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Showing papers by "Eli Lilly and Company published in 1999"


Journal ArticleDOI
16 Jun 1999-JAMA
TL;DR: The Multiple Outcomes of Raloxifene Evaluation (MORE) as discussed by the authors was a multicenter, randomized, double-blind trial, in which women taking raloxion hydrochloride or placebo were followed up for a median of 40 months at 180 clinical centers composed of community settings and medical practices in 25 countries, mainly in the United States and Europe.
Abstract: ContextRaloxifene hydrochloride is a selective estrogen receptor modulator that has antiestrogenic effects on breast and endometrial tissue and estrogenic effects on bone, lipid metabolism, and blood clotting.ObjectiveTo determine whether women taking raloxifene have a lower risk of invasive breast cancer.Design and SettingThe Multiple Outcomes of Raloxifene Evaluation (MORE), a multicenter, randomized, double-blind trial, in which women taking raloxifene or placebo were followed up for a median of 40 months (SD, 3 years), from 1994 through 1998, at 180 clinical centers composed of community settings and medical practices in 25 countries, mainly in the United States and Europe.ParticipantsA total of 7705 postmenopausal women, younger than 81 (mean age, 66.5) years, with osteoporosis, defined by the presence of vertebral fractures or a femoral neck or spine T-score of at least 2.5 SDs below the mean for young healthy women. Almost all participants (96%) were white. Women who had a history of breast cancer or who were taking estrogen were excluded.InterventionRaloxifene, 60 mg, 2 tablets daily; or raloxifene, 60 mg, 1 tablet daily and 1 placebo tablet; or 2 placebo tablets.Main Outcome MeasuresNew cases of breast cancer, confirmed by histopathology. Transvaginal ultrasonography was used to assess the endometrial effects of raloxifene in 1781 women. Deep vein thrombosis or pulmonary embolism were determined by chart review.ResultsThirteen cases of breast cancer were confirmed among the 5129 women assigned to raloxifene vs 27 among the 2576 women assigned to placebo (relative risk [RR], 0.24; 95% confidence interval [CI], 0.13-0.44; P<.001). To prevent 1 case of breast cancer, 126 women would need to be treated. Raloxifene decreased the risk of estrogen receptor–positive breast cancer by 90% (RR, 0.10; 95% CI, 0.04-0.24), but not estrogen receptor–negative invasive breast cancer (RR, 0.88; 95% CI, 0.26-3.0). Raloxifene increased the risk of venous thromboembolic disease (RR, 3.1; 95% CI, 1.5-6.2), but did not increase the risk of endometrial cancer (RR, 0.8; 95% CI, 0.2-2.7).ConclusionAmong postmenopausal women with osteoporosis, the risk of invasive breast cancer was decreased by 76% during 3 years of treatment with raloxifene.

1,692 citations


Journal ArticleDOI
TL;DR: The evolution of pharmacological agents that have been reported to target mGlu receptors are reviewed, with a focus on the known receptor subtype selectivities of current agents.

1,103 citations


Journal ArticleDOI
TL;DR: Abciximab facilitates the rate and extent of thrombolysis, producing early, marked increases in TIMI 3 flow when combined with half the usual dose of alteplase, and substantial reductions in heparin dosing may reduce the risk of bleeding even further.
Abstract: Background—The TIMI 14 trial tested the hypothesis that abciximab, the Fab fragment of a monoclonal antibody directed to the platelet glycoprotein (GP) IIb/IIIa receptor, is a potent and safe addition to reduced-dose thrombolytic regimens for ST-segment elevation MI. Methods and Results—Patients (n=888) with ST-elevation MI presenting <12 hours from onset of symptoms were treated with aspirin and randomized initially to either 100 mg of accelerated-dose alteplase (control) or abciximab (bolus 0.25 mg/kg and 12-hour infusion of 0.125 μg · kg−1 · min−1) alone or in combination with reduced doses of alteplase (20 to 65 mg) or streptokinase (500 000 U to 1.5 MU). Control patients received standard weight-adjusted heparin (70-U/kg bolus; infusion of 15 U · kg−1 · h−1), whereas those treated with a regimen including abciximab received low-dose heparin (60-U/kg bolus; infusion of 7 U · kg−1 · h−1). The rate of TIMI 3 flow at 90 minutes for patients treated with accelerated alteplase alone was 57% compared with 3...

