Prior calcium channel blockade and short-term survival following acute myocardial infarction

There is concern over the safety of calcium channel blockers (CCBs) in acute coronary disease. We sought to determine if patients taking calcium channel blockers (CCBs) at the time of admission with acute myocardial infarction (AMI) had a higher case-fatality compared with those taking beta-blockers or neither medication. Clinical and drug treatment variables at the time of hospital admission predictive of survival at 28 days were examined in a community-based registry of patients aged under 65 years admitted to hospital for suspected AMI in Perth, Australia, between 1984 and 1993. Among 7766 patients, 1291 (16.6%) were taking a CCB and 1259 (16.2%) a betablocker alone at hospital admission. Patients taking CCBs had a worse clinical profile than those taking a beta-blocker alone or neither drug (control group), and a higher unadjusted 28-day mortality (17.6% versus 9.3% and 11.1% respectively, both P < 0.001). There was no significant heterogeneity with respect to mortality between nifedipine, diltiazem, or verapamil when used alone, or with a beta-blocker. After adjustment for factors predictive of death at 28 days, patients taking a CCB were found not to have an excess chance of death compared with the control group (odds ratio [OR] 1.06, 95% confidence interval [CI]; 0.87, 1.30), whereas those taking a beta-blocker alone had a lower odds of death (OR 0.75, 95% CI; 0.59, 0.94). These results indicate that established calcium channel blockade is not associated with an excess risk of death following AMI once other differences between patients are taken into account, but neither does it have the survival advantage seen with prior beta-blocker therapy.

A randomized trial comparing hormone replacement therapy (HRT) and HRT plus calcitriol in the treatment of postmenopausal osteoporosis with vertebral fractures: Benefit of the combination on total body and hip density

We report a prospective, randomized, multi-center, open-label 2-year trial of 81 postmenopausal women aged 53-79 years with at least one minimal-trauma vertebral fracture (VF) and low (T-score below 2) lumbar bone mineral density (BMD). Group HRT received piperazine estrone sulfate (PES) 0.625 - 1.25 mg/d +/- medroxyprogesterone acetate (MPA) 2.5 - 5 mg/d,- group HRT/D received HRT plus calcitriol 0.25 mug bd. All with a baseline dietary calcium (Ca) of < I g/d received Ca carbonate 0.6 g nocte. Final data were on 66 - 70 patients. On HRT/D, significant (P < 0.001) BNID increases from baseline by DXA were at total body - head, trochanter, Ward's, total hip, inter-trochanter and femoral shaft (% group mean Delta 4.2, 6.1, 9.3. 3.7. 3.3 and 3.3%, respectively). On HRT, at these significant Deltas were restricted to the trochanter and sites. si Wards. Significant advantages of HRT/D over HRT were in BMD of total body (- head), total hip and trochanter (all P = 0.01). The differences in mean Delta at these sites were 1.3, 2.6 and 3.9%. At the following, both groups Improved significantly -lumbar spine (AP and lateral), forearm shaft and ultradistal tibia/fibula. The weightbearing, site - specific benefits of the combination associated with significant suppression of parathyroid hormone-suggest a beneficial effect on cortical bone. Suppression of bone turnover was significantly greater on HRT/D (serum osteocalcin P = 0.024 and urinary hydroxyproline/creatinine ratio P = 0.035). There was no significant difference in the number of patients who developed fresh VFs during the trial (HRT 8/36, 22%; HRT/D 4/34, 12% - intention to treat); likewise in the number who developed incident nonvertebral fractures. This Is the first study comparing the 2 treatments in a fracture population. The results indicate a significant benefit of calcitriol combined with HRT on total body BMD and on BNID at the hip, the major site of osteoporotic fracture.

