bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibitory effect of a new steroidal saponin, OSW‐1, on ovarian functions in rats
Authors: Tamura Kazuhiro , Honda Hideo , Mimaki Yoshihiro , Sashida Yutaka , Kogo Hiroshi 
Published: August 2006

This study was undertaken to determine the effects of OSW‐1 (3β, 16β, 17α‐trihydroxycholest‐5‐en‐22‐one 16‐O‐(2‐O‐4‐methoxybenzoyl‐β‐D‐xylopyranosyl)‐(1→3)‐(2‐O‐acetyl‐α‐L‐arabinopyranoside)) on the pituitary‐ovarian system and the functions of aortic smooth muscle.
A single s.c. injection of OSW‐1 (9 μg kg−1) on the morning of pro‐oestrus inhibited the occurrence of the expected next pro‐oestrus, whereas administration of OSW‐1 at a dose of 4.5 μg kg−1 did not affect the oestrous cycle. OSW‐1 treatment on the day of dioestrus‐l did not affect the oestrous cycle.
At doses of 4.5 and 9 μg kg−1 OSW‐1, the serum oestradiol (E2) levels at the expected next pro‐oestrus were significantly lower than in control (pro‐oestrus). The serum luteinizing hormone (LH) levels 4 days after 9 μg kg−1 OSW‐1 treatment were also markedly lower than those of control. OSW‐1 (4.5 μg kg−1) did not affect the levels of inhibin, progesterone and gonadotrophins on the same day.
OSW‐1 did not inhibit the preovulatory LH surge which occurs on the afternoon of pro‐oestrus day.
The expression of mRNA coding for the cholesterol side chain cleavage cytochrome P‐450 (p450scc), an ovarian steroidal limiting enzyme, was suppressed at 24 and 96 h after OSW‐1 treatment.
Administration of OSW‐1 (9 μg kg−1) tended to reduce the relaxation of isolated thoracic aorta ring preparations induced by acetylcholine, while there was no difference in the relaxation induced by sodium nitroprusside.
Our results show that OSW‐1 inhibits ovarian E2 secretion and that the decrease in E2 secretion may contribute to its effects on the oestrous cycle and the sensitivity of the thoracic aorta to relaxation. The decrease in the levels of ovarian steroids induced by OSW‐1 may be due to its direct inhibitory action on the gene expression of the steroidal enzyme and on the proliferation of granulosa cells in the ovary.

British Journal of Pharmacology (1997) 121, 1796–1802; doi:10.1038/sj.bjp.0701309
Long lasting smooth muscle relaxation by a novel PACAP analogue in guinea‐pig and primate airways in vitro
Authors: Yoshihara Shigemi , Lindén Anders , Kashimoto Kazuhisa , Nagano Yumiko , Ichimura Tohju , Nadel Jay A. 
Published: August 2006

We compared the relaxant effect of pituitary adenylate cyclase activating peptide (PACAP) 1–27 with that of a newly developed PACAP 1–27 analogue, [Arg15,20,21Leu17]‐PACAP‐Gly‐Lys‐Arg‐NH2, in the guinea‐pig trachea and primate bronchi in vitro (n=4–5).
In the guinea‐pig trachea precontracted by a submaximally effective carbachol concentration (0.1 μM), cumulative administration of PACAP 1–27 and the β2‐adrenoceptor agonist salbutamol (3 nM–3 μM) caused significant and concentration‐dependent smooth muscle relaxation, with salbutamol being approximately one log‐step more potent in this model. However, in primate bronchi precontracted by carbachol (0.1 μM), cumulative administration of PACAP 1–27 and salbutamol caused concentration‐dependent smooth muscle relaxation with very similar potencies and maximum relaxant effects.
In the guinea‐pig trachea, non‐cumulative administration of the PACAP 1–27 analogue and the original PACAP 1–27 (0.3–3 μM) caused concentration‐dependent relaxation with a very similar maximum relaxant effect and potency. However, the onset and offset of action was markedly slower for the PACAP 1–27 analogue than for the original PACAP 1–27 (>90% versus <10% of peak relaxation remaining 6 h after administration). Separate experiments confirmed that the PACAP 1–27 analogue also caused significant relaxation with slower onset and offset of action than did the original PACAP 1–27 in primate bronchi.
Peptidase inhibition by captopril (10 μM) and phosphoramidon (1 μM) significantly increased the maximum relaxant effect and duration of action of PACAP 1–27 but not of the PACAP 1–27 analogue, during the 3 h of observation in the guinea‐pig trachea.
We conclude that [Arg15,20,21Leu17]‐PACAP‐Gly‐Lys‐Arg‐NH2 produces significant, concentration‐dependent and sustained airway smooth muscle relaxation in vitro. The sustained relaxant effect is due, at least in part, to the PACAP 1–27 analogue being less susceptible to cleavage by peptidases than the original peptide PACAP 1–27.

