bluuebunny/crossref_metadata_2025 huggingface dataset:
Mianserin‐induced 5‐HT2 receptor downregulation results in anxiolytic effects in the elevated plus‐maze test
Authors: Benjamin D. , Saiff E. I. , Nevins T. , Lal H.
Published: January 2005

Several agents that downregulate 5‐HT2 receptors produce anxiolytic effects in humans, but the role of 5‐HT2 receptor downregulation has been difficult to assess because of their other actions. To test the effects of pharmacological downregulation of 5‐HT2 receptors on exploratory behavior in the mouse, mianserin, a drug known to downregulate 5‐HT2 receptors after a single dose, was administered 30 min, 48 hr, or 18 days prior to testing in the elevated plus‐maze. Following testing in the elevated maze, the head‐shake response to 4‐iodo‐R‐(—)‐2,5‐dimethoxyphenylisopropylamine (DOI), a selective 5‐HT2/5‐HT1C agonist was assessed, and in a separate group of animals 5‐HT1A, 5‐HT1B, 5‐HT1C, β1,β2, and 5‐HT2 agonist and antagonist binding was quantified autoradiographically. Mianserin pretreatment resulted in a significant dose‐related anxiolytic effect in the elevated plus maze evidenced by increases in the percentage of entries to, and time spent on the open arms. Head‐shakes induced by DOI were also dose‐dependently decreased as a result of mianserin pretreatment. At this time, the binding of the 5‐HT2 receptor antagonist, 7‐amino‐8[125I]ketanserin was decreased by 50%. Binding of DOI to 5‐HT2 receptors was decreased by 46%, and to 5‐HT1C receptors was decreased by 53%, but no other changes were found in any of the other receptor types examined. These findings demonstrate that the 5‐HT2 receptor plays at least a permissive role in anxiety‐like behaviors, since an intact 5‐HT2 system is necessary for the full expression of the anxiety‐like response, but the role of 5‐HT1C receptor downregulation in the effects of mianserin cannot be ruled out at this time. © 1992 Wiley‐Liss, Inc.
Use of tissue plasminogen activator for rapid dissolution of fibrin and blood clots in the eye after surgery for glaucoma and cataract in humans
Authors: Tripathi Ramesh C. , Tripathi Brenda J. , Bornstein Scott , Gabianelli Eugene , Ernest J. Terry
Published: January 2005

We treated 10 patients with tissue plasminogen activator (tPA) for complications that threatened the successful outcome of anterior segment surgery for glaucoma and/or cataract, and that endangered the structural and functional integrity of the eye. Eight patients who had developed massive fibrin or blood clots in the anterior chamber each received 10–20 μg of tPA intracamerally, and two patients who had and extensive subconjunctival blood clot that blocked the filtration site received 25 or 30 μg of tPA subconjunctivally. The clots dissolved within 30 min to a few hours in all patients. Except in one patient who developed a 10% hyphema after the tPA injection, we observed no ocular complications in any of our patients during a follow‐up period that ranged from 2–22 months. Our preliminary investigations show that intracameral injection of tPA is highly effective and safe for the rapid dissolution of fibrin and blood clots in the anterior chamber that obstruct the visual axis, obscure the view of the fundus, or cause failure of filtering blebs, and for lysis of synechiae of 2 to 3 days duration. Optimal results were obtained with intracameral injection of ≥ 10 μg tPA at 4 to 10 days after surgery. However, tPA should be regarded as an acute therapy and adjunctive modality for the treatment of fibrin and blood clots in the anterior segment of the eye. To avoid possible drug‐induced complications, we advocate titration of the dose and repeat injection rather than a single large bolus of the drug. © 1992 Wiley‐Liss, Inc.
Effect of pravastatin and cholestyramine on triglyceride‐rich lipoprotein particles and Lp(a) in patients with type II hypercholesterolemia
Authors: Barbi Giorgio , Corder Clinton N. , Koren Eugen , McConathy Walter , Ye S. Q. , Wilson Paul
Published: January 2005

The effects of treatment, on plasma lipids in patients with Type II hypercholesterolemia, for 8–24 weeks was determined with pravastatin (PR) and cholestyramine (CH) given alone or in combination. The first 8 weeks of treatment included a parallel placebo (P) control, while the subsequent period to 24 weeks compared four groups (40 and 80 mg PR, CH, and PR + CH). There were seven to nine patients per group (average age of 58 years). Cholesterol (C) and low‐density lipoprotein cholesterol (LDL‐C) decreased with PR and CH. There were inconsistent and nonsignificant effects on triglycerides and high‐density lipoprotein cholesterol (HDL‐C). Apolipoproteins A‐I, A‐II, B, and Lp(a) were measured, and only Apo‐B decreased with drug therapy. Lipoprotein particles characterized by their specific apolipoprotein content were also measured. LpB Cholesterol ester‐rich, containing predominantly Apo‐B, decreased with PR and CH relative to their respective baselines, but not relative to P. Similarly, triglyceride‐rich, LpBc, a complex lipoprotein particle containing apolipoproteins A‐I, A‐II, B, C, D, and E decreased relative to baseline, but not with respect to P. This study has further defined the effect of PR and CH on lipids and lipoprotein particles in patients with Type II hypercholesterolemia. These effects might be favorable in relation to reduction of risk factors in atherosclerosis. © 1992 Wiley‐Liss, Inc.
Memory‐enhancing effect of a cerulein analogue following peripheral administration in the rat
Authors: Itoh Shinji , Takashima Akira , Igana Ken'ichi , Maeda Yumino
Published: January 2005

