bluuebunny/crossref_metadata_2025_split huggingface dataset:
Haem arginate infusion stimulates haem oxygenase‐1 expression in healthy subjects
Authors: Doberer D , Haschemi A , Andreas M , Zapf T‐C , Clive B , Jeitler M , Heinzl H , Wagner O , Wolzt M , Bilban M. 
Published: August 2010

BACKGROUND AND PURPOSEHaem oxygenase 1 (HO‐1) is an inducible protein that plays a major protective role in conditions such as ischaemia‐reperfusion injury and inflammation. In this study, we have investigated the role of haem arginate (HA) in human male subjects in the modulation of HO‐1 expression and its correlation with the GT length polymorphism (GTn) in the promoter of the HO‐1 gene.EXPERIMENTAL APPROACHIn a dose‐escalation, randomized, placebo‐controlled trial, seven healthy male subjects with a homozygous short (S/S) and eight with a long (L/L) GTngenotype received intravenous HA. HO‐1 protein expression and mRNA levels in peripheral blood monocytes, bilirubin, haptoglobin, haemopexin and haem levels were analysed over a 48 h observation period.KEY RESULTSWe found that the baseline mRNA levels of HO‐1 were higher in L/L subjects, while protein levels were higher in S/S subjects. HA induced a dose‐dependent increase in the baseline corrected area under the curve values of HO‐1 mRNA and protein over 48 h. The response of HO‐1 mRNA was more pronounced in L/L subjects but the protein level was similar across the groups.CONCLUSIONS AND IMPLICATIONHA is an effective inducer of HO‐1 in humans irrespective of the GTngenotype. The potential therapeutic application of HA needs to be evaluated in clinical trials.
6‐Shogaol, an active constituent of ginger, inhibits breast cancer cell invasion by reducing matrix metalloproteinase‐9 expression via blockade of nuclear factor‐κB activation
Authors: Ling H , Yang H , Tan S‐H , Chui W‐K , Chew E‐H 
Published: August 2010

BACKGROUND AND PURPOSE Shogaols are reported to possess anti‐inflammatory and anticancer activities. However, the antimetastatic potential of shogaols remains unexplored. This study was performed to assess the effects of shogaols against breast cancer cell invasion and to investigate the underlying mechanisms.EXPERIMENTAL APPROACH The anti‐invasive effect of a series of shogaols was initially evaluated on MDA‐MB‐231 breast cancer cells using the matrigel invasion assay. The suppressive effects of 6‐shogaol on phorbol 12‐myristate 13‐acetate (PMA)‐induced matrix metalloproteinase‐9 (MMP‐9) gelatinolytic activity and nuclear factor‐κB (NF‐κB) activation were further determined.KEY RESULTS Shogaols (6‐, 8‐ and 10‐shogaol) inhibited PMA‐stimulated MDA‐MB‐231 cell invasion with an accompanying decrease in MMP‐9 secretion. 6‐Shogaol was identified to display the greatest anti‐invasive effect in association with a dose‐dependent reduction in MMP‐9 gene activation, protein expression and secretion. The NF‐κB transcriptional activity was decreased by 6‐shogaol; an effect mediated by inhibition of IκB phosphorylation and degradation that subsequently led to suppression of NF‐κB p65 phosphorylation and nuclear translocation. In addition, 6‐shogaol was found to inhibit JNK activation with no resulting reduction in activator protein‐1 transcriptional activity. By using specific inhibitors, it was demonstrated that ERK and NF‐κB signalling, but not JNK and p38 signalling, were involved in PMA‐stimulated MMP‐9 activation.CONCLUSIONS AND IMPLICATIONS 6‐Shogaol is a potent inhibitor of MDA‐MB‐231 cell invasion, and the molecular mechanism involves at least in part the down‐regulation of MMP‐9 transcription by targeting the NF‐κB activation cascade. This class of naturally occurring small molecules thus have potential for clinical use as antimetastatic treatments.
Overview of the Pharmacological Features of Honokiol
Authors: Maruyama Yuji , Kuribara Hisashi 
Published: August 2010