694 citations


Journal ArticleDOI
TL;DR: Results establish Cdk4 as an essential regulator of specific cell types as well as establishing its role as a regulator of insulin-deficient diabetes and pancreatic hyperplasia in mice expressing a mutant Cdk 4 that cannot bind the cell-cycle inhibitor P16INK4a.
Abstract: To ascertain the role of cyclin-dependent kinase 4 (Cdk4) in vivo, we have targeted the mouse Cdk4 locus by homologous recombination to generate two strains of mice, one that lacks Cdk4 expression and one that expresses a Cdk4 molecule with an activating mutation. Embryonic fibroblasts proliferate normally in the absence of Cdk4 but have a delayed S phase on re-entry into the cell cycle. Moreover, mice devoid of Cdk4 are viable, but small in size and infertile. These mice also develop insulin-deficient diabetes due to a reduction in beta-islet pancreatic cells. In contrast, mice expressing a mutant Cdk4 that cannot bind the cell-cycle inhibitor P16INK4a display pancreatic hyperplasia due to abnormal proliferation of beta-islet cells. These results establish Cdk4 as an essential regulator of specific cell types.

647 citations


Journal Article
TL;DR: Therapy with anti-EGFR MAb C225 has a significant antitumor effect mediated, in part, by inhibition of angiogenesis, and down-regulation of these angiogenic factors preceded the involution of blood vessels.
Abstract: Epidermal growth factor receptor (EGFR) regulates the growth and progression of human transitional cell carcinoma (TCC) of the bladder. We have shown that therapy targeting EGFR inhibited the growth of human TCC established orthotopically in nude mice. The purpose of this study was to evaluate whether EGFR-directed therapy affects angiogenesis associated with the growth and metastasis of human TCC. We determined the cytostatic effect and the effect on production of angiogenic factors after in vitro treatment of the human TCC cell line 253J B-V with MAb C225, a chimerized monoclonal anti-EGFR antibody. The 253J B-V cells were implanted orthotopically into athymic nude mice, and established tumors (4 weeks) were treated with i.p. MAb C225. Expression of the angiogenic factors vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and basic fibroblast growth factor (bFGF) was evaluated by immunohistochemistry and in situ mRNA hybridization analyses and correlated with microvessel density evaluated after immunohistochemical staining with anti-CD31. In vitro treatment with MAb C225 inhibited mRNA and protein production of VEGF, IL-8, and bFGF by 253J B-V cells in a dose-dependent manner. MAb C225 therapy of nude mice with established TCCs growing orthotopically resulted in inhibition of growth and metastasis compared with controls (P <0.0005). VEGF, IL-8, and bFGF expression was significantly lower in treated tumors than in controls. The down-regulation of these angiogenic factors preceded the involution of blood vessels. These studies indicate that therapy with anti-EGFR MAb C225 has a significant antitumor effect mediated, in part, by inhibition of angiogenesis.

589 citations


Journal ArticleDOI
TL;DR: The olanzapine group experienced significantly greater mean mean scores than the placebo group in the treatment of acute mania, and the primary efficacy measure was defined as a change from baseline to endpoint in total score on the Young Mania Rating Scale.
Abstract: OBJECTIVE: The primary intent of this study was to compare the efficacy and safety of olanzapine and placebo in the treatment of acute mania. METHOD: The design involved a random-assignment, double-blind, placebo-controlled parallel group study of 3 weeks’ duration. After a 2- to 4-day screening period, qualified patients were assigned to either olanzapine (N=70) or placebo (N=69). Patients began double-blind therapy with either olanzapine, 10 mg, or placebo given once per day. After the first day of treatment, the daily dose could be adjusted upward or downward, as clinically indicated, by one capsule (olanzapine, 5 mg/day) within the allowed range of one to four capsules. The primary efficacy measure in the protocol was defined as a change from baseline to endpoint in total score on the Young Mania Rating Scale. Clinical response was defined a priori as a decrease of 50% or more from baseline in Young Mania Rating Scale total score. RESULTS: The olanzapine group experienced significantly greater mean im...

