bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potentiation of halofantrine‐induced QTc prolongation by mefloquine: correlation with blood concentrations of halofantrine
Authors: Lightbown Ian D , Lambert James P , Edwards Geoffrey , Coker Susan J 
Published: January 2005

The antimalarial drug halofantrine can prolong the QT interval and this may be enhanced by prior use of mefloquine. This possible interaction has been investigated by examining the effects of halofantrine and mefloquine alone and in combination.
In anaesthetized rabbits (n=6 per group), halofantrine given as bolus doses of 1, 3, 10, and 30 mg kg−1 at 25 min intervals dose‐dependently prolonged the rate‐corrected QT (QTc) interval from 313±12 ms pre‐drug to 410±18 ms after the highest dose. Similar doses of mefloquine did not alter QTc intervals significantly. The highest dose of mefloquine (30 mg kg−1) caused cardiac contractile failure.
Pretreatment with 3 mg kg−1 mefloquine 25 min before the first dose of halofantrine potentiated the effects of all doses of halofantrine on QTc intervals.
The blood concentrations of halofantrine were two to six times higher in the group pretreated with mefloquine compared to the halofantrine alone group; e.g. 1.03±0.17 and 0.16±0.02 μM respectively after 1 mg kg−1 halofantrine. There was a significant correlation between blood halofantrine concentrations and QTc intervals (r=0.673). Even after making allowance for overestimation of the potency of halofantrine that may result from the hypokalaemia that is prevalent in anaesthetized rabbits, these effects occurred with concentrations of halofantrine that are found in clinical use.
These data indicate clearly that while mefloquine does not alter QTc intervals itself, it does enhance the effects of halofantrine by increasing the circulating concentration of halofantrine.

British Journal of Pharmacology (2001) 132, 197–204; doi:10.1038/sj.bjp.0703823
Effects of γ‐HCH and δ‐HCH on human recombinant GABAA receptors: dependence on GABAA receptor subunit combination
Authors: Maskell P D , Wafford K A , Bermudez I 
Published: January 2005

Human GABAA receptors containing different α and β subunits with or without the γ2S or γ2L subunits were expressed in Xenopus oocytes and the effects of the insecticides γ‐ and δ‐hexachlorocyclohexane (γ‐HCH and δ‐HCH, respectively) on these receptor subunit combinations were examined using two electrode voltage‐clamp procedures.
γ‐HCH produced incomplete inhibition of GABA responses on all receptor combinations examined with affinities in the range of 1.1 – 1.9 μM. Affinity was not dependent on subunit composition but the maximum percentage of inhibition was significantly reduced in β1‐containing receptors.
δ‐HCH both potentiated GABAA receptors and activated them in the absence of GABA at concentrations higher than those producing potentiation. Allosteric enhancement of GABAA receptor function by δ‐HCH was not affected by the subunit composition of the receptor, By contrast the GABA mimetic actions of δ‐HCH were abolished in receptors containing either α4, β1 or γ2L subunits.
Sensitivity to the direct actions were not restored in receptors containing the mutant β1(S290N) subunit, but α1β2γ2L receptors became sensitive to the direct actions of δ‐HCH when oocytes were treated for 24 h with the protein kinase inhibitor isoquinolinesulphonyl‐2‐methyl piperazine dihydrochloride (H‐7).
We have shown the influence of various α, β and γ subunits on the inhibitory, GABA mimetic and allosteric effects of HCH isomers. The data reveal that neither the inhibitory actions of γ‐HCH nor the allosteric effects δ‐HCH has a strict subunit dependency. By contrast, sensitivity to the direct actions of δ‐HCH are abolished in receptors containing α4, β1 or γ2L subunits.