British Journal of Pharmacology (1997) 121, 1730–1734; doi:10.1038/sj.bjp.0701310
Comparison of the effects of sibutramine and other monoamine reuptake inhibitors on food intake in the rat
Authors: Jackson Helen C. , Needham Andrew M. , Hutchins Lisa J. , Mazurkiewicz Sarah E. , Heal David J. 
Published: August 2006

The effects of the potent 5‐hydroxytryptamine (5‐HT) and noradrenaline reuptake inhibitor (serotonin‐noradrenaline reuptake inhibitor, SNRI), sibutramine, on the cumulative food intake of freely‐feeding male Sprague‐Dawley rats during an 8 h dark period were investigated and compared to those of the selective 5‐HT reuptake inhibitor (selective serotonin reuptake inhibitor, SSRI), fluoxetine; the selective noradrenaline reuptake inhibitor, nisoxetine; the 5‐HT and noradrenaline reuptake inhibitors, venlafaxine and duloxetine; and the 5‐HT releaser and 5‐HT reuptake inhibitor, (+)‐fenfluramine.
Sibutramine (3 and 10 mg kg−1, p.o.) and (+)‐fenfluramine (1 and 3 mg kg−1, p.o.) produced a significant, dose‐dependent decrease in food intake over the 8 h dark period. These responses became apparent within the first 2 h following drug administration.
Fluoxetine (3, 10 and 30 mg kg−1, p.o.), and nisoxetine (3, 10 and 30 mg kg−1, p.o.) had no significant effect on food intake during the 8 h dark period. However, a combination of fluoxetine and nisoxetine (30 mg kg−1, p.o., of each) significantly decreased food intake 2 and 8 h after drug administration.
Venlafaxine (100 and 300 mg kg−1, p.o.) and duloxetine (30 mg kg−1, p.o.) also significantly decreased food intake in the 2 and 8 h following drug administration.
The results of this study demonstrate that inhibition of 5‐HT and noradrenaline reuptake by sibutramine, venlafaxine, duloxetine, or by a combination of fluoxetine and nisoxetine, markedly reduces food intake in freely‐feeding rats and suggest that this may be a novel approach for the treatment of obesity.

British Journal of Pharmacology (1997) 121, 1758–1762; doi:10.1038/sj.bjp.0701312
Catecholamine modulatory effects of nepicastat (RS‐25560‐197), a novel, potent and selective inhibitor of dopamine‐β‐hydroxylase
Authors: Stanley William C. , Li Bin , Bonhaus Douglas W. , Johnson Lowell G. , Lee Keiho , Porter Seth , Walker Keith , Martinez Greg , Eglen Richard M. , Whiting Roger L. , Hegde Sharath S. 
Published: August 2006