518 citations


Journal ArticleDOI
TL;DR: Multicentre trials in patients with schizophrenia confirm that olanzapine is a novel antipsychotic agent with broad efficacy, eliciting a response in both the positive and negative symptoms of schizophrenia, and dosage modification should be considered for patients characterised by a combination of factors associated with decreased oxidative metabolism.
Abstract: Multicentre trials in patients with schizophrenia confirm that olanzapine is a novel antipsychotic agent with broad efficacy, eliciting a response in both the positive and negative symptoms of schizophrenia. Compared with traditional antipsychotic agents, olanzapine causes a lower incidence of extrapyramidal symptoms and minimal perturbation of prolactin levels. Generally, olanzapine is well tolerated. The pharmacokinetics of olanzapine are linear and dose-proportional within the approved dosage range. Its mean half-life in healthy individuals was 33 hours, ranging from 21 to 54 hours. The mean apparent plasma clearance was 26 L/h, ranging from 12 to 47 L/h. Smokers and men have a higher clearance of olanzapine than women and nonsmokers. After administering [14C]olanzapine, approximately 60% of the radioactivity was excreted in urine and 30% in faeces. Olanzapine is predominantly bound to albumin (90%) and alpha 1-acid glycoprotein (77%). Olanzapine is metabolised to its 10- and 4'-N-glucuronides, 4'-N-desmethylolanzapine [cytochrome P450 (CYP) 1A2] and olanzapine N-oxide (flavin mono-oxygenase 3). Metabolism to 2-hydroxymethylolanzapine via CYP2D6 is a minor pathway. The 10-N-glucuronide is the most abundant metabolite, but formation of 4'-N-desmethylolanzapine is correlated with the clearance of olanzapine. Olanzapine does not inhibit CYP isozymes. No clinically significant metabolic interactions were found between olanzapine and diazepam, alcohol (ethanol), imipramine, R/S-warfarin, aminophylline, biperiden, lithium or fluoxetine. Fluvoxamine, an inhibitor of CYP1A2, increases plasma concentrations of olanzapine; inducers of CYP1A2, including tobacco smoke and carbamazepine, decrease olanzapine concentrations. Orthostatic changes were observed when olanzapine and diazepam or alcohol were coadministered. Pharmacodynamic interactions occurred between olanzapine and alcohol, and olanzapine and imipramine, implying that patients should avoid operating hazardous equipment or driving an automobile while experiencing the short term effects of the combinations. Individual factors with the largest impact on olanzapine pharmacokinetics are gender and smoking status. The plasma clearance of olanzapine generally varies over a 4-fold range, but the variability in the clearance and concentration of olanzapine does not appear to be associated with the severity or duration of adverse effects or the degree of efficacy. Thus, dosage adjustments appear unnecessary for these individual factors. However, dosage modification should be considered for patients characterised by a combination of factors associated with decreased oxidative metabolism, for example, debilitated or elderly women who are nonsmokers.

482 citations


Journal ArticleDOI
TL;DR: It is postulated that apoE promotes both the deposition and fibrillization of Abeta, ultimately affecting clearance of protease-resistant Abeta/apoE aggregates.
Abstract: We quantified the amount of amyloid beta-peptide (Abeta) immunoreactivity as well as amyloid deposits in a large cohort of transgenic mice overexpressing the V717F human amyloid precursor protein (APP(V717F+/-) TG mice) with no, one, or two mouse apolipoprotein E (Apoe) alleles at various ages. Remarkably, no amyloid deposits were found in any brain region of APP(V717F+/-) Apoe(-/-) TG mice as old as 22 mo of age, whereas age-matched APP(V717F +/-) Apoe(+/-) and Apoe(+/+) TG mice display abundant amyloid deposition. The amount of Abeta immunoreactivity in the hippocampus was also markedly reduced in an Apoe gene dose-dependent manner (Apoe(+/+) > Apoe(+/-) >> Apoe(-/-)), and no Abeta immunoreactivity was detected in the cerebral cortex of APP(V717F+/-) Apoe(-/-) TG mice at any of the time points examined. The absence of apolipoprotein E protein (apoE) dramatically reduced the amount of both Abeta(1-40) and Abeta(1-42) immunoreactive deposits as well as the resulting astrogliosis and microgliosis normally observed in APP(V717F) TG mice. ApoE immunoreactivity was detected in a subset of Abeta immunoreactive deposits and in virtually all thioflavine-S-fluorescent amyloid deposits. Because the absence of apoE alters neither the transcription or translation of the APP(V717F) transgene nor its processing to Abeta peptide(s), we postulate that apoE promotes both the deposition and fibrillization of Abeta, ultimately affecting clearance of protease-resistant Abeta/apoE aggregates. ApoE appears to play an essential role in amyloid deposition in brain, one of the neuropathological hallmarks of Alzheimer's disease.

