bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ezetimibe potently inhibits cholesterol absorption but does not affect acute hepatic or intestinal cholesterol synthesis in rats
Authors: Van Heek Margaret , Farley Constance , Compton Douglas S , Hoos Lizbeth M , Smith‐Torhan April , Davis Harry R 
Published: April 2003

Ezetimibe (1‐(4‐fluorophenyl)‐(3R)‐[3‐(4‐fluorophenyl)‐(3S)‐hydroxypropyl]‐(4S)‐(4‐hydroxyphenyl)‐2‐azetidinone) and its analog SCH48461 are potent and selective cholesterol absorption inhibitors that inhibit the transport of cholesterol across the intestinal wall, thereby lowering plasma cholesterol.
After a dose response for ezetimibe in rats was established, experiments were conducted to determine whether acute administration could alter hepatic or intestinal cholesterol synthesis. To determine whether this class of intestinal cholesterol absorption inhibitors could discriminate between newly synthesized cholesterol in the intestine versus exogenously administered cholesterol, rats were intraduodenally dosed with 14C‐cholesterol and 3H‐mevalonate, and mesenteric lymph was analyzed for radiolabeled cholesterol and cholesteryl ester content.
Ezetimibe attenuated diet‐induced hypercholesterolemia 60–94% at doses of 0.1–3 mg kg−1 in rats. A single administration of ezetimibe did not have a direct effect on intestinal or hepatic cholesterol synthesis, while ketoconazole significantly inhibited cholesterol synthesis after a single dose. The ezetimibe analog, SCH48461, inhibited the movement of exogenously administered cholesterol into lymph, but did not affect the appearance of newly synthesized cholesterol into lymph.
These data suggest that this class of cholesterol absorption inhibitors does discriminate by blocking the movement of exogenous cholesterol in the enterocyte before it reaches the intracellular cholesterol pool to be incorporated into intestinal lipoproteins, without affecting the incorporation of newly synthesized cholesterol into intestinal lipoproteins.

British Journal of Pharmacology (2003) 138, 1459–1464. doi:10.1038/sj.bjp.0705187
Cacospongionolide B suppresses the expression of inflammatory enzymes and tumour necrosis factor‐α by inhibiting nuclear factor‐κB activation
Authors: Posadas Inmaculada , De Rosa Salvatore , Carmen Terencio M , Payá Miguel , José Alcaraz M 
Published: April 2003

The marine product cacospongionolide B, a sesterterpene isolated from the Mediterranean sponge Fasciospongia cavernosa, is an inhibitor of secretory phospholipase A2 with anti‐inflammatory properties. In this work, we have studied the mechanism of action of this compound in the inflammatory response induced by zymosan in primary cells and in the mouse air pouch.
In mouse peritoneal macrophages, cacospongionolide B was able to downregulate the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase‐2 (COX‐2), resulting in decreased production of NO and prostaglandin E2 (PGE2). This compound also reduced tumour necrosis factor‐α (TNF‐α) mRNA expression and TNF‐α levels.
Cacospongionolide B inhibited nuclear factor‐κB (NF‐κB)‐DNA binding activity and the nuclear translocation of this transcription factor.
Treatment of cells with cacospongionolide B impaired NF‐κB inhibitory protein (IκB‐α) phosphorylation and enhanced IκB‐α expression.
Inhibition of iNOS, COX‐2 and inflammatory mediators was confirmed in the mouse air pouch.
These results show that cacospongionolide B is able to control NO, PGE2 and TNF‐α production in vitro and in vivo, effects likely dependent on NF‐κB inhibition.