Our previous studies demonstrated that cerulein (CER) has a potent preventive action on amnesia induced by electroconvulsive shock, administration of scopolamine, puromycin, anisomycin, NMDA receptor antagonists, and protein kinase C inhibitors. The present study was aimed at finding more effective CER analogues which could enhance memory processes. Five CER analogues were synthesized and the potencies in passive and active avoidance responses and in the Morris water pool test were examined in the rat. Among the preparations, des‐Gln2‐[Leu5, Nle8]‐CER was found to possess particularly potent effects on memory acquisition and/or storage. The effects were apparent in less than 1 μg/kg single subcutaneous (s.c.) injection for at least 120 hr in passive avoidance response and 15 days in active avoidance response. Memory impairments induced by scopolamine and puromycin were well improved in passive avoidance response. In the Morris water maze test, disordered behaviors caused by scopolamine and protein kinase C inhibitor were totally restored to the normal state by s.c. injection of this CER analogue. © 1992 Wiley‐Liss, Inc.
Pharmacological properties of adenosine receptors and adenosine binding proteins
Authors: Schwabe U. , Fein T. , Lorenzen A.
Published: January 2005

Two major subtypes of adenosine receptors occur in different tissues which have been distinguished by pharmacological and biochemical criteria. The A1 adenosine receptor has a high‐affinity for adenosine and mediates inhibition of adenylyl cyclase, whereas the A2 adenosine receptor usually has a lower affinity and mediates stimulation of the enzyme. Furthermore, evidence has been obtained that A1 receptors increase the conductance of receptor‐regulated potassium channels, induce inactivation of calcium channels, and modulate the breakdown of phosphoinositides by phospholipase C. Selective agonists and antagonists have been developed for both receptor subtypes. In addition, both adenosine receptors have extensively been characterized by radioligand binding studies. Suitable radioligands for the A1 receptor are the agonist [3H]2‐chloro‐N6‐cyclopentyladenoisine (CCPA) and the antagonist [3H]8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX)and for the A2a receptor [3H]2‐[p‐(carboxyethyl)phenethylamino]‐ 5′‐N‐carboxamidoadenosine (CGS 21860). Furthermore, photoaffinity ligands were developed from adenosine derivatives, which can be covalently incorporated into the binding unit of both receptor subtypes. With this approach, it has been shown that the A1 receptor has an apparent molecular weight of approximately 36 kDa and the A2a receptor of 45 kDa. A second approach to elucidate the structure of adenosine receptors involves the purification of receptor protein by affinity chromatography. With this procedure, cerebral A1 receptors have been purified to apparent homogeneity. More recently, the structure of receptor subtypes has been elucidated by cloning the receptors from a cDNA library. Furthermore, a novel adenosine binding with [3H] 5′ ‐N‐ethylcarboxamidoadenosine ([3H]NECA). The pharmacological profile of this NECA‐binding protein has been determined in competition experiments with adenosine receptor ligands. It can be distinguished from that of A2a adenosine receptors and other adenosine binding proteins. We propose the name Ax for this unique adenosine binding protein. © 1993 Wiley‐Liss, Inc.
Acadesine: Prototype adenosine regulating agent for treating myocardial ischemia‐reperfusion injury
Authors: Mullane Kevin , Young Mark
Published: January 2005

Acadesine is an adenosine regulating agent currently being developed for treatment of ischemia‐reperfusion injury in the setting of cardiac surgery. While the cardioprotective effects of adenosine are well recognized, the intrinsic hemodynamic and cardiac effects of adenosine limit its potential usefulness as a therapeutic agent. In contrast, acadesine has been shown to elevate endogenous levels of adenosine during periods of ischemia without exhibiting systemic hemodynamic action. The site‐specific and event‐specific mechanism of action thus provides cardioprotection without the adverse sequelae commonly observed with adenosine. This review describes the pertinent literature which establishes acadesine's action as an adenosine regulating agent, and discusses past and recent studies which focus on the cardioprotective actions of acadesine. These studies include in vitro and in vivo models of regional and global ischemia, and models of cardiac surgery. Aspects of dose‐response, timing of administration, and pharmacokinetics of acadesine are described which reconcile prior controversy regarding acadesine'e cardioprotective actions. These studies, taken together, demonstrate that acadesine is the prototype of a new class of adenosine regulating agents useful as therapy for cardiac ischemia. © 1993 Wiley‐Liss, Inc.
Beneficial role of adenosine in myocardial ischemic and reperfusion injury
Authors: Hori Masatsugu , Kitakaze Masafumi , Takashima Seiji , Morioka Toshikazu , Sato Hiroshi , Minamino Tetsuo , Inoue Michitoshi , Kamada Takenobu
Published: January 2005

Adenosine has been recognized as an important regulator of myocardial function and coronary vascular tone in the ischemic myocardium. 5′‐Nucleotides, which converts 5′‐adenosine monophosphate to adenosine, is responsible for adenosine production in the ischemic myocardium. We have found that α1‐adrenergic receptors activated in ischemic hearts increase both 5′‐nucleotidase activity and adenosine production. The primary role of endogenous adenosine is to increase coronary blood flow through adenosine A2 receptors. This adenosine‐induced coronary vasodilation is amplified by α2‐adenosine stimulation. Stimulation of adenosine A2 receptors also attenuates both free radical generation by activated leukocytes and the aggregation of platelets. In turn, adenosine A1 receptor activation attenuates β‐adrenoceptor‐mediated increases in myocardial contractility, Ca2+ influx into myocytes and norepinephrine release form the presynaptic nerves. Any or all of these effects may attenuate ischemic and reperfusion injury. Indeed, endogenous and exogenous adenosine appears to ameliorate contractile dysfunction and infarct size following ischemia and reperfusion. Therefore, we believe that adenosine plays an important role as a modulator of ischemic and reperfusion injury. © 1993 Wiley‐Liss, Inc.
Amantadine increases striatal dopamine turnover in MPTP‐treated mice
Authors: Rojas Patricia , Altagracia Marina , Kravzov Jaime , Rios Camilo
Published: January 2005