475 citations


Journal ArticleDOI
TL;DR: In failed human heart, PKC-beta1 and -beta2 expression and contribution to total PKC activity are significantly increased, which may signal a role for Ca2+-sensitive PKC isoforms in cardiac mechanisms involved in heart failure.
Abstract: Background—Increased expression of Ca2+-sensitive protein kinase C (PKC) isoforms may be important markers of heart failure. Our aim was to determine the relative expression of PKC-β1, -β2, and -α in failed and nonfailed myocardium. Methods and Results—Explanted hearts of patients in whom dilated cardiomyopathy or ischemic cardiomyopathy was diagnosed were examined for PKC isoform content by Western blot, immunohistochemistry, enzymatic activity, and in situ hybridization and compared with nonfailed left ventricle. Quantitative immunoblotting revealed significant increases of >40% in PKC-β1 (P<0.05) and -β2 (P<0.04) membrane expression in failed hearts compared with nonfailed; PKC-α expression was significantly elevated by 70% in membrane fractions (P<0.03). PKC-e expression was not significantly changed. In failed left ventricle, PKC-β1 and -β2 immunostaining was intense throughout myocytes, compared with slight, scattered staining in nonfailed myocytes. PKC-α immunostaining was also more evident in card...

455 citations


Journal ArticleDOI
01 Jan 1999-Urology
TL;DR: The I-QOL proved to be valid, reproducible, and responsive to treatment for UI in women in a clinical trial assessing the efficacy of duloxetine.

431 citations


Journal Article
TL;DR: It is shown that methylation-associated inactivation of TIMP-3 is frequent in many human tumors, and that discrete regions within the TIMp-3 CpG island may be important for the silencing of this gene.
Abstract: Tissue inhibitor of metalloproteinase-3 (TIMP-3) antagonizes matrix metalloproteinase activity and can suppress tumor growth, angiogenesis, invasion, and metastasis. Loss of TIMP-3 has been related to the acquisition of tumorigenesis. Herein, we show that TIMP-3 is silenced in association with aberrant promoter-region methylation in cell lines derived from human cancers. TIMP-3 expression was restored after 5-aza-2'deoxycytidine-mediated demethylation of the TIMP-3 proximal promoter region. Genomic bisulfite sequencing revealed that TIMP-3 silencing was related to the overall density of methylation and that discrete regions within the TIMP-3 CpG island may be important for the silencing of this gene. Aberrant methylation of TIMP-3 occurred in primary cancers of the kidney, brain, colon, breast, and lung, but not in any of 41 normal tissue samples. The most frequent TIMP-3 methylation was found in renal cancers, which originate in the tissue that normally expresses the highest TIMP-3 levels. This methylation correlated with a lack of detectable TIMP-3 protein in these tumors. Together, these data show that methylation-associated inactivation of TIMP-3 is frequent in many human tumors.

Journal ArticleDOI
TL;DR: It is hypothesized that two different treatment strategies converge to produce an identical functional endpoint: a region-specific dampening of NMDA receptor function, providing a rudimentary framework for discovering novel antidepressants.


Journal ArticleDOI
18 Nov 1999-Nature
TL;DR: It is found that LY382884 is a selective antagonist at neuronal kainate receptors containing the GluR5 subunit, which has no effect on long-term potentiation (LTP) that is dependent onNMDA receptors but prevents the induction of mossy fibre LTP, which is independent of NMDA receptors.
Abstract: The ability of synapses to modify their synaptic strength in response to activity is a fundamental property of the nervous system and may be an essential component of learning and memory. There are three classes of ionotropic glutamate receptor, namely NMDA (N-methyl-D-aspartate), AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionic acid) and kainate receptors; critical roles in synaptic plasticity have been identified for two of these. Thus, at many synapses in the brain, transient activation of NMDA receptors leads to a persistent modification in the strength of synaptic transmission mediated by AMPA receptors. Here, to determine whether kainate receptors are involved in synaptic plasticity, we have used a new antagonist, LY382884 ((3S, 4aR, 6S, 8aR)-6-((4-carboxyphenyl)methyl-1,2,3,4,4a,5,6,7,8,8a-decahydro isoquinoline-3-carboxylic acid), which antagonizes kainate receptors at concentrations that do not affect AMPA or NMDA receptors. We find that LY382884 is a selective antagonist at neuronal kainate receptors containing the GluR5 subunit. It has no effect on long-term potentiation (LTP) that is dependent on NMDA receptors but prevents the induction of mossy fibre LTP, which is independent of NMDA receptors. Thus, kainate receptors can act as the induction trigger for long-term changes in synaptic transmission.