British Journal of Pharmacology (2003) 138, 1571–1579. doi:10.1038/sj.bjp.0705189
Localization of the GSH‐dependent photolabelling site of an agosterol A analog on human MRP1
Authors: Ren Xiao‐Qin , Furukawa Tatsuhiko , Aoki Shunji , Sumizawa Tomoyuki , Haraguchi Misako , Che Xiao‐Fang , Kobayashi Motomasa , Akiyama Shin‐ichi 
Published: April 2003

Human multidrug resistance protein 1 (MRP1) is a 190 kDa membrane glycoprotein that confers multidrug resistance (MDR) to tumor cells. We recently demonstrated that glutathione (GSH) is required for the labelling of the C‐terminal half of MRP1 with a photoanalog of agosterol A (azido AG‐A). In this study, we further characterized the GSH‐dependent photolabelling site of azido AG‐A on MRP1.
An epitope‐inserted MRP1, MRP1 1222HA, which has two hemagglutinin A (HA) epitopes in the extracellular loop between transmembrane segment (TM) 16 and TM17 of the transporter, could bind azido AG‐A in a GSH‐dependent manner.
Protease digestion of the photolabelled MRP1 1222HA, followed by immunoprecipitation with an anti‐HA antibody suggested that the GSH‐dependent azido AG‐A photolabelling site on MRP1 resides in the region within TM14‐17 and the cytoplasmic region proximate to the C‐terminus of TM17.
Arg1210 in human MRP2 that corresponds to Arg1202 in human MRP1 has an important role in the transporting activity of MRP2. Therefore, we replaced the Arg residue at position 1202 of MRP1 with Gly. Whereas photolabelling of the mutant MRP1 R1202G was greatly reduced, it retained leukotriene C4 (LTC4) transport activity and conferred Vincristine resistance in LLC‐PK1 cells.
In summary, this study demonstrated that the GSH‐dependent azido AG‐A photolabelling site on MRP1 resides in the region within TM14‐17 and the cytoplasmic region proximate to the C‐terminus of TM17. The charged amino acid Arg1202 proximate to TM helix 16 is of critical importance for the GSH‐dependent photolabelling of MRP1 with azido AG‐A. Arg1202 itself or the region nearby Arg1202 may be involved in azido AG‐A photolabelling.

British Journal of Pharmacology (2003) 138, 1553–1561. doi:10.1038/sj.bjp.0705197
The vasoactive peptide urotensin II stimulates spontaneous release from frog motor nerve terminals
Authors: Brailoiu E , Brailoiu G C , Miyamoto M D , Dun N J 
Published: April 2003

The effect of urotensin II (U‐II) on spontaneous transmitter release was examined in the frog to see if the biological activity of this vasoactive peptide extended to neural tissues.
In normal Ringer solution, frog and human U‐II (fU‐II and hU‐II, respectively) caused concentration‐dependent, reversible increases in miniature endplate potential (MEPP) frequency, with hU‐II about 22 times more potent than fU‐II. hU‐II caused a dose‐dependent increase in MEPP amplitude, whereas fU‐II caused an increase, followed by a decrease with higher concentrations.
Increasing extracellular Ca2+ three‐fold had no effect on the MEPP frequency increase to 25 μM hU‐II. Pretreatment with thapsigargin to deplete endoplasmic reticulum Ca2+ caused a 61% reduction in the MEPP frequency increase to 25 μM hU‐II.
Pretreatment with the phospholipase C inhibitor U‐73122 caused a 93% reduction in the MEPP frequency increase to 25 μM hU‐II and a 15% reduction in the increase in MEPP amplitude. Pretreating with antibodies against the inositol 1,4,5‐trisphosphate (IP3) type 1 receptor using liposomal techniques reduced the MEPP frequency increase by 83% but had no effect on MEPP amplitude.
Pretreating with protein kinase C inhibitors (bisindolylmaleimide I and III) had no effect on the response to 25 μM hU‐II, but pretreating with protein kinase A inhibitors (H‐89 and KT5720) reduced the MEPP frequency increase by 88% and completely abolished the increase in MEPP amplitude.
Our results show that hU‐II is a potent stimulator of spontaneous transmitter release in the frog and that the effect is mediated by IP3 and cyclic AMP/protein kinase A.