British Journal of Pharmacology (2001) 132, 205–212; doi:10.1038/sj.bjp.0703824
Rasagiline [N‐propargyl‐1R(+)‐aminoindan], a selective and potent inhibitor of mitochondrial monoamine oxidase B
Authors: Youdim Moussa B H , Gross Aviva , Finberg John P M 
Published: January 2005

Rasagiline [N‐propargyl‐1R(+)‐aminoindan], was examined for its monoamine oxidase (MAO) A and B inhibitor activities in rats together with its S(−)‐enantiomer (TVP 1022) and the racemic compound (AGN‐1135) and compared to selegiline (1‐deprenyl). The tissues that were studied for MAO inhibition were the brain, liver and small intestine.
While rasagiline and AGN1135 are highly potent selective irreversible inhibitors of MAO in vitro and in vivo, the S(−) enantiomer is relatively inactive in the tissues examined.
The in vitro IC50 values for inhibition of rat brain MAO activity by rasagiline are 4.43±0.92 nM (type B), and 412±123 nM (type A). The ED50 values for ex vivo inhibition of MAO in the brain and liver by a single dose of rasagiline are 0.1±0.01, 0.042±0.0045 mg kg−1 respectively for MAO‐B, and 6.48±0.81, 2.38±0.35 mg kg−1 respectively for MAO‐A.
Selective MAO‐B inhibition in the liver and brain was maintained on chronic (21 days) oral dosage with ED50 values of 0.014±0.002 and 0.013±0.001 mg kg−1 respectively.
The degree of selectivity of rasagiline for inhibition of MAO‐B as opposed to MAO‐A was similar to that of selegiline. Rasagiline was three to 15 times more potent than selegiline for inhibition of MAO‐B in rat brain and liver in vivo on acute and chronic administration, but had similar potency in vitro.
These data together with lack of tyramine sympathomimetic potentiation by rasagiline, at selective MAO‐B inhibitory dosage, indicate that this inhibitor like selegiline may be a useful agent in the treatment of Parkinson's disease in either symptomatic or L‐DOPA adjunct therapy, but lack of amphetamine‐like metabolites could present a therapeutic advantage for rasagiline.

British Journal of Pharmacology (2001) 132, 500–506; doi:10.1038/sj.bjp.0703826
Impaired response to interferon‐γ in activated macrophages due to tyrosine nitration of STAT1 by endogenous nitric oxide
Authors: Llovera Marta , Pearson Jeremy D , Moreno Carlos , Riveros‐Moreno Valentina 
Published: January 2005

Inducible NO synthase (iNOS) expression and activity were measured in the mouse macrophage cell line J774 after exposure to bacterial lipopolysaccharide (LPS) with or without interferon‐γ (IFN‐γ).
Inhibition of NOS activity by concomitant NG‐monomethyl‐L‐arginine (L‐NMMA) treatment further increased iNOS protein levels, with a substantial increase in iNOS half‐life.
Western blotting and ELISA demonstrated that several cell proteins were tyrosine‐nitrated when iNOS activity was high.
Rapid IFN‐γ‐induced phosphorylation of STAT1 was reduced by about 40% when cells were pretreated to induce iNOS, unless L‐NMMA was present during the pretreatment period. 2D gel electrophoresis demonstrated the presence of nitrotyrosine in STAT1 after iNOS induction, and confirmed the reduction in phospho‐STAT1 on subsequent stimulation with IFN‐γ for 15 min and its partial restoration when L‐NMMA was present during the pretreatment period.
We did not detect tyrosine nitration of the upstream kinase JAK2 in LPS+IFN‐γ pretreated cells, but JAK2 activity was also impaired, and was partially restored by concomitant L‐NMMA pretreatment.
We conclude that endogenous production of NO induces feedback inhibition of signalling pathways activated by IFN‐γ, at least in part by nitrating tyrosine residues in STAT1 which prevents phosphorylation.