Journal ArticleDOI
TL;DR: Evaluation of the functional effects of (-)-9 and (-)-10 on second-messenger responses in nonneuronal cells expressing human mGlu receptor subtypes demonstrated each to be a highly potent agonist for group II mGLU receptors.
Abstract: As part of our ongoing research program aimed at the identification of highly potent, selective, and systemically active agonists for group II metabotropic glutamate (mGlu) receptors, we have prepared novel heterobicyclic amino acids (-)-2-oxa-4-aminobicyclo[3.1. 0]hexane-4,6-dicarboxylate (LY379268, (-)-9) and (-)-2-thia-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate (LY389795, (-)-10). Compounds (-)-9 and (-)-10 are structurally related to our previously described nanomolar potency group II mGlu receptor agonist, (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740 monohydrate, 5), with the C4-methylene unit of 5 being replaced with either an oxygen atom (as in (-)-9) or a sulfur atom (as in (-)-10). Compounds (-)-9 and (-)-10 potently and stereospecifically displaced specific binding of the mGlu2/3 receptor antagonist ([3H]LY341495) in rat cerebral cortical homogenates, displaying IC50 values of 15 +/- 4 and 8.4 +/- 0.8 nM, respectively, while having no effect up to 100 000 nM on radioligand binding to the glutamate recognition site on NMDA, AMPA, or kainate receptors. Compounds (-)-9 and (-)-10 also potently displaced [3H]LY341495 binding from membranes expressing recombinant human group II mGlu receptor subtypes: (-)-9, Ki = 14.1 +/- 1.4 nM at mGlu2 and 5.8 +/- 0.64 nM at mGlu3; (-)-10, Ki = 40.6 +/- 3.7 nM at mGlu2 and 4.7 +/- 1.2 nM at mGlu3. Evaluation of the functional effects of (-)-9 and (-)-10 on second-messenger responses in nonneuronal cells expressing human mGlu receptor subtypes demonstrated each to be a highly potent agonist for group II mGlu receptors: (-)-9, EC50 = 2.69 +/- 0.26 nM at mGlu2 and 4.58 +/- 0.04 nM at mGlu3; (-)-10, EC50 = 3.91 +/- 0.81 nM at mGlu2 and 7.63 +/- 2. 08 nM at mGlu3. In contrast, neither compound (up to 10 000 nM) displayed either agonist or antagonist activity in cells expressing recombinant human mGlu1a, mGlu5a, mGlu4a, or mGlu7a receptors. The agonist effects of (-)-9 and (-)-10 at group II mGlu receptors were not totally specific, however, as mGlu6 agonist activity was observed at high nanomolar concentrations for (-)-9 (EC50 = 401 +/- 46 nM) and at micromolar concentrations (EC50 = 2 430 +/- 600 nM) for (-)-10; furthermore, each activated mGlu8 receptors at micromolar concentrations (EC50 = 1 690 +/- 130 and 7 340 +/- 2 720 nM, respectively). Intraperitoneal administration of either (-)-9 or (-)-10 in the mouse resulted in a dose-related blockade of limbic seizure activity produced by the nonselective group I/group II mGluR agonist (1S,3R)-ACPD ((-)-9 ED50 = 19 mg/kg, (-)-10 ED50 = 14 mg/kg), indicating that these molecules effectively cross the blood-brain barrier following systemic administration and suppress group I mGluR-mediated limbic excitation. Thus, heterobicyclic amino acids (-)-9 and (-)-10 are novel pharmacological tools useful for exploring the functions of mGlu receptors in vitro and in vivo.