British Journal of Pharmacology (2003) 138, 1580–1588. doi:10.1038/sj.bjp.0705204
Effects of different beta adrenoceptor ligands in mice with permanent occlusion of the left anterior descending coronary artery
Authors: Callaerts‐Vegh Zsuzsanna , Evans Kenda L J , Shipley Gregory L , Davies Peter J A , Cuba Donald L , Gurji Hunaid A , Giles Heather , Bond Richard A 
Published: April 2003

We have studied the effects of three βAR ligands (carvedilol, alprenolol, and ICI‐118,551) with different pharmacological profiles and negative efficacy at the β2AR on cardiac in vivo, in vitro, biochemical and gene expression parameters in mice with permanent occlusion of the left anterior descending coronary artery.
Cardiac in vivo parameters were determined using Doppler studies. Mitral‐wave E peak velocity (EPV) and aortic peak velocity (AoPV) decreased in the first 2 weeks postocclusion. After 3 weeks of drug treatment, EPV was improved in the carvedilol group to preocclusion values; however, a further reduction in EPV in the alprenolol and control permanent occlusion group was measured and there was no change after ICI‐118,551 treatment. AoPV was unchanged between weeks 2 and 5 in all groups.
The left atria were isolated to record isometric tension responses to isoprenaline. Permanent occlusion significantly reduced the maximum isoprenaline response to 30% of control and carvedilol increased the maximum response to isoprenaline significantly to 60%.
The biochemical and gene expression studies revealed different effects of the three βAR ligands. Most notably, carvedilol reduced gene expression of myosin heavy chain β.
These results indicate that chronic treatment with carvedilol is beneficial in a mouse model of myocardial damage resulting from ischaemia. We hypothesise that these beneficial effects of the drug may be because of the negative efficacy at the β2AR, combined with β1AR antagonism.

British Journal of Pharmacology (2003) 138, 1505–1516. doi:10.1038/sj.bjp.0705205
Implication of the bradykinin receptors in antigen‐induced pulmonary inflammation in mice
Authors: Eric Jadranka , Gabra Bichoy H , Sirois Pierre 
Published: April 2003

The involvement of bradykinin (BK) receptors in the allergic inflammation associated with airway hyper‐reactivity (AHR) was evaluated by means of the selective bradykinin B1 receptor (BKB1‐R) antagonists R‐715 (Ac‐Lys‐[D‐βNal7, Ile8]desArg9‐BK) and R‐954 (Ac‐Orn[Oic2, α‐MePhe5, D‐βNal7, Ile8]desArg9‐BK) or the selective bradykinin B2 receptor (BKB2‐R) antagonist HOE‐140 (D‐Arg0‐Hyp3‐Thi5‐D‐Tic7‐Oic8‐BK). Cellular migration and AHR were examined 24 h after the second ovalbumin (OA) challenge.
R‐715 (10–500 μg kg−1) and R‐954 (1–100 μg kg−1) injected intravenously (i.v.), 5 min prior to aerosol OA challenges, decreased by approximately 50% the induced lung eosinophilia in OA‐sensitized mice but did not reduce AHR.
HOE‐140 (1 μg kg−1) administered in the same manner, decreased mononuclear cell and eosinophil infiltration in the bronchoalveolar lavage fluid (BALF) of OA‐sensitized mice. Moreover, treatment of OA‐sensitized mice with HOE‐140 (100 μg kg−1) completely abolished the AHR to carbachol.
The BKB1‐R agonist desArg9‐BK (DBK; 10–1000 μg kg−1) administered intratrachealy to normal mice had no effect on the basal cell counts recovered in BALF nor on the plasma extravasation, while the BKB2‐R selective agonist BK (20 μg kg−1) stimulated mononuclear cell migration, neutrophilia and plasma extravasation in normal mouse lungs. Such effects were inhibited by HOE‐140 (10 μg kg−1).
Our results suggest that the airway inflammatory response induced by antigen challenge in mice is mediated by stimulation of both BKB1‐R and BKB2‐R.