ABSTRACTThis paper provides an overview of the pharmacological features of honokiol (3′,5‐di‐2‐propenyl‐1,1′‐biphenyl‐2,4′‐diol), an isomer of neolignans isolated and identified from the stem bark of Magnoliaceous plants (Magnolia obovataThunb, Wa‐Koboku in Japanese). The magnolia bark has been utilized as a herbal remedy for the treatment of a wide variety of clinical disorders. Honokiol and magnolol (an isomer of honokiol) were recently identified as anxiolytic agents in the extracts of Saiboku‐to, an oriental herbal medicine (Kampo). Behavioral evaluation through an elevated plus‐maze test demonstrated that honokiol, 0.2–2 mg/kg, p.o., for 7 days, was at least 5000 times more potent than Saiboku‐to. Honokiol has a comparatively lower risk of causing benzodiazepine‐like side effects, such as central depression, muscle relaxation, amnesia, or physical dependence. In addition to these central actions, a wide variety of pharmacological effects and biochemical activities of honokiol have been reported during the past 10 years. The main effects, including the limited information regarding the metabolism and kinetics of the compound, are briefly introduced in this text. Information available on honokiol, including its specific and simple chemical structure, suggests the possibility of deriving more potent compounds in the drug design process.
Sipatrigine (BW 619C89) is a Neuroprotective Agent and a Sodium Channel and Calcium Channel Inhibitor
Authors: Hainsworth Atticus H. , Stefani Alessandro , Calabresi Paolo , Smith Terence W. , Leach Michael J. 
Published: August 2010

AbstractSipatrigine is a substituted pyrimidine derived from lamotrigine. It attenuates glutamate releasein vitroandin vivo, probably as a result of sodium and calcium channel inhibition. It consistently reduces cortical infarct volume in rodent models of global, permanent focal, and transient focal ischemia (typically 50–60% reduction with maximum effective doses >20 mg/kg). Striatal protection was found in some studies but not others. The drug was effective also in a rat optic nerve model of white matter ischemia, providing complete neuroprotection at the highest concentration (100 μM) used. In monkeys, CNS penetration by sipatrigine was rapid and the steady state brain/plasma ratio was >40. In humans, low doses (< 2 mg/kg, then 1 mg/kg/8 h) were well tolerated. At higher doses a significant incidence of hallucinations and vomiting was observed. These adverse effects were speculated to be due to interactions with muscarinic receptors and 5‐HT3(or sigma) receptors, respectively. Cardiovascular side effects appeared not to be a major concern. In electrophysiological studies, sipatrigine inhibited native neuronal sodium and calcium channels (including L, N, and P/Q type) and recombinant type IIA sodium and N and T type calcium channels, all with similar potency (IC50in the range 5–16 μM). Inhibitory potency was increased by high action potential firing frequencies and a depolarized resting voltage. These properties may account for its actionsin vitroand in animal models but do not exclude possible additional actions in later stages of ischemic damage.
SNX‐482: A Novel Class E Calcium Channel Antagonist from Tarantula Venom
Authors: Newcomb Robert , Chen Xiao‐hua , Dean Robin , Dayanithi Govindin , Cong Ruth , Szoke Balazs , Lemos Jose , Bowersox Scott , Miljanich George 
Published: August 2010