Amantadine is used in the symptomatic treatment of Parkinson's disease to improve the akinesia and rigidity associated with this neurodegenerative disorder. Amantadine acts on the synthesis and release of dopamine (DA). In order to further characterize its mechanism of action, the drug was administered to MPTP‐treated mice which were used as a model of the neurochemical deficits associated with Parkinson's disease. The DA turnover in corpus striatum was evaluated. Adult male Swiss albino mice were injected ip with 12.5 mg/kg (82.6 μmol/kg) or 25 mg/kg (165 μmol/kg) of amantadine and 30 min later with MPTP (30 mg/kg, 143 μmol/kg). Both the amantadine and MPTP treatments were repeated for 3 consecutive days. Groups of mice were treated with amantadine or MPTP alone. Seven days after the last injection of drugs, the striatal content of DA and homovanillic acid (HVA) were measured by HPLC‐EC analysis. Additional groups of mice were treated with 3 consecutive daily doses of MPTP (30 mg/kg, 143 μmol/kg) and 7 days after the last administration received a single dose of amantadine at 25 mg/kg (165 μmol/kg). Turnover rate was measured by HVA content determination. The results indicate that amantadine induced a significantly increased striatal DA turnover rate (34%) in MPTP‐treated animals as compared with those animals treated with only MPTP. © 1993 Wiley‐Liss, Inc.
N‐(n‐propyl)‐n‐(3‐fluoro‐4‐pyridinyl)‐1h‐3‐methylindol‐1‐amine hydrochloride (HP 184): In vitro spontaneous release of acetylcholine and norepinephrine
Authors: Smith Craig P. , Brougham Linda R. , Huger Francis P. , Davis Larry , Klein Joseph T. , Effland Richard C.
Published: January 2005

It has been shown that a single injection of N‐(n‐propyl)‐N‐(3‐fluoro‐4‐pyridinyl‐1H‐3‐methylindol‐1‐amine hydrochloride) (HP 184) (0.6‐4.8 mg/kg, or 2‐15 μmoles/kg, sc) reversed passive avoidance deficits in rats with combined cholinergic and noradrenergic lesions. This report describes the effects of HP 184 on NE and ACh release from rat brain slices. In contrast to 4‐aminopyridine (4‐AP), tyramine, or veratridine, HP 184 only enhanced spontaneous release and had no effect on electrical stimulation (ES). Chromatographic analysis showed that the spontaneous release from [3H]choline‐loaded striatal slices correlated with increased release of ACh, not choline efflux. HP 184 also enhanced ACh spontaneous release in the absence of both extracellular calcium and functional vesicles (as defined by ES and vesamicol). In frontal cortical slices, HP 184 caused [3H]NE release in a calcium independent fashion different from that induced by veratridine, and was not affected by uptake blockers. In contrast to the cholinergic profile, the [3H]NE release induced by HP 184 required intact storage vesicles, since release was blocked by reserpine pretreatment. The results show that HP 184 can release both NE and ACh in vitro, and, coupled with the dual lesion results, suggest it may have use in diseases involving cholinergic and noradrenergic deterioration. © 1993 wiley‐Liss, Inc.
Potentiation of 5‐methoxy‐n,n‐dimethyltryptamine‐induced head‐twitches by diazepam: Evidence for involvement of adenosine uptake inhibition
Authors: Moser Paul C.
Published: January 2005

Previous work shows that benzodiazepines potentiate head‐twitches induced by 5‐HT agonists and that this action is not mediated via the GABA receptor complex. In the present study the involvement of adenosinergic mechanisms in this effect has been examined, as in addition to their actions at the GABA receptor, benzodiazepines also inhibit adenosine uptake. The adenosine antagonists caffeine (0.3‐30 mg/kg ip) and 1,3‐dipropyl‐8‐(2‐amino‐4‐chlorophenyl)xanthine (0.03‐1 mg/kg ip) dose‐dependently inhibited the ability of diazepam (4 mg/kg ip) to potentiate head‐twitches induced by 5‐methoxy‐N,N‐dimethyltryptamine (5‐MeODMT; 2.5 mg/kg ip) without affecting head‐twitches induced by 5‐MeODMT alone at a higher dose (10 mg/kg), which induced a similar number of head‐twitches to the combination of 5‐MeODMT and diazepam. The adenosine uptake inhibitors papaverine, mioflazine, and dilazep all potentiated head‐twitches induced by 5‐MeODMT, but this effect was seen at only a single dose of each compound. The benzodiazepine antagonist flumazenil did not inhibit the potentiation of head‐twitches by diazepam but did itself potentiate head‐twitches at 30 mg/kg, consistent with its ability to inhibit adenosine uptake. In contrast, the adenosine uptake inhibitor dipyridamole and the peripheraltype benzodiazepine receptor antagonist Ro 5‐4864, which also inhibits adenosine uptake, failed to potentiate head‐twitches. The adenosine agonists N6‐cyclohexyladenosine, 5'‐(N‐ethylcarboxamido‐adenosine), and (–)‐N6‐(R‐phenylisopropyl)adenosine were similarly without effect. These results confirm previous findings that the potentiation of head‐twitches by benzodiazepines is not mediated via an action at benzodiazepine receptors and suggest that inhibition of adenosine uptake is an important component of the mechanism involved. © 1993 wiley‐Liss, Inc.
Amiridine (NIK‐247) and cerebrocrast in the alleviation of cholinergic lesion‐induced learning deficit in male rats
Authors: Männistö Pekka T. , Kutepova Olga , Leinonen Katri , Lang Aavo , Soosaar Andres , Suomela Annika , Borisenko Sergey A.
Published: January 2005