British Journal of Pharmacology (2003) 138, 1589–1597. doi:10.1038/sj.bjp.0705207
Gene therapy for cerebral vascular disease: update 2003
Authors: Toyoda Kazunori , Chu Yi , Heistad Donald D 
Published: May 2003

Gene therapy is a promising strategy for cerebrovascular diseases. Several genes that encode vasoactive products have been transferred via cerebrospinal fluid for the prevention of vasospasm after subarachnoid hemorrhage. Transfer of neuroprotective genes, including targeting of proinflammatory mediators, is a current strategy of gene therapy for ischemic stroke. Stimulation of growth of collateral vessels, stabilization of atherosclerotic plaques, inhibition of thrombosis, and prevention of restenosis are important objectives of gene therapy for coronary and limb arteries, but application of these approaches to carotid and intracranial arteries has received little attention. Several fundamental advances, including development of safer vectors, are needed before gene therapy achieves an important role in the treatment of cerebrovascular disease and stroke.British Journal of Pharmacology (2003) 139, 1–9. doi:10.1038/sj.bjp.0705217
Alteration of the purinergic modulation of enteric neurotransmission in the mouse ileum during chronic intestinal inflammation
Authors: De Man Joris G , Seerden Tom C , De Winter Benedicte Y , Van Marck Eric A , Herman Arnold G , Pelckmans Paul A 
Published: May 2003

The effect of chronic intestinal inflammation on the purinergic modulation of cholinergic neurotransmission was studied in the mouse ileum. Chronic intestinal inflammation was induced by infection of mice with the parasite Schistosoma mansoni during 16 weeks.
S. mansoni infection induced a chronic inflammatory response in the small intestine, which was characterised by intestinal granuloma formation, increased intestinal wall thickness, blunted mucosal villi and an enhanced activity of myeloperoxidase.
In control ileum and in chronically inflamed ileum, electrical field stimulation (EFS) of longitudinal muscle strips induced frequency‐dependent contractions that were abolished by tetrodotoxin (TTX) and atropine. Carbachol induced dose‐dependent contractions that were not affected by TTX but abolished by atropine.
In control ileum, adenosine and ATP dose‐dependently inhibited the contractions to EFS. Theophylline and 8‐phenyltheophylline, P1 and A1 receptor antagonists respectively, prevented this inhibitory effect of adenosine and ATP. PPADS, DMPX and MRS 1220, antagonists of P2, A2 and A3 receptors, respectively, did not prevent this inhibitory effect of adenosine and ATP. Adenosine and ATP did not affect the contractions to carbachol.
The inhibitory effect of adenosine and ATP on contractions to EFS in control ileum was mimicked by the stable adenosine analogue methyladenosine and by the A1‐receptor agonist N(6)‐cyclohexyladenosine, but not by the A3 receptor agonist 2‐Cl IB‐MECA or by the ATP analogues αβ‐methylene‐ATP and ADPβS. The inhibitory effect of adenosine on contractions to EFS was lost after prolonged (90 min) treatment of control ileum with methyladenosine (100 μM).
In chronically inflamed ileum, adenosine, methyladenosine, N(6)‐cyclohexyladenosine and ATP all failed to inhibit the cholinergic nerve‐mediated contractions to EFS. Also theophylline, 8‐phenyltheophylline, PPADS, DMPX and MRS 1220 had no effect on the contractions to EFS and carbachol. The loss of effect of adenosine and ATP was still evident after 52 weeks of infection.
These results indicate that in physiological conditions neuronal adenosine A1 receptors modulate cholinergic nerve activity in the mouse ileum. However, during chronic intestinal inflammation, this purinergic modulation of cholinergic nerve activity is impaired. This suggests that chronic intestinal inflammation leads to a dysfunction of specific neuronal regulatory mechanisms in the enteric nervous system.

British Journal of Pharmacology (2003) 139, 172–184. doi:10.1038/sj.bjp.0705218
Phoneutria nigriventer spider venom activates 5‐HT4 receptors in rat‐isolated vagus nerve
Authors: Costa Soraia K P , Brain Susan D , Antunes Edson , De Nucci Gilberto , Docherty Reginald J 
Published: May 2003