ABSTRACTCalcium channels are represented by at least 9 distinct genes (calcium channel classes A‐I), corresponding to at least 5 functional and pharmacological “types” (L, N, P/Q, R and T). Selective L‐, N‐, and T‐type channel antagonists are either in clinical use or in late stage clinical trials, while antagonists of P/Q channels are known to be toxic. No selective ligand has been identified for the R‐type (class E), and its function and pharmacology are consequently, poorly understood. We review recent work on the discovery and initial characterization of SNX‐482, the first known selective antagonist of R‐type calcium channels. SNX‐482 is a 41 residue acidic peptide with three disulfide bonds that has been isolated from the venom of the African tarantula,Hysterocrates gigas.In cell‐based assays, it is a potent and selective inhibitor of the class E or R‐type calcium channel. SNX‐482 blocks some but not all native R‐type currents: it blocks an R‐type current in vertebrate neurohypophysis, but it does not block an R‐type current in cerebellar granule cells. The peptide blocks oxytocin but not vasopressin release, suggesting a possible utility for SNX‐482 as a neuroendocrine modulator. The peptide possesses antiseizure activity in several animal models of epilepsy, suggesting that class E antagonists may have pharmacological use in seizure disorders.
Preclinical Pharmacology of ABT‐594: A Nicotinic Acetylcholine Receptor Agonist for the Treatment of Pain
Authors: Meyer Michael D. , Anderson David J. , Campbell Jeffrey E. , Carroll Sherry , Marsh Kennan C. , Rodrigues A. David , Decker Michael W. 
Published: August 2010

ABSTRACTABT‐594 [(R)‐5‐(2‐azetedinylmethoxy)‐2‐chloropyridine mono‐tosylate salt] is a neuronal nicotinic acetylcholine receptor (nAChR) agonist with antinociceptive activity in rodent pain models. Whereas the binding affinity of ABT‐594 at α4β2‐containing nAChRs is comparable to that of (±)‐epibatidine, ABT‐594 has lower affinity than (±)‐epibatidine at α3‐containing nAChRs. Similarly, ABT‐594 is approximately equivalent to (±)‐epibatidine in a Ca2+flux assay in K‐177 cells that express 04132 nAChRs but less potent than (±)‐epibatidine in the IMR‐32 (α3‐containing) cell line. ABT‐594 is active in a variety of rodent models of acute thermal (mouse hot‐plate, rat thermal paw withdrawal), persistent chemical (mouse abdominal constriction, rat formalin) and neuropathic (diabetic neuropathy and Chung spinal nerve ligation in rats) pain. Effects of ABT‐594 on acute thermal pain appear to be mediated centrally and may involve activation of descending inhibition originating in the brainstem. ABT‐594 decreases responses of wide dynamic range neurons in the dorsal lumbar spinal cord to noxious thermal and mechanical stimuli but does not alter responses of these neurons to innocuous stimuli. ABT‐594 has plasma elimination half life ranging from < 0.5 h in mice to 4.7 h in dogs and readily penetrates the CNS. Oral bioavailability ranges from 35 to 80% in a variety of species. In rats, the majority of ABT‐594 is excreted in the urine after both oral and intravenous administration, and parent drug accounts for better than 75% of total radioactivity in plasma after administration of labeled ABT‐594 (AUC0–12)
A Novel Approach to the Identification of Psychiatric Drugs: Serotonin‐Glutamate Interactions in the Prefrontal Cortex
Authors: Marek Gerard J. 
Published: August 2010

ABSTRACTActivation of neocortical 5‐hydroxytryptamine2A(5‐HT2A) receptors is thought to mediate the profound psychomimetic effects of hallucinogenic drugs such as LSD and mescaline. These effects include alteration in mood, perception, and cognition. Conversely, blockade of neocortical 5‐HT2receptor may be related to the thymoleptic effects of newly released antidepressant (e.g., mirtazepine, nefazodone) and atypical antipsychotic drugs (e.g., risperidone, olanzapine). Therefore, one strategy to develop novel antidepressant drugs might be to identify drugs which suppress the effects of 5‐HT2Areceptor activation in key neurocircuits. Electrophysiological experiments usingin vitrorat slices of the medial prefrontal cortex have found that activation of 5‐HT2Areceptors results in glutamate release from thalamocortical terminals by a novel focal effect. A number of monoamine (5‐HT1/7, β2), metabotropic glutamate (mGlu2), and neuropeptide (μ‐opioid) receptors suppress the glutamate release induced by 5‐HT2Areceptor activation. Clinical studies examining the effects of serotonin or catecholamine depletion suggest the activation of 5‐HT or catecholamine receptors mediate the therapeutic effects of selective serotonin reuptake inhibitors (SSRIs) or tricyclic antidepressants (TCAs), respectively. In addition, opiate agonists may have antidepressant properties. Therefore, it is suggested that elucidation of the specific receptors that suppress glutamate release induced by 5‐HT2Areceptor activation in the medial prefrontal cortex may have several effects. First, this might lead to a more complete understanding of the 5‐HT receptor(s) that mediate the therapeutic effects of presently used drugs such as SSRIs. This site might be a therapeutic target free of side effects such as sexual dysfunction. Second, this strategy might lead to novel therapeutic targets for depression, such as metabotropic glutamate agonists which may not be efficacious in screening strategies primarily dependent on synaptic availability of monoaminergic neurotransmitters.
Genetically Epilepsy‐Prone Rats (GEPRs) in Drug Research
Authors: Jobe Phillip C. , Dailey John W. 
Published: August 2010