Development and subunit composition of synaptic NMDA receptors in the amygdala: NR2B Synapses in the adult central amygdala

NMDA receptors are well known to play an important role in synaptic development and plasticity. Functional NMDA receptors are heteromultimers thought to contain two NR1 subunits and two or three NR2 subunits. In central neurons, NMDA receptors at immature glutamatergic synapses contain NR2B subunits and are largely replaced by NR2A subunits with development. At mature synapses, NMDA receptors are thought to be multimers that contain either NR1/NR2A or NR1/NR2A/NR2B subunits, whereas receptors that contain only NR1/NR2B subunits are extrasynaptic. Here, we have studied the properties of NMDA receptors at glutamatergic synapses in the lateral and central amygdala. We find that NMDA receptor-mediated synaptic currents in the central amygdala in both immature and mature synapses have slow kinetics and are substantially blocked by the NR2B-selective antagonists (1S, 2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propano and ifenprodil, indicating that there is no developmental change in subunit composition. In contrast, at synapses on pyramidal neurons in the lateral amygdala, whereas NMDA EPSCs at immature synapses are slow and blocked by NR2B-selective antagonists, at mature synapses their kinetics are faster and markedly less sensitive to NR2B-selective antagonists, consistent with a change from NR2B to NR2A subunits. Using real-time PCR and Western blotting, we show that in adults the ratio of levels of NR2B to NR2A subunits is greater in the central amygdala than in the lateral amygdala. These results show that the subunit composition synaptic NMDA receptors in the lateral and central amygdala undergo distinct developmental changes.

Attenuation of Pseudomonas aeruginosa virulence by quorum sensing inhibitors

Traditional treatment of infectious diseases is based on compounds that kill or inhibit growth of bacteria. A major concern with this approach is the frequent development of resistance to antibiotics. The discovery of communication systems (quorum sensing systems) regulating bacterial virulence has afforded a novel opportunity to control infectious bacteria without interfering with growth. Compounds that can override communication signals have been found in the marine environment. Using Pseudomonas aeruginosa PAO1 as an example of an opportunistic human pathogen, we show that a synthetic derivate of natural furanone compounds can act as a potent antagonist of bacterial quorum sensing. We employed GeneChip((R)) microarray technology to identify furanone target genes and to map the quorum sensing regulon. The transcriptome analysis showed that the furanone drug specifically targeted quorum sensing systems and inhibited virulence factor expression. Application of the drug to P.aeruginosa biofilms increased bacterial susceptibility to tobramycin and SDS. In a mouse pulmonary infection model, the drug inhibited quorum sensing of the infecting bacteria and promoted their clearance by the mouse immune response.

Molecular diversity through sugar scaffolds

Monosaccharides provide an excellent platform to tailor molecular diversity by appending desired substituents at selected positions around the sugar scaffold. The presence of five functionalized and stereo-controlled centres on the sugar scaffolds gives the chemist plenty of scope to custom design molecules to a pharmacophore model. This review focuses on the peptidomimetic developments in this area, as well as the concept of tailoring structural and functional diversity in a library using carbohydrate scaffolds and how this can lead to increased hit rates and rapid identification of leads, which has promising prospects for drug development.

Regulation of the gene encoding glutathione S-transferase M1 (GSTM1) by the Myb oncoprotein

The identification of Myb 'target' genes will not only aid in the understanding of how overexpression of Myb, or expression of activated forms of Myb, leads to cellular transformation but will also shed light on its role in normal cells. Using a combination of an estrogen-regulated Myb-transformed cell line (ERMYB) and PCR-based subtractive hybridization, we have identified the gene (GSTM1) encoding the detoxification enzyme glutathione S-transferase M1 as being transcriptionally upregulated by Myb. Functional analysis of the GSTM1 promoter using reporter assays indicated that both the DNA binding and transactivation domains of Myb were required for transcriptional activation. Mutational analysis of consensus Myb-binding sites (MBS) in the promoter and electrophoretic mobility gel shift analysis indicated that one of the three potential MBS can bind Myb protein, and is the primary site involved in the regulation of this promoter by Myb.