The venom of Phoneutria nigriventer spider (PNV) causes intense pain and inflammation following an attack. We have investigated the involvement of capsaicin‐sensitive nerve fibres by utilizing an in vitro nerve preparation. Extracellular DC potential recordings were made from the rat‐isolated vagus nerve, a preparation that is rich in capsaicin‐sensitive, that is, nociceptive, C‐fibres.
PNV (1–10 μg ml−1), capsaicin (0.03–0.3 μM) or 5‐hydroxytriptamine (5‐HT) (0.3–3 μM) induced dose‐dependent depolarizations of vagus nerve fibres. Depolarizing responses to capsaicin were blocked by ruthenium red (RR, 10 μM), but responses to PNV were not. Depolarizing responses to PNV or veratridine (50 μM) were inhibited by tetrodotoxin (TTX, 10 μM), but those to capsaicin were not. This suggests that capsaicin and PNV depolarize the nerve fibres by distinct mechanisms.
Depolarization in response to 5‐HT (3 μM) was reduced by the 5‐HT3 receptor antagonists Y25130 (0.5 μM) and tropisetron (10 nM) or, to a lesser extent, by the 5‐HT4 receptor antagonist RS39604 (1 or 10 μM). Depolarizing responses to PNV were not affected significantly by Y25130 or tropisetron, but were blocked by RS39604.
These data show that 5‐HT4 receptors play a significant role in the activation of nociceptive sensory nerve fibres by PNV and suggest that this is of importance in the development of the pain and inflammation associated with bites from the P. nigriventer spider.

British Journal of Pharmacology (2003) 139, 59–64. doi:10.1038/sj.bjp.0705240
Ovarian hemangioma presenting as pseudo–Meigs’ syndrome with elevated CA125
Authors: Kaneta Yoshibumi , Nishino Ruriko , Asaoka Kentaro , Toyoshima Kiwamu , Ito Kimihiko , Kitai Hirokatsu 
Published: May 2003

AbstractWe report the first case of ovarian hemangioma presenting as pseudo–Meigs’ syndrome with elevated CA125. Abdominopelvic computed tomography (CT) assumed ovarian carcinoma. Chest CT revealed pleural effusion. Intraoperative frozen‐section examination of the right ovary showed benign hemangioma. After operation, chest radiograph and ultrasonography showed no pleural effusion or ascites.
Utero‐vaginal prolapse due to portio vaginal fibroma
Authors: Gurung Geeta , Rana Ashma , Bahadur Rana Magar Dhan 
Published: May 2003

AbstractUtero‐vaginal prolapse can be caused by traction on to the cervix by heavy myoma. Here we present a unique case of huge, compressed, pedunculated fibromyoma of the cervix, which led to cervical elongation and third‐degree utero‐vaginal prolapse.
The ‘frameless’ intrauterine system for long‐term, reversible contraception: A review of 15 years of clinical experience
Authors: Wildemeersch Dirk , Batár István , Affandi Biran , Andrade Amaury , Shangchun Wu , Jing Hu , Xiaoming Cao 
Published: May 2003

AbstractAim:  The development of the ‘frameless’ intrauterine system (IUS) is a response to the growing need to develop high‐performing, long‐acting, reversible, and acceptable contraceptives with a high continuation of use.Methods:  This is a review of 15 years of clinical experience in randomized controlled and non‐randomized clinical trials.Results:  The IUS has a similar failure rate as the TCu380A Intrauterine device (IUD), considered the ‘golden standard’ IUD, which is attributed to the optimal target delivery of the copper ions in the upper part of the uterine cavity. Its performance is further optimized by the atraumatic design, which reduces partial and total expulsion and minimizes the side‐effects and discomforts experienced with conventional ‘framed’ IUDs. The mini IUS is likely to further reduce the menstrual blood loss due to the very small size. The safety of the anchoring concept is beyond doubt as was demonstrated in all clinical studies covering 15 000 woman‐years experience.Conclusions:  Young nulliparous/nulligravid and parous women may significantly benefit from the advantages the ‘frameless’ IUS, which could be strategically important to help in reducing the increasing number of unintended pregnancies and induced abortions worldwide. Furthermore, the ‘frameless’ IUS has been shown to be highly effective for emergency contraception and for immediate postabortal insertion. The long lifespan of the IUS could constitute a cost‐effective reversible alternative to irreversible female sterilization.
Alterations in hepatic lipase and lipoprotein subfractions with transdermal testosterone replacement therapy
Authors: Tan K. C. B. , Shiu S. W. M. , Kung A. W. C. 
Published: May 2003