ABSTRACTTwo independently derived, inbred strains of genetically epilepsy‐prone rats (GEPRs) have been developed, the moderately epileptic GEPR‐3 and the more severely epileptic GEPR‐9. Seizures expressed by GEPRs model human generalized tonic/clonic seizures (GTCSs) and partial seizures secondarily generalized to tonic/clonic seizures. Several types of existing antiepileptic drugs have been tested in the GEPR model. Without exception, the seizure suppressing properties of these drugs occur both in GEPR‐3 s and GEPR‐9s. The differential responses of the two GEPR strains separate the antiepileptic drugs into three categories: (1) those effective in GTCSs and partial seizures; (2) those that are additionally effective in absence seizures; and (3) those effective in absence seizures but not in convulsive seizures. No known false positives have yet been detected in GEPR tests. In addition to the utility of the seizures expressed by GEPRs in drug development paradigms, these animals also have potential in the search for drugs that are specifically “antiseizure predisposition” rather than merely anticonvulsant. Heretofore, worldwide drug development efforts have emphasized the discovery of drugs that are anticonvulsant in nonepileptic animals. As might have been anticipated, these same drugs have proven to be anticonvulsant in epileptic subjects. Paradigms that would detect drugs with the capacity to correct the biological determinants of predisposition are in early stages of application. Kindling seizures provide a means to identify drugs that might be useful in correcting stimulus‐induced seizure predisposition. The GEPR and other genetic models of the epilepsies provide models for developing treatments to correct genetically determined seizure predisposition. Emerging evidence supports the hypothesis that GEPRs model comorbidity between the epilepsies and affective disorders. Understanding the basis of this comorbidity has the potential to enable the development of treatments that reverse the underlying abnormalities of the coexisting disorders. Because human epilepsies and affective disorders are environmentally and genetically complex, the abnormalities of the GEPR probably will not account for all predispositions leading to this comorbidity.
2‐(2‐aminoethyl)‐quinoline (D‐1997): A Novel Agonist at Craniovascular 5‐HT1Receptors Relevant to Migraine Therapy
Authors: Terrón José A. 
Published: August 2010

ABSTRACTThe functional pharmacological properties of a group of quinoline‐derivatives were screened for agonist activity at 5‐HT1‐like receptors mediating vasoconstriction. In experimental models predictive of antimigraine activity, 2‐(2‐aminoethyl) quinoline hydrochloride (D‐1997) exhibited higher potency and efficacy at vasoconstrictor 5‐HT1‐like receptors than quipazine. D‐1997 was also found to activate a novel vasoconstrictor mechanism in the carotid circulation. It is suggested D‐1997 may represent a useful lead in the search for better acute antimigraine therapies.
Pitrazepin: Interactions with Transmitter Receptors of the Central and Peripheral Nervous Systems
Authors: Demuro Angelo , Miledi Ricardo 
Published: August 2010