Pindolol potentiates the panicolytic effect of paroxetine in the elevated T-maze

Aims: The beta-adrenergic and 5-HT(1A) receptor antagonist pindolol has been used in combination with antidepressant drugs, to shorten the time of onset of clinical efficacy and/or increase the proportion of responders in depressive and anxiety disorders. The aim of this study was to examine the interaction between pindolol and the selective serotonin reuptake inhibitor (SSRI), paroxetine in rats submitted to the elevated T-maze (ETM). Main methods: For assessing the drug combination effect, rats were administered with pindolol before paroxetine, using oral or intraperitoneal (i.p.) routes of acute administration, and were submitted to the ETM model. Key findings: The highest dose of pindolol used (15.0 mg/kg, i.p.) increased both inhibitory avoidance and escape latencies in the ETM, probably due to nonspecific motor deficit, since locomotion in a circular arena was also significantly decreased. The highest dose of paroxetine (3.0 mg/kg, i.p.) selectively impaired escape, considered a panicolytic effect. Combination of pindolol (5.0 mg/kg, i.p.) with an ineffective dose of paroxetine (1.5 mg/kg, i.p.) impaired escape, indicating a potentiation of the panicolytic effect of paroxetine. By the oral route, neither paroxetine (3.0 mg/kg) nor pindolol (5.0 mg/kg) alone were effective, but the combination treatment had a marked panicolytic effect, again indicating drug potentiation. Significance: The present results show that the combination of the ineffective doses of pindolol and paroxetine significantly increased escape latency, indicating a selective panicolytic effect. These findings give preclinical support for the use of this drug combination in the treatment of panic disorder (PD). (C) 2010 Elsevier Inc. All rights reserved.

Glutamatergic neurotransmission mediated by NMDA receptors in the inferior colliculus can modulate haloperidol-induced catalepsy

The inferior colliculus (IC) is primarily involved in the processing of auditory information, but it is distinguished from other auditory nuclei in the brainstem by its connections with structures of the motor system. Functional evidence relating the IC to motor behavior derives from experiments showing that activation of the IC by electrical stimulation or excitatory amino acid microinjection causes freezing, escape-like behavior, and immobility. However, the nature of this immobility is still unclear. The present study examined the influence of excitatory amino acid-mediated mechanisms in the IC on the catalepsy induced by the dopamine receptor blocker haloperidol administered systemically (1 or 0.5 mg/kg) in rats. Haloperidol-induced catalepsy was challenged with prior intracollicular microinjections of glutamate NMDA receptor antagonists, MK-801 (15 or 30 mmol/0.5 mu l) and AP7 (10 or 20 nmol/0.5 mu l), or of the NMDA receptor agonist N-methyl-D-aspartate (NMDA, 20 or 30 nmol/0.5 mu l). The results showed that intracollicular microinjection of MK-801 and AP7 previous to systemic injections of haloperidol significantly attenuated the catalepsy, as indicated by a reduced latency to step down from a horizontal bar. Accordingly, intracollicular microinjection of NMDA increased the latency to step down the bar. These findings suggest that glutamate-mediated mechanisms in the neural circuits at the IC level influence haloperidol-induced catalepsy and participate in the regulation of motor activity. (C) 2010 Published by Elsevier B.V.