Learning of the male rats was impaired by injecting ethylcholine aziridinium (AF64A) bilaterally into the basal magnocellular nuclei of Meynert. The performance of the rats in a passive avoidance test and in a one‐way active avoidance test was significantly improved by giving a novel acetylcholinesterase inhibitor, amiridine (NIK‐247; 9‐amino‐2,3,5,6,7,8‐hexahydro‐1H‐cyclopenta(b)‐quinoline monohydrate hydrochloride) after each learning session but not when the drug was given before the sessions. Cerebrocrast, an antagonist of L‐type calcium channels, was not effective in either case. Rather it worsened the learning results when given after the sessions of the active avoidance test. The conclusions in the passive avoidance test were hampered by the observed inconsistent effects of cholinotoxin. © 1993 wiley‐Liss, Inc.
Cloning and sequence of the human α7 nicotinic acetylcholine receptor
Authors: Doucette‐Stamm Lynn , Monteggia Lisa M. , Donnelly‐Roberts Diana , Wang Mei Tai , Lee John , Tian Jingxiang , Giordano Tony
Published: January 2005

A rat clone for the nicotinic acetylcholine receptor (nAChR) α7, generated by reverse transcriptase‐polymerase chain reaction (rtPCR) from a region which did not exhibit significant homology to other rat nAChRs, was used to probe human cDNA libraries. A number of clones corresponding to the human α7 were isolated and sequenced. The human sequence showed 87% identity at the nucleic acid level to the rat sequence and 96% identity at the amino acid level. Unlike the rat α7 nAChR, the human gene does not appear to be the most divergent member of the nAChR family. The cloning of the human α7 will make it possible to study the functional formation of human neuronal nAChR channels containing the α7 subtype. © 1993 wiley‐Liss, Inc.
Effects of chlorisondamine on nicotinic receptor binding in whole brain and nicotine‐induced changes in locomotor activity in rats
Authors: Decker Michael W. , Majchrzak Mark J. , Cadman Evelyn D. , Arnerić Stephen P.
Published: January 2005

Chlorisondamine, a nicotinic cholinergic receptor antagonist, can block many of the in vivo effects of nicotine for weeks after a single icv injection. The time course of this effect was examined in a single group of rats by assessing the effects of nicotine on locomotor activity at 1, 3, and 6 weeks after the icv administration of 23 nmol of chlorisondamine. The effects of nicotine on locomotor activity were biphasic as has been previously reported, with decreases in activity early in the session and increases in activity later in the session. These effects of nicotine were blocked in chlorisondamine‐treated rats at 1 or 3 weeks but not 6 weeks after administration of chlorisondamine. Nicotinic receptor binding in the brains of chlorisondamine‐treated rats revealed no change in Bmax but a significant increase in affinity (47–59% decrease in Kd) 1, 3, 6, or 7 weeks after treatment. In contrast to its effects on affinity when administered icv, chlorisondamine did not alter binding affinity when added directly to the incubation buffer in vitro. Thus, although chlorisondamine significantly alters neuronal nicotinic cholinergic receptor binding affinity, this effect of chlorisondamine on binding affinity does not appear to be a direct effect of chlorisondamine on the receptor or to match the time course of chlorisondamine blockade of nicotine‐induced changes in locomotor activity. © 1994 Wiley‐Liss, Inc.
Actions of the general anesthetic propofol (2,6‐diisopropylphenol) on the binding of [3h]nicotine to rat cortical membranes
Authors: Prince Richard J. , Lineberry Jeffrey W. , Lippiello Patrick M.
Published: January 2005

[3H]nicotine bound to rat cortical membranes in a biphasic manner consistent with previous models of receptor function. The kinetics of binding were characterized by a rapid component with a rate constant of 0.007 min−1 nM−1 and a slower component with an apparent rate constant of 0.024 min−1. Dissociation was monophasic with a rate constant of 0.046 min−1. Addition of 3 mM propofol caused the abolition of the slow component of association and increased the rate constants for the rapid component to 0.012 min−1 and for dissociation to 0.086 min−1. Under non‐equilibrium conditions propofol caused a dose‐dependent increase in the binding of [3]Hnicotine, which reached 147% of the control value at 3 mM propofol. The equilibrium binding of [3H]nicotine was unaffected by the drug. These results are consistent with propofol causing enhanced desensitization at the cortical nicotinic acetylcholine receptor, suggesting an alternative to receptor agonists which bind to active sites as a method of modulating receptor function. © 1994 Wiley‐Liss, Inc.
Effects of Japanese herbal medicine “Sho‐saiko‐to” on in vitro production of tumor necrosis factor‐alpha on peripheral blood mononuclear cells
Authors: Yamashiki Masayoshi , Nishimura Akira , Nomoto Minoru , Nakano Takeshi , Sato Tetsuro , Suzuki Hiroyuki , Zheng Qiao‐Xi , Klapproth Jan‐Michael , James Stephen P. , Kosaka Yoshitane
Published: January 2005