ABSTRACTPitrazepin [3‐(piperazinyl‐1)‐9H‐dibenz(c.f)triazolo(4,5‐a)azepin], is an N‐aryl‐piperazine derivative, whose heterocyclic structure is similar to that of atypical antipsychotics like clozapine. This paper is an overview of the pharmacological actions of pitrazepin, with an emphasis on its actions on GABAAand glycine neurotransmitter receptors. Recent results on the antagonist actions of pitrazepin on acetylcholine (ACh) currents in oocytes expressing either rat neuronal or mouse muscle nicotinic acetylcholine receptors are presented. Many of the pharmacological features of the new‐generation antipsychotics have been derived from studies of structurally treated drugs. A detailed understanding of the ineractions of these drugs with neurotransmitter receptor is necessary to develop more effective antipsychotics.
BTS 72664 – A Novel CNS Drug With Potential Anticonvulsant, Neuroprotective, and Antimigraine Properties
Authors: Smith Sharon L. , Thompson Kevin S. J. , Sargent Bruce J. , Heal David J. 
Published: August 2010

ABSTRACTBTS 72664, (R)‐7‐[1‐(4‐chlorophenoxy)]ethyl]‐1,2,4‐triazolo(1,5‐α)pyrimidine, was identified as a drug development candidate from a research program designed to discover novel, broad‐spectrum, non‐sedative anticonvulsant drugs. BTS 72664 antagonized bicuculline (BIC)‐ and maximal electroshock (MES)‐induced convulsions with ED50values of 1.9 and 47.5 mg/kg p.o., respectively. In rodents, it has a wide spectrum of activity preventing seizures induced by picrotoxin, pentylenetetrazol, i.c.v. 4‐aminopyridine or NMD A, and audiogenic seizures in DBA‐2 mice and GEPR‐9 rats. BTS 72664 was also effective in preventing convulsions in amygdala‐kindled rats The lack of sedative potential was predicted on the basis of wide separation between ED50in anticonvulsant models and TD50for motor impairment in mice in rotating rod and inverted horizontal grid tests. BTS 72664 is likely to produce its anticonvulsant effect by enhancing chloride currents through picrotoxin‐sensitive chloride channels, and by weak inhibition of Na+and NMDA channels. It does not act, however, at the benzodiazepine binding site. In addition to its potential use in the treatment of epilepsy BTS 72664 may be useful in the treatment of stroke. At 50 mg/kg p.o. x 4, given to rats at 12 hourly intervals, starting at 15 min after permanent occlusion of middle cerebral artery (MCA), it reduced cerebral infarct size by 31% (measured at 2 days after insult) and accelerated recovery in a functional behavioral model. BTS 72664 prevented increases in extraneuronal concentrations of glutamate, glycine and serine brain levels induced by a cortical insult to rats (cf. cortical spreading depression). It may, therefore, have also antimigraine activity.
Pharmacology of the Atypical Antipsychotic Remoxipride, a Dopamine D2Receptor Antagonist
Authors: Nadal Roser 
Published: August 2010

ABSTRACTRemoxipride is a substituted benzamide that acts as a weak but very selective antagonist of dopamine D2receptors. It was introduced by Astra (Roxiam) at the end of the eighties and was prescribed as an atypical antipsychotic. This article reviews its putative selective effects on mesolimbic versus nigrostriatal dopaminergic systems. In animals, remoxipride has minimal cataleptic effects at doses that block dopamine agonist‐induced hyperactivity. These findings are predictive of antipsychotic activity with a low likelihood of extrapyramidal symptoms. Remoxipride also appears to be effective in more recent animal models of schizophrenia, such as latent inhibition or prepulse inhibition. In clinical studies, remoxipride shows a relatively low incidence of extrapyramidal side effects and its effects on prolactin release are short‐lasting and generally mild. The clinical efficacy of remoxipride is similar to that of haloperidol or chlorpromazine. Although its clinical use was severely restricted in 1993, due to reports of aplastic anemia in some patients receiving remoxipride, this drug has been found to exhibit relatively high selectivity for dopamine D2receptors making remoxipride an interesting tool for neurochemical and behavioral studies.
SCH 23390: The First Selective Dopamine D1‐Like Receptor Antagonist
Authors: Bourne James A. 
Published: August 2010