Journal Article
TL;DR: The marked mGlu2/3 receptor-mediated inhibitions of PCP-evoked behaviors by LY354740 and LY379268, with minimal effects on AMP, may indicate potential antipsychotic effects in humans in the absence of dopamine mediated extrapyramidal side effects.
Abstract: Previous animal studies have indicated that drugs targeted at metabotropic glutamate (mGlu) receptors may be useful for treatment of psychosis. In this article, the effects of the novel, potent, and selective mGlu2/3 receptor agonists LY354740 and LY379268, and the clinically effective agents clozapine and haloperidol, were investigated using phencyclidine (PCP; 5 mg/kg)- versus d-amphetamine (AMP; 3 mg/kg)-evoked motor activities. LY354740 (1-10 mg/kg s.c.), LY379268 (0.3-3 mg/kg s.c.), clozapine (1-10 mg/kg s.c.), and haloperidol (0.03-1 mg/kg s.c.) reversed the increases in ambulations, fine motor (nonambulatory) movements, and decreased time at rest evoked by PCP. Furthermore, the inhibitions of the PCP response by the mGlu2/3 agonist LY379268, but not by clozapine, were completely reversed by the selective mGlu2/3 receptor antagonist LY341495. Doses of LY354740 and LY379268 that blocked the effects on PCP had no effects on rotorod performance, and (with the exception of rearing behavior) had minimal effects on AMP-evoked motor activities. Clozapine blocked AMP-induced rearing but enhanced AMP-induced ambulations and fine movements at the lower doses (1 and 3 mg/kg). Unlike the mGlu2/3 agonists, the highest dose of clozapine tested (10 mg/kg) impaired animals on the rotorod. Haloperidol potently blocked all PCP and AMP effects, but only at doses associated with motor impairment. These data demonstrate that mGlu2/3 receptor agonists act via a unique mechanism to selectively block PCP-induced behaviors. Moreover, the marked mGlu2/3 receptor-mediated inhibitions of PCP-evoked behaviors by LY354740 and LY379268, with minimal effects on AMP, may indicate potential antipsychotic effects in humans in the absence of dopamine mediated extrapyramidal side effects.

Journal ArticleDOI
TL;DR: A new, sensitive, rapid, and nonradioactive method involving the use of the commercially available BOCILLIN FL, a fluorescent penicillin, as a labeling reagent for the detection and study ofPenicillin-binding proteins (PBPs) is described.
Abstract: Penicillin-binding proteins (PBPs) are the enzymes that are required for the biosynthesis of the bacterial cell wall (10, 11, 23, 31). PBPs catalyze the final steps of the polymerization (transglycosylation) and cross-linking (transpeptidation) of peptidoglycan, an essential component of the bacterial cell wall (10, 11, 23, 31). PBPs are membrane-bound enzymes and targets of β-lactam antibiotics (6, 7, 10, 11, 14, 24, 28–31). The emerging resistance of pathogenic gram-positive bacteria to β-lactam antibiotics is a serious clinical problem (6, 25, 29, 30). Resistance to β-lactam antibiotics in some species such as Streptococcus pneumoniae has occurred by development of altered high-molecular-mass PBPs which have reduced affinity for the antibiotics (6, 7, 10, 11, 14, 24, 25, 29, 30). Extensive molecular and genetic studies have been devoted to the understanding of the mechanisms of bacterial resistance to β-lactam antibiotics (6, 7, 10, 11, 25, 29, 30). PBPs have often been detected by labeling bacterial membrane preparations with 3H-, 14C-, or 125I-labeled penicillin, separating the labeled proteins by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and exposing the gels to X-ray films (22, 27, 28). The major limitations of this type of methodology are time intensiveness (days to weeks), accumulation of hazardous materials, and lack of commercial availability. In this study, we describe a new, rapid, sensitive, and nonradioactive method for the detection and study of bacterial PBPs. This method involves the use of BOCILLIN FL (Fig. ​(Fig.1),1), a newly synthesized and commercially available fluorescent penicillin, as a labeling reagent (Molecular Probes, Inc., Eugene, Oreg.). The BOCILLIN FL-labeled PBPs were separated by SDS-PAGE and detected with a FluorImager or with the naked eye under UV light. FIG. 1 Structure of BOCILLIN FL.

Journal ArticleDOI
TL;DR: A higher than standard dose of nicotine patch was associated with an increase in the long-term success in smoking cessation but continuation of treatment beyond 8-12 weeks did not increase the success rates.
Abstract: The Collaborative European Anti-Smoking Evaluation (CEASE) was a European multicentre, randomized, double-blind placebo controlled smoking cessation study. The objectives were to determine whether higher dosage and longer duration of nicotine patch therapy would increase the success rate. Thirty-six chest clinics enrolled a total of 3,575 smokers. Subjects were allocated to one of five treatment arms: placebo and either standard or higher dose nicotine patches (15 mg and 25 mg daily) each given for 8 or 22 weeks with adjunctive moderately intensive support. The 12 month sustained success rates were: 25 mg patch for 22 weeks (L-25), 15.4%; 25 mg patch for 8 weeks (S-25), 15.9%; 15 mg patch for 22 weeks (L-15), 13.7%; 15 mg patch for 8 weeks (S-15), 11.7%; and placebo (P-0) 9.9% (placebo versus 15 mg, p<0.05; 25 mg versus 15 mg, p<0.03; 25 mg versus placebo, p<0.001, Chi- squared test). There was no significant difference in success rate between the two active treatment durations. Of the first week abstainers (n=1,698), 25.1% achieved success at 12 months as opposed to first week smokers, 2.7% of 1,877 subjects (p<0.001). In summary, a higher than standard dose of nicotine patch was associated with an increase in the long-term success in smoking cessation but continuation of treatment beyond 8-12 weeks did not increase the success rates. Eur Respir J 1999; 13: 238-246.

