibition was 1.230 mg/kg, and in no case was inhibition of 50% or greater observed. By comparison, clomipramine very reliably inhibited DR neurons (ED50 = 0.501 mg/kg, i.v.). For SN neurons, the effects of i.v. nefazodone were also variable, with no consistent effects observed. These results indicate that acute nefazodone produces relatively weak effects on monoaminergic neuronal impulse flow in anesthetized rats, and suggest that major modifications of monoaminergic neuronal impulse flow probably do not play an important role in any neuroadaptive changes that may contribute to the clinical antidepressant actions of nefazodone.
Comparative effects of valproate, anxiolytic, or anxiogenic drugs on the light/dark aversion test
Authors: De Angelis Luisa 
Published: January 2005

AbstractThe potential anxiolytic‐like effects of 200, 300, and 400 mg/kg i.p. of sodium valproate were evaluated in the light/dark aversion test in mice. For comparison, we included the reference anxiolytic drug, diazepam (2.5, 5.0, 10 mg/kg i.p.) as well as putative anxiolytics, i.e., clonidine (0.015, 0.030, 0.060 mg/kg i.p.), verapamil (5, 10, 20 mg/kg i.p.), or anxiogenic drugs, pentylenetetrazol (5, 10, 15 mg/kg i.p.).Results showed that control mice preferred the dark compartment where they spent approximately 70% of their time. After administration of 5 and 10 mg/kg i.p. of diazepam or 400 mg/kg i.p. of valproate, the increase in exploratory behavior in the lit area was associated with an increase both in the number of transitions and in the time spent in the lit area. Pretreatment with 0.030 and 0.060 mg/kg i.p. clonidine caused an increase in the time spent in the lit area. Verapamil had no significant effect on both measures of this test. Pentylenetetrazol, in doses which did not cause convulsions, was anxiogenic.In conclusion, these results in the light/dark aversion test are consistent with clinical data showing that valproate, a GABA‐agonist, and clonidine, an α2 adrenoceptor agonist, possess anxiolytic properties. © 1992 Wiley‐Liss, Inc.
S 14506: A novel, potent, high‐efficacy 5‐HT1A agonist and potential anxiolytic agent
Authors: Colpaert Francis C. , Koek Wouter , Lehmann John , Rivet Jean‐Michel , Lejeune Françoise , Canton Hervé , Bervoets Karin , Millan Mark J. , Laubie Michel , Lavielle Gilbert 
Published: January 2005

AbstractThe studies characterized the newly discovered 7‐methoxy naphtylpiperazine S 14506 and examined the possible relationship between the apparent in vivo efficacy of 5‐HT1A ligands and the magnitude of their anxiolytic potential. In vitro radioligand binding studies indicated S 14506 to bind with high affinity and in an apparently competitive manner to 5‐HT1A sites, while having much less affinity for other 5‐HT binding sites. S 14506 demonstrated exceptional anxiolytic potential in the pigeon conflict procedure; the magnitude of its effects exceeded that of the other 5‐HT1A ligands 8‐hydroxy‐2‐(n‐propylamino) tetralin (8‐OH‐DPAT), (+)‐flesinoxan, buspirone, and BMY 7378. The anticonflict action of S 14506 was antagonized by the 5‐HT1A antagonist (–)‐alprenolol. Like the prototypical 5‐HT1A agonist 8‐OH‐DPAT, S 14506 induced forepaw treading, hypothermia and spontaneous tail flicks, antagonized morphine‐induced analgesia, and produced stimulus generalization in rats discriminating 8‐OH‐DPAT from saline. The apparent in vivo efficacy of the 5‐HT1A ligands in stimulating corticosterone release varied as follows: S 14506 > 8‐OH‐DPAT > (+)‐flesinoxan > buspirone > BMY 7378. This rank order corresponded with the rank order of magnitude of the anxiolytic action which the same compounds produced in the pigeon conflict procedure. The rank order of in vivo potency of these compounds in producing 5‐HT1A agonist actions in rodents. (i.e., S 14506) > 8‐OH‐DPAT > (+)‐flesinoxan > bus‐pirone > BMY 7378) also corresponded with their rank order of potency in producing anticonflict effects. The data characterize S 14506 as an extremely potent, orally active, high‐efficacy agonist at 5‐HTl1A receptors that demonstrates exceptional anxiolytic potential in the pigeon conflict procedure. The results provide strong evidence that the activation of central nervous system (CNS) 5‐HT1A receptors yields marked anticonflict effects and that the anxiolytic potential of 5‐HT1A ligands is proportional to their efficacy at 5‐HT1A re‐ceptors. © 1992 Wiley‐Liss, Inc.
Anti‐Inflammatory activity of 11β‐hydroxypregna‐1,4‐diene‐3,20‐dione
Authors: Rondinone Cristina M. , Schillaci Roxana , Roldán Alicia 
Published: January 2005