Effect of estradiol benzoate microinjection into the median raphe nucleus on contextual conditioning

Estrogen deficiency has been associated with stress, anxiety and depression. Estrogen receptors have been identified in the median raphe nucleus (MRN). This structure is the main source of serotonergic projections to the hippocampus, a forebrain area implicated in the regulation of defensive responses and in the resistance to chronic stress. There is reported evidence indicating that estrogen modulates 5-HT(1A) receptor function. In the MRN, somatodendritic 5-HT(1A) receptors control the activity of serotonergic neurones by negative feedback. The present study has evaluated the effect of intra-MRN injection of estradiol benzoate (EB, 600 or 1200 ng/0.2 mu l) on the performance of ovariectormized rats submitted to contextual conditioning. Additionally, the same treatment was given after intra-MRN injection of Way 100635 (100 ng/0.2 mu l). a 5-HT(1A) receptor antagonist. Both doses of EB decreased freezing and increased rearing, indicating an anxiolytic effect. Pretreatment with Way 100635 antagonized the anxiolytic effect of estradiol. On the basis of these results, it may be suggested that estrogens modulate anxiety by acting on 5-HT(1A) receptors localized in the MRN. (C) 2009 Elsevier B.V. All rights reserved.

Hormone replacement therapy and breast cancer: estimate of risk: Education debate

The risk of breast cancer arises from a combination of genetic susceptibility and environmental factors. Recent studies show that type and duration of use of hormone replacement therapy affect a women's risk of developing breast cancer.1-7 The women's health initiative trial was stopped early because of excess adverse cardiovascular events and invasive breast cancer with oestrogen and progestogen.6 The publicity increased public awareness of the risks of hormone replacement therapy, and this was heightened by the publication of the million women study.2 However, the recently published oestrogen only arm of the women's health initiative trial suggests that this formulation may reduce the risk of breast cancer.8 To help make sense of the often confusing information,9 women and clinicians need individual rather than population risk data. We have produced estimates that can be used to calculate individual risk for women living up to the age of 79 and suggest the risk

Influence of ovariectomy and masticatory hypofunction on mandibular bone remodeling

Introduction: This study was designed to examine the effect of masticatory hypofunction and estrogen deficiency on mandible bone mass and compare this site with spine and femoral bone. Methods: Twenty-four rats were ovariectomized (OVX) or Sham-operated (Sham) and analyzed after feeding with hard diet (Hard) or soft diet (Soft). They were divided into four groups: (GI)Sham-Hard; (GII)OVX-Hard; (GIII)Sham-Soft and (GIV)OVX-Soft. Bone mineral density (BMD) was measured in the spine and femur in the baseline and at the end of the study, and Delta BMD (final BMD - baseline BMD) was calculated. In mandible bone, BMD and histomorphometry were analyzed at the end of the experiment. Results: Sham rats showed higher spine (GI: 13.5%vs GII: 0.74%, P < 0.01; GIII: 10.67%vs GIV: -4.36%, P < 0.001) and femur Delta BMD (GI: 14.43%vs GII: 4.42%, P < 0.01; GIII: 10.58%vs GIV: 0.49%, P < 0.001) than OVX, but no difference was observed in mandible BMD among these groups (P > 0.05). Soft-diet groups showed decreased mandible BMD compared with hard-diet groups (GIV vs GII, P < 0.01; GIII vs GI, P < 0.01). Similarly, mandibular condyle histomorphometry showed that soft-diet groups presented a significant decrease in trabecular thickness and volume (GIV vs GII, P < 0.05; GIII vs GI, P < 0.01) compared with hard diet. Conclusion: Our results suggest that mandibular bone loss resulted from decreased of mechanical loading during mastication, and was not affect by estrogen depletion.