“Xiao‐Chai‐Hu‐Tang” is a herbal medicine that has been used for the treatment of pyretic diseases in China for several thousand years. In Japan, this medicine was modified into “Sho‐saiko‐to,” a prescription drug with standard quality and volume of ingredients. It is widely used as a biological response modifier in the treatment of chronic viral liver diseases. Several researchers have reported improvement of general physical conditions and the drug's usefulness in preventing liver cancer development. In this in vitro study, peripheral blood mononuclear cells (PBMC) were obtained from 12 healthy volunteers, and Sho‐saiko‐to (TJ‐9) was added to the cultures of the PBMC. Dose‐dependent increases in the levels of tumor necrosis factor‐α (TNF‐α) were observed in the cultures. Similar but smaller increases in the TNF‐α levels were also observed when other Japanese herbal medicines, Dai‐saiko‐to (TJ‐8) or Saiko‐keishi‐to (TJ‐10), were added to the cultures. These results demonstrated that the increases of TNF‐α levels are specifically due to Sho‐saiko‐to and other drugs with similar ingredients. TNF‐α is believed to have anti‐tumor effects and also to have an important role as IL‐1 in the defense mechanism of the body. Therefore, the induction of TNF‐α could also be useful in clinical treatment, and this effect could be one of the mechanisms by which Sho‐saiko‐to demonstrates efficacy in the treatment of patients with chronic viral liver diseases. © 1994 Wiley‐Liss, Inc.
Synthesis and biological evaluation of lorglumide‐like hybrid cholecystokinin‐A receptor antagonists
Authors: van der Bent Arie , van den Brink Ingrid , Ijzerman Adriaan P. , van Wijngaarden Ineke , Soudijn Willem
Published: January 2005

The evaluation of gross structural homologies between the competitive cholecystokinin‐A (CCK‐A) receptor antagonists lorglumide and devazepide formerly enabled the development of compact hybrid analogues [Van der Bent et al. (1992): J Med Chem 35:1042–1049]. In the follow‐up study described here, we aimed to closely examine the structural and functional relationship between N‐acyglutamic acids like lorglumide and our hybrid derivatives. For this purpose, the most potent hybrid CCK‐A antagonist (Ki = 0.09 μM) was modified by the addition of the propionic acid moiety that is unique to the N‐acylglutamic acids. Additionally, a number of propionic acid and butyric acid derivatives were prepared in order to explore the SAR profile of the carboxylic acid moiety in this series. The prepared compounds were tested in vitro as antagonists of the binding of [3H]‐(±)‐L‐364,718 to rat pancreas membranes. With CCK‐A affinities above 1 μM, all derivatives of the initial hybrid structure, including the propionic acid derivative that closely resembles lorglumide, proved to be considerably less potent. It would appear that the retained structural differences between lorglumide and the novel hybrid antagonists result in a divergence of their binding modes that precludes a favourable interaction of the added functionality of the latter compounds. Alternatively, the obtained results may question the vital role that has been attributed to the carboxylic acid function of the N‐acylglutamic acids as a counterion to a cationic residue in the binding site. © 1994 Wiley‐Liss, Inc.
Analgesic interactions produced by dipyrone and either morphine or D‐propoxyphene in the pain‐induced functional impairment model in rat
Authors: López‐Muñnoz Francisco J. , Villalón Carlos M. , Terrón José A. , Salazar Luis A.
Published: January 2005

The analgesic synergism of drug mixtures containing dipyrone in combination with either morphine or d‐propoxyphene were examined in the pain‐induced functional impairment model in the rat (PIFIR). Pain was produced by intra‐articular injection of uric acid in the right hind limb, inducing its dysfunction. Animals then received the following treatments: dipyrone (160, 285, 506, 900, 1,600 or 2,846 μmoles·kg−1, sc), morphine (3, 6, 10, 18, 31, or 55 μmoles·kg−1, sc), d‐propoxyphene (84, 150, 266, 473, or 841 μmoles·kg−1) or a combination using the ED33 of each drug, namely, dipyrone/morphine (834/18 μmoles·kg−1) or dipyrone/d‐propoxyphene (834/187 μmoles·kg−1). The recovery of functionality after the above treatments was considered as an expression of analgesia. The analgesic effects produced by the combination dipyrone/morphine were similar to those expected on the basis of addition of analgesic effects of the individual drugs. However, analgesia produced by the combination dipyrone/d‐propoxyphene was significantly higher (P < 0.01) than that induced by each component alone. The percent change was 33% over the addition of individual analgesic effects. The analysis of the time‐course curve of the simultaneous administration of dipyrone/d‐propoxyphene showed a maximum of analgesia of 95% at 1 h after administration and then persisted until the end of the experiment (up to 3 h). The total analgesic effect determined from the area under the time‐course curve showed 332.5 area units; this represented the highest analgesic effect among the drugs tested. These results are relevant in view of the inability of dipyrone, morphine, and d‐propoxyphene to produce that highest analgesic effect.
Pathomorphologic effects of N‐methyl‐D‐aspartate antagonists in the rat posterior ingulate/retrosplenial cerebral cortex: A review
Authors: Fix Andrew S. , Long Gerald G. , Wozniak David F. , Olney John W.
Published: January 2005

This review discusses available information on the neurotoxicity of N‐methyl‐D‐aspartate (NMDA) antagonists in the posterior cingulate/retrosplenial (PC/RS) cortex of rats. NMDA antagonists block the NMDA receptor, a central nervous system ionotropic glutamate receptor, and are neuroprotective since they reduce injury in animal models of ischemia. There is interest in the development and use of NMDA antagonists in treating human cerebrovascular diseases. However, with certain NMDA antagonists, dose‐dependent vacuolization of neurons in the neuroanatomically localized PC/RS cortex occurs as a side effect in rats. NMDA antagonists that cause vacuolization also appear to induce heat shock protein expression and heightened glucose metabolism in the same cortical region. Electron microscopy has shown that after treatment with MK‐801 (dizocilpine maleate), a prototypic noncompetitive NMDA antagonist, the onset of vacuolization is very rapid. Additional studies with MK‐801 have indicated that susceptibility to vacuolization increases between 30 and 90 days of age. Histologic time course studies have demonstrated that as the dose of MK‐801 is increased, some vacuolated neurons become necrotic. Necrotic neurons are readily evident by light microscopy in routine preparations. At a given dose of MK‐801, neuronal necrosis is more extensive in female rats than male rats. Furthermore, necrosis increases along an anterior to posterior gradient within the susceptible PC/RS cortex. A number of compounds with varied central nervous system (CNS) pharmacologic activity (anticholinergics, GABAmimetics, antipsychotics, and general anesthetics) partially or completely prevent neuronal vacuolization. These data suggest a complex pathogenesis for NMDA antagonist‐mediated neurotoxicity and indicate variables which require consideration when designing and interpreting studies with these compounds. Since recent reports have described failure of some NMDA antagonists to produce these side effects, the issues discussed in this review may or may not apply to all NMDA antagonists.
Models used to assess renal function
Authors: Chiu Peter J. S.
Published: January 2005