Inhibitory modulation of sympathetic nerve function may have a favourable impact on the progression of congestive heart failure. Nepicastat is a novel inhibitor of dopamine‐β‐hydroxylase, the enzyme which catalyses the conversion of dopamine to noradrenaline in sympathetic nerves. The in vitro pharmacology and in vivo catecholamine modulatory effects of nepicastat were investigated in the present study.
Nepicastat produced concentration‐dependent inhibition of bovine (IC50=8.5±0.8 nM) and human (IC50=9.0±0.8  nM)dopamine‐β‐hydroxylase. The corresponding R‐enantiomer (RS‐25560‐198) was approximately 2–3 fold less potent than nepicastat. Nepicastat had negligible affinity (>10 μM) for twelve other enzymes and thirteen neurotransmitter receptors.
Administration of nepicastat to spontaneously hypertensive rats (SHRs) (three consecutive doses of either 3, 10, 30 or 100 mg kg−1, p.o.; 12 h apart) or beagle dogs (0.05, 0.5, 1.5 or 5 mg kg−1, p.o.; b.i.d., for 5 days) produced dose‐dependent decreases in noradrenaline content, increases in dopamine content and increases in dopamine/noradrenaline ratio in the artery (mesenteric or renal), left ventricle and cerebral cortex. At the highest dose studied, the decreases in tissue noradrenaline were 47%, 35% and 42% (in SHRs) and 88%, 91% and 96% (in dogs) in the artery, left ventricle and cerebral cortex, respectively. When tested at 30 mg kg−1, p.o., in SHRs, nepicastat produced significantly greater changes in noradrenaline and dopamine content, as compared to the R‐enantiomer (RS‐25560‐198), in the mesenteric artery and left ventricle.
Administration of nepicastat (2 mg kg−1, b.i.d, p.o.) to beagle dogs for 15 days produced significant decreases in plasma concentrations of noradrenaline and increases in plasma concentrations of dopamine and dopamine/noradrenaline ratio. The peak reduction (52%) in plasma concentration of noradrenaline and the peak increase (646%) in plasma concentration of dopamine were observed on day‐6 and day‐7 of dosing, respectively.
The findings of this study suggest that nepicastat is a potent, selective and orally active inhibitor of dopamine‐β‐hydroxylase which produces gradual modulation of the sympathetic nervous system by inhibiting the biosynthesis of noradrenaline. This drug may, therefore, be of value in the treatment of cardiovascular disorders associated with over‐activation of the sympathetic nervous system, such as congestive heart failure.

British Journal of Pharmacology (1997) 121, 1803–1809; doi:10.1038/sj.bjp.0701315
Gabapentin (neurontin) and S‐(+)‐3‐isobutylgaba represent a novel class of selective antihyperalgesic agents
Authors: Field M. J. , Oles R. J. , Lewis A. S. , McCleary S , Hughes J , Singh L 
Published: August 2006

Gabapentin (neurontin) is a novel antiepileptic agent that binds to the α2δ subunit of voltage‐dependent calcium channels. The only other compound known to possess affinity for this recognition site is the (S)‐(+)‐enantiomer of 3‐isobutylgaba. However, the corresponding (R)‐(−)‐enantiomer is 10 fold weaker. The present study evaluates the activity of gabapentin and the two enantiomers of 3‐isobutylgaba in formalin and carrageenan‐induced inflammatory pain models.
In the rat formalin test, S‐(+)‐3‐isobutylgaba (1–100 mg kg−1) and gabapentin (10–300 mg kg−1) dose‐dependently inhibited the late phase of the nociceptive response with respective minimum effective doses (MED) of 10 and 30 mg kg−1, s.c. This antihyperalgesic action of gabapentin was insensitive to naloxone (0.1–10.0 mg kg−1, s.c.). In contrast, the R‐(−)‐enantiomer of 3‐isobutylgaba (1–100 mg kg−1) produced a modest inhibition of the late phase at the highest dose of 100 mg kg−1. However, none of the compounds showed any effect during the early phase of the response.
The s.c. administration of either S‐(+)‐3‐isobutylgaba (1–30 mg kg−1) or gabapentin (10–100 mg kg−1), after the development of peak carrageenan‐induced thermal hyperalgesia, dose‐dependently antagonized the maintenance of this response with MED of 3 and 30 mg kg−1, respectively. Similar administration of the two compounds also blocked maintenance of carrageenan‐induced mechanical hyperalgesia with MED of 3 and 10 mg kg−1, respectively. In contrast, R‐(−)‐3‐isobutylgaba failed to show any effect in the two hyperalgesia models.
The intrathecal administration of gabapentin dose‐dependently (1–100 μg/animal) blocked carrageenan‐induced mechanical hyperalgesia. In contrast, administration of similar doses of gabapentin into the inflamed paw was ineffective at blocking this response.
Unlike morphine, the repeated administration of gabapentin (100 mg kg−1 at start and culminating to 400 mg kg−1) over 6 days did not lead to the induction of tolerance to its antihyperalgesic action in the formalin test. Furthermore, the morphine tolerance did not cross generalize to gabapentin. The s.c. administration of gabapentin (10–300 mg kg−1), R‐(−) (3–100 mg kg−1) or S‐(+)‐3‐isobutylgaba (3–100 mg kg−1) failed to inhibit gastrointestinal motility, as measured by the charcoal meal test in the rat. Moreover, the three compounds (1–100 mg kg−1, s.c.) did not generalize to the morphine discriminative stimulus. Gabapentin (30–300 mg kg−1) and S‐(+)‐isobutylgaba (1–100 mg kg−1) showed sedative/ataxic properties only at the highest dose tested in the rota‐rod apparatus.
Gabapentin (30–300 mg kg−1, s.c.) failed to show an antinociceptive action in transient pain models. It is concluded that gabapentin represents a novel class of antihyperalgesic agents.