Hormone replacement therapy and breast cancer risk in California

Numerous studies have documented increased breast cancer risks with hormone replacement therapy (HRT), but these do not give a woman her specific absolute risk for the remainder of her life. This article estimates the magnitude of the effect of HRT on breast cancer incidence in California and calculates a woman's cumulative risk of breast cancer with different formulations and durations of HRT use. The effects of HRT on the underlying breast cancer incidence were estimated using the attributable fraction method, applying HRT prevalence data from the 2001 California Health Interview Survey and published rates of higher relative risk (RR) from HRT use from the Women's Health Initiative (WHI) study and Million Women's Survey (MWS). The annual number of breast cancers potentially attributable to HRT in California was estimated, along with individual cumulative risk of breast cancer for various ages to 79 years according to HRT use, duration, and formulation. Using the WHI data, 829 of 19,000 breast cancers (4.3%) in California may be attributable to HRT This figure increases to 3401 (17.4%) when the MWS RRs are applied. Use of estrogen-only HRT or short-term (approximately 5 years) use of combined HRT has a minimal effect on the cumulative risk calculated to the age of 79 years; application of the MWS data to a Californian woman commencing HRT at the age of 50 years (no HRT, 8.5%; estrogen only, 8.6%; combined, 9.1%). Prolonged (approximately 10 years) use of combined HRT increases the cumulative risk to 10.3%. This article demonstrates that HRT will generate a small additional risk of breast cancer in an individual. The reduction in perimenopausal symptoms may be considered sufficient to warrant this extra risk. However, this view needs to be balanced because the small increases in individual risk will be magnified, producing a noticeable change in population cancer caseload where HRT use is high.

The structure of a novel insecticidal neurotoxin, omega-atracotoxin-HV1, from the venom of an Australian funnel web spider

A family of potent insecticidal toxins has recently been isolated from the venom of Australian funnel web spiders. Among these is the 37-residue peptide omega-atracotoxin-HV1 (omega-ACTX-HV1) from Hadronyche versuta. We have chemically synthesized and folded omega-ACTX-HV1, shown that it is neurotoxic, ascertained its disulphide bonding pattern, and determined its three-dimensional solution structure using NMR spectroscopy. The structure consists of a solvent-accessible beta-hairpin protruding from a disulphide-bonded globular core comprising four beta-turns. The three intramolecular disulphide bonds form a cystine knot motif similar to that seen in several other neurotoxic peptides. Despite limited sequence identity, omega-ACTX-HV1 displays significant structural homology with the omega-agatoxins and omega-conotoxins, both of which are vertebrate calcium channel antagonists; however, in contrast with these toxins, we show that omega-ACTX-HV1 inhibits insect, but not mammalian, voltage-gated calcium channel currents.

Double-blind, Randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: Results from EFECT

Purpose The third-generation nonsteroidal aromatase inhibitors (AIs) are increasingly used as adjuvant and first-line advanced therapy for postmenopausal, hormone receptor-positive (HR +) breast cancer. Because many patients subsequently experience progression or relapse, it is important to identify agents with efficacy after AI failure. Materials and Methods Evaluation of Faslodex versus Exemestane Clinical Trial (EFECT) is a randomized, double-blind, placebo controlled, multicenter phase III trial of fulvestrant versus exemestane in postmenopausal women with HR + advanced breast cancer (ABC) progressing or recurring after nonsteroidal AI. The primary end point was time to progression (TTP). A fulvestrant loading-dose (LD) regimen was used: 500 mg intramuscularly on day 0, 250 mg on days 14, 28, and 250 mg every 28 days thereafter. Exemestane 25 mg orally was administered once daily. Results A total of 693 women were randomly assigned to fulvestrant (n = 351) or exemestane ( n = 342). Approximately 60% of patients had received at least two prior endocrine therapies. Median TTP was 3.7 months in both groups ( hazard ratio = 0.963; 95% CI, 0.819 to 1.133; P = .6531). The overall response rate ( 7.4% v 6.7%; P = .736) and clinical benefit rate ( 32.2% v 31.5%; P = .853) were similar between fulvestrant and exemestane respectively. Median duration of clinical benefit was 9.3 and 8.3 months, respectively. Both treatments were well tolerated, with no significant differences in the incidence of adverse events or quality of life. Pharmacokinetic data confirm that steady-state was reached within 1 month with the LD schedule of fulvestrant. Conclusion Fulvestrant LD and exemestane are equally active and well-tolerated in a meaningful proportion of postmenopausal women with ABC who have experienced progression or recurrence during treatment with a nonsteroidal AI.