OBJECTIVESThe effect of sex hormone replacement therapy on lipoprotein metabolism is thought to be less marked with the transdermal route because of the lack of hepatic first‐pass effect. The aim of this study was to evaluate the effects of testosterone replacement therapy given transdermally via a permeation‐enhanced system on plasma lipolytic enzymes (hepatic and lipoprotein lipase), LDL and HDL subfraction concentrations.MEASUREMENTSTen patients with primary testicular failure were started on transdermal testosterone (Testoderm®). Plasma lipids, lipoproteins and post‐heparin plasma lipolytic enzymes were evaluated before and after 3 months of treatment. LDL and HDL subfractions were measured by density gradient ultracentrifugation and hepatic and lipoprotein lipase activities by radio‐enzymatic method.RESULTSSerum testosterone level increased to within the normal range in all subjects whereas serum dihydrotestosterone (DHT) increased to supra‐normal values. Plasma hepatic lipase (HL) activity increased after testosterone replacement (24.7 ± 7.5 vs. 29.2 ± 8.3 μmol free fatty acid released per hour, P < 0.05) and the increase in HL correlated with the increase in DHT (r = 0.64, P < 0.05). Small changes were observed in LDL subfraction pattern with an increase in the concentration of small dense LDL‐III (80.1 ± 30.3 vs. 93.0 ± 27.8 mg/l, P < 0.05). No significant change was seen in the HDL2 subfraction but HDL3 decreased after treatment (0.93 ± 0.17 vs. 0.79 ± 0.14 mmol/l, P < 0.01).CONCLUSIONSTestosterone replacement, given via a permeation‐enhanced transdermal system, is associated with changes in hepatic lipase activity and in LDL and HDL subfractions. Whether these changes adversely influence the cardiovascular risk in the longterm remains to be determined.
Polycystic ovaries and associated clinical and biochemical features in young women
Authors: Michelmore K. F. , Balen A. H. , Dunger D. B. , Vessey M. P. 
Published: May 2003

OBJECTIVETo determine the prevalence of polycystic ovaries as identified by ultrasound in a group of young, postmenarcheal women in the normal population, and to investigate how polycystic ovaries are related to the spectrum of clinical and biochemical symptoms associated with the polycystic ovary syndrome (PCOS).DESIGNCross‐sectional observational study.SUBJECTS AND METHODSVolunteers were recruited from two universities and two general practice surgeries in Oxford. 230 women aged 18–25 years participated. Information collected and measurements performed included: a menstrual history, anthropometric measurements, clinical observation of acne and hirsutism, transabdominal pelvic ultrasound, and biochemical analysis of a fasting blood sample.MAIN OUTCOME MEASURESPrevalence of polycystic ovaries and their association with symptoms of the polycystic ovary syndrome.RESULTSPolycystic ovarian morphology was identified in 74 (33%, 95% CI = 27–39%) of the 224 women who attended for an ultrasound scan. In the non‐users of hormonal contraception, irregular menstrual cycles were 20% more common in women with polycystic ovaries than in women with normal ovaries (P = 0.07). There were no significant differences in acne, hirsutism, body mass index or body fat percentage between women with polycystic and normal ovaries. Analysis of biochemical data showed that women with polycystic ovaries had higher total serum testosterone concentrations (P = 0.03). The prevalence of PCOS in this age group was as low as 8% or as high as 26% depending on which criteria were applied to define the syndrome. Sub‐group analyses of women according to ovarian morphology and features of PCOS revealed greater mean BMI in women with PCOS, and also indicated lower fasting insulin concentrations and greater insulin sensitivity in polycystic ovary and PCOS groups when compared to women with normal ovaries.CONCLUSIONSPolycystic ovaries are very common in this age group but are not necessarily associated with other symptomatology. The prevalence of polycystic ovary syndrome varies widely according to the definition applied. Sub‐group analysis of women with polycystic ovaries according to the presence or absence of features of polycystic ovary syndrome does not reveal an increasing trend for progression of endocrine abnormalities usually associated with polycystic ovary syndrome.