AbstractThis work demonstrates that in acute and chronic injectable treatments, as well as in topical application, ΔHOP is efficient as an anti‐inflammatory drug, equivalent to dexamethasone on carrageenan‐induced edema of rat paws and on croton oil‐induced ear inflammation. The difference between both steroids resides in the low potency of ΔHOP, since 60 times higher doses of ΔHOP are needed to achieve pharmacological effects similar to dexamethasone. However, even at these high doses ΔHOP, unlike glucocorticoids, did not decrease thymus nor adrenal weight although increasing liver glycogen deposition. © 1992 Wiley‐Liss, Inc.
Effect of fenoldopam prodrug, SK&F R‐105058, on renal function in rats
Authors: Sakamoto Takashi , Lokhandwala Mustafa F. 
Published: January 2005

AbstractRecent development of and studies on fenoldopam prodrugs have shown their prolonged hemodynamic effects. This study was carried out in order to examine the effect of a fenoldopam prodrug on renal function in rats. In the present study we administered SK&F R‐105058, the 4′,7,8‐tris‐N‐ethyl carbamate ester of R‐fenoldopam, at a dose of 30 μg/kg/min intravenously to the anesthetized rats. This prodrug produced long‐lasting increases in water and sodium excretion after termination of the 30‐min drug infusion with minimum changes in hemodynamic parameters. The diuresis and natriuresis were attenuated in the presence of a selective DA1 receptor antagonist SCH 23390. Therefore, it is suggested that production of fenoldopam from its precursor drug SK&F R‐105058 caused these prolonged renal effects, which were mediated via the activation of DA1 receptors located on renal tubules. © 1992 Wiley‐Liss, Inc.
Memory impairments induced by peripherally administered cholecystokinin a‐type receptor antagonists in rats
Authors: Itoh Shinji , Takashima Akira , Maeda Yumino 
Published: January 2005

AbstractIntraperitoneal injection of cholecystokinin (CCK) A‐type receptor antagonists, L‐364,718 and CR 1409, caused dose‐dependent memory impairments in passive and active avoidance responses and in Morris water pool test in rats. These antagonist effects were significant at a dose of 1 mg/kg, while with proglumide, 50–100 mg/kg were required to produce a similar memory deficit. The results suggest that loss of biologically active CCK octapeptide (CCK‐8), not only in the brain but also in the peripheral tissues, causes memory impairmets in rats. © 1992 Wiley‐Liss, Inc.
Antipsychotic profile and side‐effect liability of haloperidol, risperidone, and ocaperidone as predicted from their differential interaction with amphetamine in rats
Authors: Megens Anton A. H. P. , Niemegeers Carlos J. E. , Awouters Frans H. L. 
Published: January 2005

AbstractMotor activity effects of haloperidol, risperidone, and ocaperidone were studied in rats challenged with amphetamine. At a low dose of amphetamine, the compounds were about equipotent in reducing amphetamine‐induced hyperactivity to normal values (lowest ED50s: 0.015–0.023 mg/kg). Haloperidol completely blocked motility at a slightly higher dose (0.14 mg/kg). In contrast, much higher doses of risperidone and ocaperidone were required for complete blockade of motility (ED50s: 2.0 and 1.7 mg/kg, respectively). With increasing dose of amphetamine, risperidone became considerably less potent than haloperidol in reducing hyperactivity; ocaperidone remained at least as potent as haloperidol in this respect. Moreover, risperidone lost, while ocaperidone maintained, its high margin towards complete blockade of motility. The compounds were also equipotent (lowest ED50s: 0.0075–0.0089 mg/kg) in reversing amphetamine‐induced behavioral withdrawal (stationary stereotypy) to more environment directed behavior (active exploration). However, this ‘disinhibitory’ effect was maintained over a much wider dose range with risperidone than with haloperidol and ocaperidone. The observed differences in interaction with amphetamine are presumably related to relative serotonin 5HT2/dopamine D2 antagonistic activity and suggest important differences in therapeutic profile and side‐effect liability of the compounds. The implications for distinct clinical applications of the compounds are discussed: risperidone might be the drug of choice for maintenance therapy of chronic schizophrenics, especially for patients with mild positive symptoms and type II patients with predominant negative symptoms and ocaperidone for therapeutic treatment of the pronounced positive symptoms in acute schizophrenia or during exacerbations of chronic schizophrenia. © 1992 Wiley‐Liss, Inc.
Diurnal variation in hepatic glutathione content as a function of age
Authors: Rikans Lora E. , Nokubo Munetaka , Kanai Setsuko , Kitani Kenichi 
Published: January 2005