British Journal of Pharmacology (2001) 132, 419–426; doi:10.1038/sj.bjp.0703838
Nedocromil sodium inhibits histamine‐induced itch and flare in human skin
Authors: Ahluwalia Poonam , McGill James I , Church Martin K 
Published: January 2005

This study was designed to test the hypothesis that nedocromil sodium inhibits sensory nerve function to reduce flare and itch in human skin. Nedocromil sodium (2%) or water (control) was introduced into the volar forearm skin of eight non‐atopic volunteers by iontophoresis (8 mC) and histamine (20 μl of 1 μM and 300 nM) injected intradermally 10 min later at the same site. Itch was assessed on a visual analogue scale every 20 s for 5 min. Weal and flare areas and mean blood flux within the flare were assessed by scanning laser Doppler imaging at 10 min. The results showed that nedocromil sodium reduced itch scores, totalled over 5 min, by ∼74.0% (P<0.005) and flare areas by ∼65% (P<0.03). Neither weal areas nor blood flux within were reduced. These data demonstrate that nedocromil sodium is effective in reducing neurogenic itch and flare in the skin. We suggest that its mechanism of action is modulation of sensory neurone activation or conduction in the skin.British Journal of Pharmacology (2001) 132, 613–616; doi:10.1038/sj.bjp.0703852
Indoxacarb, an oxadiazine insecticide, blocks insect neuronal sodium channels
Authors: Lapied Bruno , Grolleau Françoise , Sattelle David B 
Published: January 2005

Decarbomethoxyllated JW062 (DCJW), the active component of a new oxadiazine insecticide DPX‐JW062 (Indoxacarb), was tested on action potentials and the inward sodium current recorded from short‐term cultured dorsal unpaired median neurones of the cockroach Periplaneta americana.
Under whole‐cell current‐clamp conditions, 100 nM DCJW reduced the amplitude of action potentials and induced a large hyperpolarization of the resting membrane potential associated with a 41% increase in input resistance.
In voltage‐clamp, DCJW resulted in a dose‐dependent inhibition (IC50 28 nM) of the peak sodium current. Based on IC50 values, the effect of DCJW was about 10 fold less potent than tetrodotoxin (TTX) but 1000 fold more potent than the local anaesthetic lidocaine. DCJW (100 nM) was without effect on activation properties of the sodium current, reversal potential, voltage dependence of sodium conductance and on both fast and slow steady‐state inactivations.
TTX (2 nM) resulted in 48% inhibition of the peak inward sodium current. Co‐application of TTX (2 nM) with various concentrations of DCJW produced an additional inhibition of the peak inward current, indicating that the blocking actions of DCJW and TTX were distinct. Co‐application of lidocaine (IC50 30 μM) with various concentrations of DCJW produced a reduction of the apparent potency of DCJW, suggesting that DCJW and lidocaine acted at the same site.
DCJW (100 nM) did not affect inward calcium or outward potassium currents.
This study describes, for the first time, the action on insect neuronal voltage‐dependent sodium channels of Indoxacarb, a new class of insecticides.

British Journal of Pharmacology (2001) 132, 587–595; doi:10.1038/sj.bjp.0703853
GABAB receptor autoradiography in hippocampal sclerosis associated with human temporal lobe epilepsy
Authors: Billinton Andrew , Baird Virginia H , Thom Maria , Duncan John S , Upton Neil , Bowery Norman G 
Published: January 2005

Metabotropic γ‐aminobutyric acid receptors (GABAB) exist both pre‐ and postsynaptically throughout the brain, mediating the suppression of neurotransmitter release and late inhibitory postsynaptic potentials. Investigation of GABAB receptors in rodent models of temporal lobe epilepsy (TLE) suggests that expression or function of these receptors may be altered in the disorder.
The aim of the present study was to investigate the expression of GABAB receptors in samples of hippocampus surgically resected from patients with hippocampal sclerosis (HS) related intractable TLE, and compare this expression with samples of neurologically normal post‐mortem (PM) control hippocampal tissue. Appropriate measures of neuronal loss associated with HS were investigated for comparison with receptor binding data.
Receptor autoradiography with [3H]‐GABA in the presence of isoguvacine, and quantitative densitometric analysis were used to investigate GABAB receptor expression (Bmax) and affinity (KD) in 11 HS samples and eight controls. A three‐dimensional cell counting technique was used to assess neuronal density in both groups.
GABAB receptor density was significantly reduced in CA1, CA2, CA3, hilus and dentate gyrus, and increased in the subiculum, of HS cases as compared with PM controls. Neuronal loss was significant in all regions measured. When adjusted for neuronal loss, CA1 GABAB receptor expression appeared significantly upregulated (P<0.05).
In HS/TLE, GABAB receptor expression per remaining neurone appears increased in CA1. This finding, and increased [3H]‐GABA affinity at CA3 and hilar GABAB receptors, suggests altered GABAB receptor function may occur in human HS/TLE, possibly as a result of synaptic reorganization.