The kidney as a primary excretory organ is a major route of elimination for numerous xenobiotic agents. In the process, it is liable to the hemodynamic and injurious actions of drugs due to their concentration in the kidney. In this brief review, a number of methods for assessing kidney function (e.g., serum creatinine, enzymuria, inulin, and PAH clearances, etc.), with their advantages and limitations, are described. Various acute and chronic animal models (rats and dogs) commonly used in performing safety evaluation of drugs are described; several antihypertensive drugs are cited as examples. These models can be modified with varying number of measurements, depending on the pharmacological activity of test drugs, animal species, specific issues (e.g., vascular vs. tubular effects), pathophysiological conditions, etc.
Microdialysis assessment of the impact of (+)3,4‐methylenedioxymethamphetamine, cocaine, and cocaethylene on serotonergic neurons
Authors: Bradberry Charles W.
Published: January 2005

This overview summarizes the results of microdialysis studies into the effects of several psychoactive drugs on extracellular serotonin (5‐HT) levels in rat brain. The effects of (+)3,4‐methylenedioxymethamphetamine (MDMA, ecstasy) were examined in the brain slice preparation for comparison with parallel electrophysiological studies of the impact of (+)‐MDMA on dorsal raphe 5‐HT neuronal firing. (+)‐MDMA induced the release of 5‐HT from slices of dorsal raphe. The release was inhibited by fluoxetine, and augmented by tryptophan pretreatment. The results support a mechanism of action whereby (+)‐MDMA inhibits 5‐HT neuronal firing by releasing 5‐HT which then acts upon somatodendritic autoreceptors. In other studies, the effects of cocaine and cocaethylene (the psychoactive metabolite of concurrent cocaine/ethanol consumption) on extracellular 5‐HT and dopamine levels in the chloral hydrate‐anesthetized rat were examined. Both the intravenous and intraperitoneal routes were examined. By intravenous route, both drugs had equivalent effect at increasing dopamine levels. Cocaine significantly increased 5‐HT levels, while cocaethylene had no impact. By intraperitoneal route, cocaethylene was able to increase 5‐HT levels, but cocaine remained more potent. Route‐dependent differences in bioavailability were evident from studies of brain levels using microdialysis. By intravenous administration, equivalent amounts of both drugs entered the brain, whereas by intraperitoneal route, levels of cocaethylene were half those of cocaine. © 1994 Wiley‐Liss, Inc.
Rifampicin induced hepatotoxicity in rats: Protective effect of picrolive effect of picroliv
Authors: Saksena Seema , Rastogi Ravi , Garg Narendra K. , Dhawan Bhola N.
Published: January 2005

Rifampicin, an anti‐tubercular drug, at 100 mg/kg (122 μmol) body weight (daily single ip injection for 6 days) caused changes in most of the biochemical parameters of the liver and serum in rats, 24 h after the last injection. These included significant increase in the activities of hepatic γ‐glutamyl transpeptidase, acid ribonuclease, acid phosphatase and decrease in the activity of succinate dehydrogenase. The levels of RNA, total proteins, bilirubin, total lipids, phospholipids, cholesterol, lipid peroxides in liver and bilirubin in serum increased while hepatic glycogen and serum proteins decreased. At a lower dose (50 mg/kg; 61 μmol/kg) the changes were less as compared to 100 mg/kg dose. When Picroliv (12 mg/kg body weight), a standardized iridoid glycoside mixture of Picrorhiza kurroa was administered simultaneously with rifampicin, most of the biochemical changes in liver and serum were prevented. These results indicate protective effect of Picroliv against rifampicin‐induced hepatotoxicity in rats. © 1994 Wiley‐Liss, Inc.
Potassium channel blockers as antiarrhythmic drugs
Authors: Colatsky Thomas J. , Argentieri Thomas M.
Published: January 2005

Selective prolongation of cardiac repolarization is an effective means of suppressing a variety of cardiac arrhythmias, particularly those arising from a re‐entrant mechanism. Over the past several years, a variety of novel compounds have been discovered that increase cardiac action potential duration without slowing conduction. Most of these agents (e.g., dofetilide, E‐4031, MK‐499) act by selectively blocking the rapidly activating component of delayed rectification (IKr), although some (e.g., ibutilide, azimilide, terikalant) have been proposed to work via alternate mechanisms. While the overall efficacy of these agents against tachyarrhythmias appears to be greater than obtained for the sodium channels blockers, primary concerns remain about the ability of these agents to prolong repolarization at fast heart rates (i.e., reverse use‐dependence) and to exert proarrhythmic effects at slow heart rates (i.e., torsade de pointes). The limited clinical results obtained to date suggest that these potential limitations may be less important than previously thought, although clear pharmacodynamic differences among the various agents are beginning to emerge. While the effects of some class III agents on repolarization and refractoriness are clearly attenuated at rapid cycle lengths (e.g., sematilide, d‐sotalol), the effects of others appear to be largely rate‐independent, at least down to cycles as short as 350 msec. Also, the currently available data suggest that the risk of serious proarrhythmia may be lower (1–3%) and considerably more predictable than that seen during treatment with the class I agents. In summary, the rational design of selective blockers of cardiac K channels for development as antiarrhythmic drugs appears to have been relatively successful and continues to show considerable promise as a therapeutic approach. © 1994 Wiley‐Liss, Inc.
Antimuscarinic properties of vamicamide, a novel compound for the treatment of pollakiuria
Authors: Yamamoto Takao , Matsuo Masahiko , Yamazaki Shunji , Ueshima Koji , Sawada Tadashi , Furuichi Atsuko , Ozaki Reiko , Nishii Misako , Miura Shintaro , Kusunoki Takahiro , Sato Natsuki , Koibuchi Yasushi , Esumi Kimio , Ohtsuka Minoru
Published: January 2005