AbstractThe purpose of this study was to investigate the influence of aging on the diurnal varitaion in glutathione (GSH) content of mouse liver. Young (7 months) and old (27 months) C57BL mice were housed under standarized conditions with lighting from 0800 to 2000 and free access to food and water. GSH was determined in acid extracts of liver homogenates by HPLC separation and fluorometric detection of the o‐phthaldialdehyde derivative. A diurnal rhythm in hepatic GSH concentration was evident in young and old mice of both sexes. Peak levels of GSH occurred at 1000 and were unaffected by age or gender; however, age and sex‐dependent differences were observed in the lowest concentration of GSH and in the amplitude of the GSH cycle. Hepatic GSH levels at 2200 and 0600 were 30–35% lower in old males than in young males and 25–40% lower in young females than in young males. The results may provide an explanation for the inconsistencies in previous findings about the influence of aging on hepatic GSH concentrations. © 1992 Wiley‐Liss, Inc.
Interleukin‐2 in liposomes: Increased intravenous potency and less pulmonary toxicity in the rat
Authors: Anderson Peter M. , Hasz Diane , Dickrell Lydia , Sencer Susan 
Published: January 2005

AbstractIncorporation of interleukin‐2 (IL‐2) into multilamellar vesicles, IL‐2 liposomes, significantly modifies the biodistribution and prolongs the clearance of the cytokine. The rat was used to evaluate and characterize subacute toxicity and short‐term pathologic effects of intravenous (i.v.) IL‐2 liposomes. Once daily i.v. IL‐2 liposomes in doses of 0.3 × 106u/kg, 1.5 × 106u/kg, 4.0 × 106u/kg, and 20 × 106u/kg were given to rats for 15 days; control rats received i.v. empty liposomes or buffered saline. Hematologic parameters, serum chemistry, and gross pathologic and histopathologic findings were recorded. Only at the highest dose of IL‐2 liposomes were effects consistently severe enough to produce weight loss, decreased food consumption, hepatitis, anemia, and death. At this dose females were more susceptible to mortality than males; only 1 of 5 females survived compared to 4 of 5 males. Peripheral blood leukocyte increases after IL‐2 liposomes were mainly associated with lymphocytosis with only minor changes in neutrophils, monocytes, and eosinophils. The marrow had significant dose‐related hematopathologic findings limited to decreased percentages of lymphocytes and increased myeloid:erythroid (M:E) ratio in the 20 × 106u/kg group. No increases in marrow eosinophils or eosinophilic precursors were demonstrated. The major toxic effects of IL‐2 liposomes in rats were hepatic. Dose‐related elevations in liver enzyme serum chemistries (aspartate aminotransferase [AST], alanine aminotransferase [ALT], bilirubin, γ‐glutamyl transferase [GGT], and alkaline phosphatase) were seen. Occasional rats had evidence of bridging fibrosis in addition to centrilobular and periportal lymphocytic and eosinophilic infiltration of the liver. Pulmonary histopathology was characterized by peribronchial and perivascular lymphoid and eosinophilic infiltration with minimal or no septa1 involvement. In summary, the spectrum of pathologic and toxicologic changes in rats receiving once daily IL‐2 liposomes are similar to those previously reported in rats given the free cytokine twice daily, but occur at reduced doses with less lung pathology. Thus, compared to free cytokine i.v. IL‐2 liposomes in rats have increased potency and decreased pulmonary toxicity. © 1992 Wiley‐Liss, Inc.