British Journal of Pharmacology (1997) 121, 1513–1522; doi:10.1038/sj.bjp.0701320
Reduction of urinary 8‐epi‐prostaglandin F2α during cyclo‐oxygenase inhibition in rats but not in man
Authors: Bachi Angela , Brambilla Raffaella , Fanelli Roberto , Bianchi Roberto , Zuccato Ettore , Chiabrando Chiara 
Published: August 2006

8‐epi‐prostaglandin (PG) F2α, a major F2 isoprostane, is produced in vivo by free radical‐dependent peroxidation of lipid‐esterified arachidonic acid. Both cyclo‐oxygenase isoforms (COX‐1 and COX‐2) may also form free 8‐epi‐PGF2α as a minor product. It has been recently seen in human volunteers that the overall basal formation of 8‐epi‐PGF2αin vivo is mostly COX‐independent and urinary 8‐epi‐PGF2α is therefore an accurate marker of ‘basal’ oxidative stress in vivo.
To test the validity of this marker in the rat, we evaluated in vivo the effect of COX inhibition on the formation of 8‐epi‐PGF2α vs prostanoids. Two structurally unrelated COX inhibitors (naproxen: 30 mg kg−1 day−1; indomethacin: 4 mg kg−1 day−1) were given i.p. to rats kept in metabolic cages. In vivo formation of 8‐epi‐PGF2α was assessed by measuring its urinary excretion. Prostanoid biosynthesis was assessed by measuring urinary excretion of major metabolites of thromboxane (TX) and prostacyclin (2,3‐dinor‐TXB1 and 2,3‐dinor‐6‐keto‐PGF1α). All compounds were selectively measured by immunopurification/gas chromatography‐mass spectrometry.
Naproxen reduced urinary excretion of 2,3‐dinor‐TXB1 and 2,3‐dinor‐6‐keto‐PGF1α but, unexpectedly, also that of 8‐epi‐PGF2α (82, 49 and 52% inhibition, respectively). Indomethacin had a similar effect (77, 69 and 55% inhibition). Esterified 8‐epi‐PGF2α in liver and plasma remained unchanged after indomethacin.
These findings prompted us to re‐assess the contribution of COX activity to the systemic production of 8‐epi‐PGF2α in man. We gave naproxen (1 g day−1) to healthy subjects (four nonsmokers and four smokers). Urinary 8‐epi‐PGF2α remained unchanged in the two groups (9.63±0.99 before vs 10.24±1.01 after and 20.14±3.00 vs 19.03±2.45 ng h−1 1.73 m−2), whereas there was a marked reduction of major urinary metabolites of thromboxane and prostacyclin (about 90% for both 11‐dehydro‐TXB2 and 2,3‐dinor‐TXB2; >50% for 2,3‐dinor‐6‐keto‐PGF1α).
To investigate whether rat COX‐1 produces 8‐epi‐PGF2α more efficiently than human COX‐1, we measured the ex vivo formation of 8‐epi‐PGF2α and TXB2 simultaneously in whole clotting blood. Serum levels of 8‐epi‐PGF2α and TXB2 were similar in rats and man.
We conclude that a significant amount of COX‐dependent 8‐epi‐PGF2α is present in rat but not in human urine under normal conditions. This implies that urinary 8‐epi‐PGF2α cannot be used as an index of near‐basal oxidant stress in rats. On the other hand, our data further confirm the validity of this marker in man.