The antimuscarinic profile of vamicamide, a novel compound for the treatment of pollakiuria, was investigated in both in vitro and in vivo preparations. Vamicamide (10 nM–10 μM) inhibited the contractile response of isolated guinea‐pig detrusor muscle to transmural electrical stimulation. In isolated guinea‐pig detrusor muscle, vamicamide also inhibited contractile response to carbachol with an IC50 value of 0.71 μM, whereas it had little or no effect on detrusor contractions induced by KCl, BaCl2, or α, β‐methylene ATP. In binding studies with dog membrane preparations, the dissociation constant (Ki) of vamicamide against tritiated N‐methylscopolamine ([3H]NMS) binding was 172 ± 8 nM for the urinary bladder, which was lower (P < 0.01) than those for the heart (322 ± 31 nM), stomach (317 ± 29 nM), and salivary gland (321 ± 32 nM). The Ki value for the cerebral cortex (95 ± 4 nM) tended to be lower than that for the urinary bladder. In binding studies with cloned human muscarinic receptor subtypes (m1–m3), the dissociation constant (Ki) of vamicamide against [3H]NMS binding was 89.0 ± 3.5 nM for the m3 receptor subtype, which was lower than those for the m1 (235 ± 5 nM, P < 0.05) and m2 (593 ± 49 nM, P < 0.01) receptor subtypes. In anesthetized dogs, vamicamide (3.2–100 μg/kg; 11–336 nmol/kg, iv) inhibited the carbachol‐induced contractile responses of the urinary bladder with an ID50 value of 16.1 μg/kg (54 nmol/kg), the stomach with a value of 31.3 μg/kg (105 nmol/kg), the descending colon with a value of 10.1 μg/kg (34 nmol/kg), and secretory response of the salivary gland to carbachol with a value of 43.3 μg/kg (146 nmol/kg); the inhibitory effects of the compound on the stomach and salivary gland were weaker (P < 0.01) than that on the urinary bladder. Furthermore, duration of the action of vamicamide was longer on the urinary bladder and descending colon than those on the stomach and salivary gland. These results suggest that vamicamide has a selective binding affinity to the muscarinic m3 receptor subtype and exhibits greater and longer inhibitory action on the urinary bladder than the other organs examined. © Wiley‐Liss, Inc.
Design and development of sequence selective lexitropsin DNA minor groove binders
Authors: Lown J. William
Published: January 2005

The concept of lexitropsins, or information‐reading molecules, is introduced within the antigene strategy as an alternative to, and complementary with, the antisense approach for cellular intervention and gene control. Consideration is given to alternative approaches to the development of DNA sequence selective binding agents because of their potential applications in diagnosis and treatment of cancer as well as in molecular biology. The chemical, physical, and pharmacological factors involved in the design of effective lexitropsins are discussed and illustrated with experimental results. Among the factors contributing to the molecular recognition processes are: the presence and disposition of hydrogen bond accepting and donating groups, ligand shape, chirality, stereochemistry, flexibility, and charge. For longer ligands, such as are required to target unique sequences in biological systems (14–16 base pairs), the critical feature is the phasing or spatial correspondence between repeat units in the ligand and the receptor. The recently discovered 2:1 lexitropsin‐DNA binding motif provides a further refinement in molecular recognition in permitting discrimination between GC and CG base pairs. The application of these factors in the design and synthesis of novel agents which exhibit anticancer, antiviral, and antiretroviral properties, and in the inhibition of critical cellular enzymes including topoisomerases, is discussed. The emerging evidence of a relationship between sequence selectivity of the new agents and the biological response they invoke is also described. © 1995 Wiley‐Liss, Inc.
Cellular electrophysiological effects of MS‐551, a new class III antiarrhythmic agent
Authors: Ishii Masaaki , Kamiya Joji , Hashimoto Keitaro
Published: January 2005