British Journal of Pharmacology (2001) 132, 475–480; doi:10.1038/sj.bjp.0703854
A novel activation of Ca2+‐activated Cl− channel in Xenopus oocytes by Ginseng saponins: evidence for the involvement of phospholipase C and intracellular Ca2+ mobilization
Authors: Choi Seok , Rho Seong‐Hwan , Jung Se‐Yeon , Kim Seok‐Chang , Park Chul‐Seung , Nah Seung‐Yeol 
Published: January 2005

The signal transduction mechanism of ginsenosides, the active ingredients of ginseng, was studied in Xenopus oocytes using two‐electrode voltage‐clamp technique. Ginseng total saponin (GTS), i.e., an unfractionated mixture of ginsenosides produced a large outward current at membrane potentials more positive than −20 mV when it was applied to the exterior of oocytes, but not when injected intracellularly. The effect of GTS was concentration‐dependent (EC50: 4.4 μg ml−1) and reversible.
Certain fractionated ginsenosides (Rb1, Rb2, Rc, Rf, Rg2 and Ro) also produced an outward current in a concentration‐dependent manner with the order of potency of Rf>Ro>Rb1=Rb2>Rg2>Rc. Other ginsenosides (Rd, Re and Rg1) had little or no effect.
The GTS effect was completely blocked by bath application of the Ca2+‐activated Cl− channel blocker niflumic acid and by intracellular injection of the calcium chelator BAPTA or the IP3 receptor antagonist heparin. Also, the effect was partially blocked by bath‐applied U‐73122, a phospholipase C (PLC) inhibitor and by intracellularly injected GTPγS, a non‐hydrolyzable GTP analogue. Whereas, it was not altered by pertussin toxin (PTX) pretreatment.
These results indicate that: (1) interaction of ginsenosides with membrane component(s) at the extracellular side leads to Ca2+‐activated Cl− channel opening in Xenopus oocyte membrane; and (2) this process involves PLC activation, the release of Ca2+ from the IP3‐sensitive intracellular store and PTX‐insensitive G protein activation.

British Journal of Pharmacology (2001) 132, 641–648; doi:10.1038/sj.bjp.0703856
Somatostatin receptor‐mediated arachidonic acid mobilization: evidence for partial agonism of synthetic peptides
Authors: Alderton Forbes , Fan Tai‐Ping D , Humphrey Patrick P A 
Published: January 2005

Somatostatin and the stable octapeptide analogues, octreotide and angiopeptin, were examined for their ability to stimulate the release of tritium from [3H]‐arachidonic acid pre‐loaded CHO‐K1 cells expressing human recombinant sst2, sst3 or sst5 receptors.
Somatostatin stimulated tritium release (pEC50) through the sst2 (7.8±0.1) and sst5 (7.3±0.2), but not the sst3 receptor. Octreotide behaved as a full (sst2 receptor) or partial agonist (sst5 receptor), whereas angiopeptin behaved as a weak partial agonist at both receptor types.
Maximum responses to somatostatin through both receptor types were significantly reduced by pertussis toxin, whereas pEC50 estimates were unaffected.
Inhibition of MEK1 or Src, but not PKA, PI 3‐kinases or tyrosine kinases, by reportedly selective inhibitors reduced sst2‐mediated responses by somatostatin, but not angiopeptin. A selective inhibitor of PKC (Ro‐31‐8220) reduced both somatostatin and angiopeptin responses.
These data provide further evidence for partial agonist activity of synthetic peptides of somatostatin. Furthermore, the somatostatin receptor signalling mechanisms which mediate arachidonic acid mobilization appear to be multiple and complex.