Journal ArticleDOI
TL;DR: The effects of intra-amygdalar neuropeptide Y infusions were assessed in rats using the social interaction test and produced an anxiolytic-like effect through neuropetide Y Y1 receptors located in the basolateral amygdala.

Journal ArticleDOI
TL;DR: Patients in a randomized, placebo-controlled clinical trial of a leukotriene antagonist experienced less mean improvement from baseline than active-treated patients and younger patients, who reported minimal improvement.
Abstract: In this study, the perceptions of asthmatics to change in their disease was associated with observed changes in clinical asthma measures, in order to identify the threshold where changes in clinical asthma measures are perceivable by patients. The study included 281 asthmatic patients, aged 18-63 yrs, in a randomized, placebo-controlled clinical trial of a leukotriene antagonist. Changes were related in: 1) asthma symptom scores; 2) inhaled beta-agonist use; 3) forced expiratory volume in one second (FEV1); and 4) peak expiratory flow (PEF) to a global question that queried overall change in asthma since starting the study drug. Additional analyses examined differences in the group reporting minimal improvement by treatment (active treatment versus placebo), sex and age groups. The average minimal patient perceivable improvement for each measure was: 1) -0.31 points for the symptom score on a scale of 0-6; 2) -0.81 puffs x day(-1) for inhaled beta-agonist use; 3) 0.23 L for FEV1; and 4) 18.79 L x min(-1) for PEF. In general placebo-treated patients and older patients, who reported minimal improvement, experienced less mean improvement from baseline than active-treated patients and younger patients, who reported minimal improvement. Determining the minimal patient perceivable improvement value for a measure may be helpful to interpret changes. However, interpretation should be carried out cautiously when reporting a single value as a clinically important change.

Journal ArticleDOI
TL;DR: The results indicated a significantly lower risk of tardive dyskinesia with olanzapine than with haloperidol, which is important in the side-effect profile of antipsychotic medication.
Abstract: BACKGROUND Tardive dyskinesia is important in the side-effect profile of antipsychotic medication. AIMS The development of tardive dyskinesia was evaluated in patients treated with double-blind, randomly assigned olanzapine or haloperidol for up to 2.6 years. METHODS Tardive dyskinesia was assessed by the Abnormal Involuntary Movement Scale (AIMS) and Research Diagnostic Criteria for Tardive Dyskinesia (RD-TD), it was defined as meeting RD-TD criteria at two consecutive assessments. The risk of tardive dyskinesia, the relative risk, incidence rate, and incidence rate ratio were estimated. RESULTS The relative risk of tardive dyskinesia for the overall follow up period for haloperidol (n = 522) v. olanzapine (n = 1192) was 2.66 (95% CI = 1.50-4.70). Based on data following the initial six weeks of observation (during which patients underwent medication change and AIMS assessments as frequently as every three days), the one-year risk was 0.52% with olanzapine (n = 513) and 7.45% with haloperidol (n = 114). The relative risk throughout this follow-up period was 11.37 (95% CI = 2.21-58.60). CONCLUSION Our results indicated a significantly lower risk of tardive dyskinesia with olanzapine than with haloperidol.

Journal ArticleDOI
TL;DR: Development of specific receptor antagonists with improved pharmacokinetic properties will be required to determine the importance of NPY in human obesity and appetite disorders.

Journal ArticleDOI
TL;DR: In this paper, the incidence and severity of adverse events in postmenopausal women treated with raloxifene compared with placebo, hormone replacement therapy (HRT), or unopposed estrogen.

Journal ArticleDOI
TL;DR: Two new cloned human cDNAs encode paralogs of the 85-kDa cytosolic phospholipase A2(cPLA2), giving the name cPLA2α to the well known 85-KDa enzyme, and residues activated by phosphorylation do not appear to be well conserved in either new enzyme.