British Journal of Pharmacology (1997) 121, 1770–1774; doi:10.1038/sj.bjp.0701321
Carrier‐dependent and Ca2+‐dependent 5‐HT and dopamine release induced by (+)‐amphetamine, 3,4‐methylendioxy‐methamphetamine, p‐chloroamphetamine and (+)‐fenfluramine
Authors: Crespi Daniela , Mennini Tiziana , Gobbi Marco 
Published: August 2006

The mechanism underlying 5‐hydroxytryptamine (5‐HT) and/or dopamine release induced by (+)‐amphetamine ((+)‐Amph), 3,4‐methylendioxymethamphetamine (MDMA), p‐chloroamphetamine (pCA) and (+)‐fenfluramine ((+)‐Fen) was investigated in rat brain superfused synaptosomes preloaded with the 3H neurotransmitters.
Their rank order of potency for [3H]‐5‐HT‐releasing activity was the same as for inhibition of 5‐HT uptake (pCAMDMA(+)‐Fen>>(+)‐Amph). Similarly, their rank order as [3H]‐dopamine releasers and dopamine uptake inhibitors was the same ((+)‐Amph>>pCA=MDMA>>(+)‐Fen). We also confirmed that the release induced by these compounds was prevented by selective transporter inhibitors (indalpine or nomifensine).
[3H]‐5‐HT and/or [3H]‐dopamine release induced by all these compounds was partially (31–80%), but significantly Ca2+‐dependent. Lack of extracellular Ca2+ did not alter uptake mechanisms nor did it modify the carrier‐dependent dopamine‐induced [3H]‐dopamine release. (+)‐Amph‐induced [3H]‐dopamine release and pCA‐ and MDMA‐induced [3H]‐5‐HT release were significantly inhibited by ω‐agatoxin‐IVA, a specific blocker of P‐type voltage‐operated Ca2+‐channels, similar to the previous results on (+)‐Fen‐induced [3H]‐5‐HT release.
Methiothepin inhibited the Ca2+‐dependent component of (+)‐Amph‐induced [3H]‐dopamine release with high potency (70 nM), as previously found with (+)‐Fen‐induced [3H]‐5‐HT release. The inhibitory effect of methiothepin was not due to its effects as a transporter inhibitor or Ca2+‐channel blocker and is unlikely to be due to its antagonist properties on 5‐HT1/2, dopamine or any other extracellular receptor.
These results indicate that the release induced by these compounds is both ‘carrier‐mediated’ and Ca2+‐dependent (possibly exocytotic‐like), with the specific carrier allowing the amphetamines to enter the synaptosome. The Ca2+‐dependent release is mediated by Ca2+‐influx (mainly through P‐type Ca2+‐channels), possibly triggered by the drug interacting with an unknown intracellular target, affected by methiothepin, common to both 5‐HT and dopamine synaptosomes.

British Journal of Pharmacology (1997) 121, 1735–1743; doi:10.1038/sj.bjp.0701325
ATP release and contraction mediated by different P2‐receptor subtypes in guinea‐pig ileal smooth muscle
Authors: Matsuo Katsuichi , Katsuragi Takeshi , Fujiki Sono , Sato Chiemi , Furukawa Tatsuo 
Published: August 2006