British Journal of Pharmacology (2001) 132, 760–766; doi:10.1038/sj.bjp.0703862
β2‐Adrenoceptor agonists inhibit release of eosinophil‐activating cytokines from human airway smooth muscle cells
Authors: Hallsworth Matthew P , Twort Charles H C , Lee Tak H , Hirst Stuart J 
Published: January 2005

Airway smooth muscle (ASM) is a potential source of multiple pro‐inflammatory cytokines during airway inflammation. β‐Adrenoceptor agonist hyporesponsiveness is a characteristic feature of asthma, and interleukin (IL)‐1β and tumour necrosis factor (TNF)‐α are implicated in its cause. Here, the capacity of β‐adrenoceptor agonists to prevent release of GM‐CSF, RANTES, eotaxin and IL‐8, elicited by IL‐1β or TNFα, was examined in human ASM cells.
Isoprenaline (∼EC50 150 nM), a non‐selective β‐adrenoceptor agonist, and salbutamol (∼EC50 25 nM), a selective β2‐adrenoceptor agonist, attenuated release of GM‐CSF, RANTES and eotaxin, but not IL‐8 (EC50 >1 μM). The maximum extent of attenuation was RANTES eotaxin > GM‐CSF >> IL‐8, and was prevented by either propranolol (1 μM), a non‐selective β‐adrenoceptor antagonist, or ICI 118511 (IC50 15 nM), a selective β2‐adrenoceptor antagonist.
The cyclic AMP‐elevating agents, dibutyryl cyclic AMP (∼EC50 135 μM), forskolin (∼EC50 530 nM) and cholera toxin (∼EC50 575 pg ml−1) abolished IL‐1β‐induced release of GM‐CSF, RANTES and eotaxin, but not IL‐8.
IL‐1β (1 ng ml−1) attenuated early increases (up to 1 h) in cyclic AMP formation induced by salbutamol (1 μM), but not by forskolin (10 μM). The cyclo‐oxygenase inhibitor, indomethacin (1 μM) prevented later increases (3 – 12 h) in IL‐1β‐stimulated cyclic AMP content, but did not prevent the attenuation by salbutamol of IL‐1β‐induced cytokine release.
We conclude in human ASM cells that activation of β2‐adrenoceptors and generation of cyclic AMP is negatively‐linked to the release, elicited by IL‐1β or TNFα, of eosinophil‐activating cytokines such as GM‐CSF, RANTES and eotaxin, but not IL‐8.

British Journal of Pharmacology (2001) 132, 729–741; doi:10.1038/sj.bjp.0703866
Orphenadrine prevents 3‐nitropropionic acid‐induced neurotoxicity in vitro and in vivo
Authors: Pubill David , Verdaguer Ester , Canudas Anna Ma , Sureda Francesc Xavier , Escubedo Elena , Camarasa Jordi , Pallàs Merce , Camins Antoni 
Published: January 2005

Previous studies indicate that 3‐nitropropionic acid (3‐NPA) neurotoxicity involves the excitotoxic activation of N‐methyl‐D‐aspartate (NMDA) receptors. Thus, we examined the effect of orphenadrine (an anticholinergic drug with NMDA receptor antagonist properties) on 3‐NPA neurotoxicity in both cultured rat cerebellar granule cells (CGCs) and in rats.
Orphenadrine protected CGCs from 3‐NPA‐induced mortality, as assessed by both the neutral red viability assay and laser scanning cytometry, using propidium iodide staining.
For rats, two indirect markers of neuronal damage were used: the binding of [3H]‐PK 11195 to the peripheral‐type benzodiazepine receptor (PBR), a microglial marker, and expression of the 27 kD heat‐shock protein (HSP27), a marker of activated astroglia. Systemic administration of 3‐NPA (30 mg kg−1 per day for 3 days) induced a 170% increase in [3H]‐PK 11195 binding, and expression of HSP27.
Both the increase in [3H]‐PK 11195 and HSP 27 expression were prevented by previous administration of 30 mg kg−1 per day of orphenadrine for 3 days. Lower doses (10 and 20 mg kg−1) had no protective effect. Orphenadrine also reduced 3‐NPA‐induced mortality in a dose‐dependent manner.
We propose that orphenadrine or orphenadrine‐like drugs could be used to treat neurodegenerative disorders mediated by overactivation of NMDA receptors.