Journal ArticleDOI
TL;DR: It is hypothesized that the dysfunctional mesocortical dopamine input to the PFC may lead to abnormal modulation of ionic channels distributed in the dendritic–somatic compartments of PFC pyramidal neurons that project to the ventral tegmental area and/or nucleus accumbens.

Journal ArticleDOI
TL;DR: This review addresses the pharmaceutical potential of the intestinal peptide transport system and summarizes several studies on the mechanism and substrate structure-affinity relationship for this transport system.
Abstract: The intestinal peptide transport system has broad substrate specificities. In addition to its physiological function of absorbing di- and tripeptides resulting from the digestion of dietary proteins, this transport system also absorbs some orally administered peptidomimetic drugs, including β-lactam antibiotics, angiotensin converting enzyme inhibitors, renin inhibitors, bestatin, thrombin inhibitors, and thyrotropin-releasing hormone and its analogues. There have been several studies on the mechanism and substrate structure-affinity relationship for this transport system. Rapid progress has been made recently in studies on the molecular basis of the intestinal peptide transport system. A protein apparently involved in peptide transport has been isolated from rabbit small intestines, and genes for human intestinal peptide transporters have been cloned, sequenced and functionally expressed. This review summarizes these studies and addresses the pharmaceutical potential of the intestinal peptide transport system.

Journal ArticleDOI
TL;DR: The GH secretory response to exercise is related to exercise intensity in a linear dose-response pattern in young men, and deconvolution analysis revealed that increasing exercise intensity resulted in alinear increase in the mass of GH secreted per pulse and GH production rate.
Abstract: To investigate the effects of exercise intensity on growth hormone (GH) release, 10 male subjects were tested on 6 randomly ordered occasions [1 control condition (C), 5 exercise conditions (Ex)]. ...

Journal Article
TL;DR: Vascular permeability, which was measured by using the Miles assay in nude mice, was increased proportionately with VEGF levels in the malignant pleural effusions, and this increase in permeability induced by injection of recombinant V EGF or themalignant effusions was reduced by pretreating the mice with a VegF receptor antibody.
Abstract: Vascular endothelial growth factor (VEGF) is an important mediator of angiogenesis and vascular permeability. We hypothesized that malignant pleural effusions may contain high levels of VEGF protein as well as other cytokines implicated in these processes. Pleural effusions cytologically proven to be malignant were collected from 39 patients with various types of cancer, and VEGF, interleukin-8, and angiogenin levels in the effusions were determined by immunoassay. Negative controls were nonmalignant ascites and serum samples from healthy individuals. VEGF levels were significantly higher than those of control samples in pleural effusions secondary to breast, mesothelioma, and non-small cell lung cancer and when all malignant pleural effusion samples were pooled. Neither interleukin-8 nor angiogenin levels were elevated in malignant pleural effusions relative to the control samples. Vascular permeability, which was measured by using the Miles assay in nude mice, was increased proportionately with VEGF levels in the malignant pleural effusions; this increase in permeability induced by injection of recombinant VEGF or the malignant effusions was reduced by pretreating the mice with a VEGF receptor antibody.

Journal ArticleDOI
TL;DR: It has been hypothesized that the morbidity and mortality associated with schizophrenia can be prevented by providing effective treatment during the first episode of psychosis, and olanzapine showed a statistically significantly greater reduction in the Brief Psychiatric Rating Scale (BPRS) compared to haloperidol.
Abstract: OBJECTIVE: It has been hypothesized that the morbidity and mortality associated with schizophrenia can be prevented by providing effective treatment during the first episode of psychosis. Hence, the authors examined patients with first-episode psychosis to determine the efficacy and safety of olanzapine and haloperidol treatment. METHOD: A subpopulation of first-episode patients (N=83) from a large prospective, multicenter, international, double-blind, 6-week acute treatment study was evaluated. These patients were selected from a pool of 1,996 patients who had a DSM-III-R diagnosis of schizophrenia, schizoaffective disorder, or schizophreniform disorder and who also met the following criteria: 1) the length of their current psychotic episode had to be 5 or fewer years, and 2) patients had to be 45 years of age or younger at onset of first psychotic symptoms. RESULTS: Compared to haloperidol, olanzapine showed a statistically significantly greater reduction in the Brief Psychiatric Rating Scale (BPRS) tot...

Journal ArticleDOI
TL;DR: Results suggest central CRF and Ucn play a role in generating anxiety which may be similar to that seen in pathological conditions such as panic disorder.