The present study was addressed to clarify the subtypes of P2‐purinoceptor involved in ATP release and contraction evoked by α,β‐methylene ATP (α,β‐mATP) and other P2‐agonists in guinea‐pig ileum.
α,β‐mATP 100 μM produced a transient and steep contraction followed by ATP release from tissue segments. These maximum responses appeared with different time‐courses and their ED50 values were 5 and 25 μM, respectively. The maximum release of ATP by α,β‐mATP was markedly reduced by 250 μM suramin, 30 μM pyridoxal‐phosphate‐6‐azophenyl‐2′,5′‐disulphonic acid (PPADS) and 30 μM reactive blue 2 (RB‐2), P2‐receptor antagonists. However, the contractile response was inhibited by suramin, tetrodotoxin and atropine, but not by PPADS and RB‐2.
Although the contraction caused by α,β‐mATP was strongly diminished by Ca2+‐removal and nifedipine, and also by tetrodotoxin and atropine at 0.3 μM, the release of ATP was virtually unaffected by these procedures.
UTP, β,γ‐methylene ATP (β,γ‐mATP) and ADP at 100 μM elicited a moderate release of ATP. The release caused by UTP was virtually unaffected by RB‐2. However, these P2‐agonists failed to elicit a contraction of the segment.
The potency order of all the agonists tested for the release of ATP was α,β‐mATP>UTP>β,γ‐mATP>ADP.
In superfusion experiments with cultured smooth muscle cells from the ileum, α,β‐mATP (100 μM) enhanced the release of ATP 5 fold above the basal value. This evoked release was inhibited by RB‐2.
These findings suggest that ATP release and contraction induced by P2‐agonists such as α,β‐mATP in the guinea‐pig ileum result mainly from stimulation of different P2‐purinoceptors, P2Y‐like purinoceptors on the smooth muscles and, probably, P2X‐purinoceptors on cholinergic nerve terminals, respectively. However, the ATP release may also be mediated, in part, by P2U‐receptors, because UTP caused RB‐2‐insensitive ATP release.

British Journal of Pharmacology (1997) 121, 1744–1748; doi:10.1038/sj.bjp.0701329
Evidence for the involvement of P2‐purinoceptors in the cholinergic contraction of the guinea‐pig ileum
Authors: Barthó Loránd , Lénárd László , Maggi Carlo A. 
Published: August 2006

In the isolated ileum of the guinea‐pig the P2‐purinoceptor antagonists PPADS and suramin: (a) strongly inhibited the cholinergic contractile effect of α,β‐methylene ATP, (b) did not influence contractions evoked by exogenous acetylcholine (ACh) but, (c) moderately (by about 30%) inhibited cholinergic contractions due to electrical field stimulation (EFS), in a non‐additive manner. These results suggest that an endogenous ligand that stimulates P2‐purinoceptors (possibly ATP) is involved in the contractile effect of EFS, as a positive modulator of ACh release. British Journal of Pharmacology (1997) 121, 1507–1508; doi:10.1038/sj.bjp.0701350
Nosocomial Infection With Cephalosporin-ResistantKlebsiella pneumoniaeIs Not Associated With Increased Mortality
Authors: Gomes Cristiana C. , Vormittag Evangelina , Santos Cleide R. , Levin Anna S. 
Published: August 2006

Objective.To evaluate whether resistance to third-generation cephalosporins and/or aztreonam was associated with a higher mortality rate among patients with nosocomialKlebsiella pneumoniaeinfections.Design.Retrospective cohort study.Setting.Tertiary care university hospital.Methods.A total of 143 patients with nosocomial infections due toK. pneumoniaewere evaluated. Death within 21 days after diagnosis of infection was the outcome. Demographic data, invasive procedures, presence and severity of underlying conditions, infection diagnosis, anatomic site of isolation, and treatment of infection, as well as resistance to third-generation cephalosporins and/or aztreonam, were evaluated for association with the outcome.Results.The mortality associated with nosocomialK. pneumoniaeinfections was 22% in our study. Drug resistance was found in isolates from 48% of case patients. Multivariate analysis demonstrated that the severity of the patient's underlying condition (odds ratio, 12.50;P<.01) and isolation of the microorganism from the blood or from another usually sterile site (odds ratio, 2.94;P= .03) were associated with death. On the other hand, the presence of resistance to cephalosporins and/or aztreonam did not affect mortality, and the use of inadequate treatment was not significantly associated with increased mortality. When only the severe cases of infection were analyzed, the results were unchanged.Conclusions.Resistance to cephalosporins and/or aztreonam did not affect mortality, and the use of inadequate treatment was not significantly associated with increased mortality. The reasons for this are not clear. It is possible that the severity of the underlying disease and the patient's condition have a larger role than theK. pneumoniaeinfection in determining the outcome, and initially inadequate treatment may not have an impact sufficient to cause irreversible damage, allowing treatment to be changed to an effective drug.