British Journal of Pharmacology (2001) 132, 693–702; doi:10.1038/sj.bjp.0703869
Prostaglandin E2 increases cyclic AMP and inhibits endothelin‐1 production/secretion by guinea‐pig tracheal epithelial cells through EP4 receptors
Authors: Pelletier Stéphane , Dubé Jean , Villeneuve Annie , Gobeil Fernand , Yang Quan , Battistini Bruno , Guillemette Gaétan , Sirois Pierre 
Published: January 2005

Prostaglandin E2 (PGE2) increased adenosine 3′ : 5′‐cyclic monophosphate (cyclic AMP) formation in tracheal epithelial cells and concomitantly decreased the production/secretion of immunoreactive endothelin (irET).
Naturally occurring prostanoids and selective and non‐selective EP receptor agonists showed the following rank order of potency in stimulating cyclic AMP generation by epithelial cells: PGE2 (EP‐selective)>16,16‐dimethyl PGE2 (EP‐selective)>11‐deoxy PGE2 (EP‐selective)>>>iloprost (IP/EP1/EP3‐selective), butaprost (EP2‐selective), PGD2 (DP‐selective), PGF2α (FP‐selective). The lack of responsiveness of the latter prostanoids indicated that the prostanoid receptor present in these cells is not of the DP, FP, IP, EP1, EP2 or EP3 subtype.
Pre‐incubating the cells with the selective TP/EP4‐receptor antagonists AH23848B and AH22921X antagonized the PGE2‐evoked cyclic AMP generation. This suggested that EP4 receptors mediate PGE2 effects. However, in addition to any antagonistic effects at EP4‐receptors, both compounds, to a different extent, modified cyclic AMP metabolism. The selective EP1, DP and EP2 receptor antagonist (AH6809) failed to inhibit PGE2‐evoked cyclic AMP generation which confirmed that the EP2 receptor subtype did not contribute to the change in cyclic AMP formation in these cells.
The PGE2‐induced inhibition of irET production by guinea‐pig tracheal epithelial cells was due to cyclic AMP generation and activation of the cyclic AMP‐dependent protein kinase since this effect was reverted by the cyclic AMP antagonist Rp‐cAMPS.
These results provide the first evidence supporting the existence of a functional prostaglandin E2 receptor that shares the pharmacological features of the EP4‐receptor subtype in guinea‐pig tracheal epithelial cells. These receptors modulate cyclic AMP formation as well as ET‐1 production/secretion in these cells.

British Journal of Pharmacology (2001) 132, 999–1008; doi:10.1038/sj.bjp.0703886
Anandamide activates peripheral nociceptors in normal and arthritic rat knee joints
Authors: Gauldie S D , McQueen D S , Pertwee R , Chessell I P 
Published: January 2005

The effects of the endogenous cannabinoid anandamide were studied on peripheral, polymodal nociceptors recorded from normal and chronically inflamed (Freund's adjuvant) knee joint afferents in rats anaesthetized with pentobarbitone. Anandamide (860 nmol) caused a rapid, short lasting excitation of a sub‐population of capsaicin‐sensitive nociceptive afferents in normal knee joints (7.2±2.3 impulses s−1; n=15 units from five animals). In arthritic joints there were 9.7±3.0 impulses s−1 (n=11 from six animals), which was not significantly different from normal joints. The excitation was dose dependent (8.6 – 2900 nmol) and mediated by activation of the vanilloid receptor (VR1) as it was abolished by the VR1 antagonist capsazepine (1 mg kg−1). Our results show that anandamide, at high doses, can activate nociceptive afferents innervating the rat knee joints, in contrast with its widely described analgesic actions.British Journal of Pharmacology (2001) 132, 617–621; doi:10.1038/sj.bjp.0703890