ABSTRACTSCH 23390, the halobenzazepine (R)‐(+)‐7‐chloro‐8‐hydroxy‐3‐methyl‐1‐phenyl‐2,3,4,5‐tetrahydro‐1H–3‐benzazepine, is a highly potent and selective dopamine D1‐like receptor antagonist with aKiof 0.2 and 0.3 nM for the D1and D5dopamine receptor subtypes, respectively.In vitro, it also binds with high affinity to the 5‐HT2and 5‐HT1Cserotonin receptor subtypes. However, the doses required to induce a similar responsein vivoare greater than 10‐fold higher than those required to induce a D1‐mediated response.Previousin vivopharmacological studies with SCH 23390 have shown it to abolish generalized seizures evoked by the chemoconvulsants: pilocarpine and soman. These studies provide evidence of the potential importance of D1‐like dopaminergic receptor mechanisms in facilitating the initiation and spread of seizures. The inference from a majority of studies is that the activation of dopamine D1receptors facilitates seizure activity, whereas activation of D2receptors may inhibit the development of seizures. SCH 23390 has also been used in studies of other neurological disorders in which the dopamine system has been implicated, such as psychosis and Parkinson's disease. Apart from the study of neurological disorders, SCH 23390 has been extensively used as a tool in the topographical determination of brain D1receptors in rodents, nonhuman primates, and humans.In summary, SCH 23390 has been a major tool in gaining a better understanding of the role of the dopamine system, more specifically the D1receptor, in neurological function and dysfunction.
SB‐236057‐A: A Selective 5‐HT1B Receptor Inverse Agonist
Authors: Roberts Claire , Watson Jeanette , Price Gary W. , Middlemiss Derek N. 
Published: August 2010

ABSTRACT5‐HT1B autoreceptors are involved in the control of extracellular 5‐HT levels from both the terminal and cell body regions of serotonergic neurons. In this manuscript we review the pharmacological and pharmacokinetic data available for the selective and potent 5‐HT1B receptor inverse agonist, SB‐236057‐A (1′‐ethyl‐5‐(2′‐methyl‐4′‐(5‐methyl‐1,3,4‐oxadiazolyl‐2‐yl)biphenyl‐4‐carbonyl)‐2,3,6,7‐tetrahydrospiro (furo[2,3‐f]indole‐3,4′‐piperidine) hydrochloride). SB 236057‐A has been shown to have high affinity for human 5‐HT1B receptors (pKi= 8.2) and displays 80 or more fold selectivity for the human 5‐HT1B receptor over other 5‐HT receptors and a range of additional receptors, ion channels and enzymes. In functional studies at human 5‐HT1B receptors SB‐236057‐A displayed inverse agonism (pA2= 8.9) using [35S]GTPγS binding, and silent antagonism (pA2= 9.2) using cAMP accumulation. SB‐236057‐A also acted as an antagonist at the 5‐HT terminal autoreceptor as measured by [3H]5‐HT release from electrically stimulated guinea pig and human cortical slices.In the guinea pig, pharmacokinetic analysis demonstrated that SB‐236057‐A was bioavailable and according to in vivo pharmacodynamic assays it enters brain and has a long duration of action. Importantly no side effect liability was evident at relevant doses from anxiogenic, cardiovascular, sedative or migraine viewpoints. In vivo microdialysis studies demonstrated that SB‐236057‐A is an antagonist in the guinea pig cortex but has no effect on extracellular 5‐HT levels per se. In contrast, SB‐236057‐A increased extracellular 5‐HT levels in the guinea pig dentate gyrus. This increase in 5‐HT release was comparable to that observed after 14 days of paroxetine administration.SB‐236057‐A has been a useful tool in confirming that, in either guinea pigs or humans, the terminal 5‐HT autoreceptor is of the 5‐HT1B subtype. It appears that acute 5‐HT1B receptor blockade, by virtue of increased 5‐HT release in the dentate gyrus, may provide a rapidly acting antidepressant.