The cellular electrophysiological effects of MS‐551, a pure class III antiarrhythmic agent lacking beta‐blocking activity, were compared with those of d‐sotalol and dofetilide in canine Purkinje fibers and ventricular muscles and in guinea pig atrial muscles using the standard microelectrode technique. MS‐551 prolonged the action potential duration (APD) of these cardiac tissues to the same extent in a concentration‐dependent manner (10−6−10−4 M). MS‐551 did not affect other action potential parameters of these tissues except for the Vmax, which was depressed approximately 10% at 10−4 M MS‐551. The extents of prolongation after 10−5 M of MS‐551 were 36, 27, and 35% for canine Purkinje and ventricular muscle and guinea pig atrial muscle, respectively. d‐Stalol at a concentration 10 times higher than MS‐551 produced a similar prolongation of the APD of canine cardiac tissues but only a slight prolongation of the APD of guinea pig atrial muscles. Dofetilide at a concentration 30 times lower than MS‐551 produced a prolongation of the APD of canine Purkinje fibers but a relatively slight prolongation of the APD of both canine ventricular muscles and guinea pig atrial muscles. In canine Purkinje fibers, MS‐551 did not prevent the APD shortening induced by high extracellular potassium (8 and 12 mM), but the APD under these conditions was lengthened compared with controls. Under simulated ischemic conditions (pO2 25–30 mmHg, pH 6.5, extracellular K 8 mM and no glucose) for 30 min, the APD was abruptly shortened during the first 5 min, then gradually shortened further up until 30 min. MS‐551 did not prevent the abrupt APD shortening, but slowed the later gradual shortening. The APD prolonging action of MS‐551 was enhanced at low frequency. These data indicate that (1) MS‐551 is a pure class III antiarrhythmic agent with electrophysiological characteristics basically similar to d‐sotalol and dofetilide; (2) MS‐551 has a relatively greater potency in guinea pig atrial muscle than d‐sotalol and dofetilide; (3) the APD prolonging action of MS‐551 is preserved under high K+ or simulated ischemic conditions; and (4) MS‐551 exhibits a reverse use‐dependence in prolonging APD. © 1995 Wiley‐Liss, Inc.
Doses of acetyl salicylic acid and morphine in combination which provided either maximal levels of analgesia or the highest potentiation effect in the rat
Authors: Lopéz‐Muñoz Francisco J. , Villalón Carlos M. , Terrón José A. , Salazar Luis A.
Published: January 2005

The analgesic efficacy of the combination of acetyl salicylic acid (ASA), a nonsteroidal anti‐inflammatory drug (NSAID), and morphine, a μ‐opiate receptor agonist, was evaluated in the pain‐induced functional impairment in the rat (PIFIR) model. Groups of 6 rats received either vehicle, ASA (175.4, 311.9, 555.1, 986.9, 1,755.2, or 3,121.3 μmol/kg p.o.), morphine (3.1, 5.5, 9.8, 17.5, 31.1, or 55.2 μmol/kg s.c.), or a combination of ASA and morphine (24 different combinations). This allowed us to detect the profile of analgesic interaction of the combinations. Furthermore, we set out to determine the optimal degree of potentiation obtained with a specific combination of the above drugs by means of the “surface of synergistic interaction” of the combinations. The ED50 values for ASA and morphine were 1,167.9 ± 6.7 and 18.4 ± 3.7 μmol/kg, respectively. Eleven combinations of ASA and morphine produced a level of analgesia significantly greater than can be accounted for by simple addition of the analgesic effects of each analgesic drug alone (P < 0.01). The combination of ASA (3,121.3 μmol/kg) and morphine (31.1 μmol/kg) produced the maximum analgesic effect. However, three combinations of ASA + morphine (555.1 + 31.1, 986.9 + 9.8, and 1,755.2 + 9.8 μmol/kg, respectively) produced the highest potentiation effects (P < 0.01). The surface of synergistic interaction clearly showed which combination of these analgesic drugs produced the highest degree of potentiation in the rat. This study showed that it is possible to rationally predict the specific combinations of analgesic drugs and their dosages which will provide either maximal levels of analgesia or the highest potentiation effect in the rat. © 1995 Wiley‐Liss, Inc.
An FDA perspective on general pharmacology studies to determine activity and safety
Authors: Green Martin D.
Published: January 2005

General pharmacology studies are conducted to determine various pharmacological activities, as part of drug discovery or to define some specific issues which are relevant to safety. Regulatory submissions of biological products, unlike other therapeutics classes of agents, e.g., drugs, are frequently accompanied by extensive information regarding their preclinical aspects of physiology, biochemistry, and pharmacology. Although not true in every instances, biologic products exert their effects in a highly specific manner. Various fundamental aspects of protein chemistry and receptor function combine to restrict the spectrum of pharmacological and toxicological effects likely to occur. General pharmacology studies may be conducted either separately or nested in larger studies assessing general toxicity. Pharmacology studies are used best in an attempt to answer specific questions and are particularly effective when complementing other tests of safety. © 1995 Wiley‐Liss, Inc.
Pharmacological testing of recombinant human erythropoietin: Implications for other biotechnology products
Authors: Dempster A. Marguerite
Published: January 2005

The development of recombinant DNA and large‐scale cell culture technologies has introduced a wide range of biotechnology products or “biologics” including cytokines, vaccines, peptides, hormones, growth factors, and monoclonal antibodies that are being used in the diagnosis, prevention, and treatment of various diseases. As with any new drug development program, pharmacologic evaluation is critical to an understanding of that new drug entity. A well‐designed general/safety pharmacology program contribues to the overall safety assessment of that new entity, provides important information to the design of early clinical trials, assists in resolving any issues that arise during preclinical or clinical development, and assists in deciding whether to continue its development. This has been the case for many small molecular weight compounds and is no less important for the new biotechnology products. Because of their complex structural and biological characteristics, biotechnology products present unusual challenges in their development, resulting in pharmacology programs designed on a “case by case” basis. The pharmacologic evaluation of r‐HuEPO may well serve as an model for understanding some of the potential issues associated with the development of biologics. With r‐HuEPO being marketed worldwide for approximately five years, clinical data are available to assess the predictive value of the pharmacology studies. An analysis of these data serves as a guide to determine which preclinical studies best reflect the clinical data. Appropriate design of a pharmacology program depends on an understanding of the structure of the molecule, the mechanism of action at the cellular level, species specificity, and the clinical plan. On this basis a program can be developed to accurately assess the potential non‐pharmacologic effects and ultimately establish a benefit‐to‐risk ratio. © 1995 Wiley‐Liss, Inc.