Temocillin: a new candidate antibiotic for local antimicrobial delivery in orthopaedic surgery?

Objectives: To assess the performance of the Gram-negative-specific antibiotic temocillin in polymethylmethacrylate bone cement pre-loaded with gentamicin, as a strategy for local antibiotic delivery.

Methods: Temocillin was added at varying concentrations to commercial gentamicin-loaded bone cement. The elution of the antibiotic from cement samples over a 2 week period was quantified by LC-MS.

The renin-angiotensin system in the breast and breast cancer.

Much evidence now suggests that angiotensin II has roles in normal functions of the breast that may be altered or attenuated in cancer. Both angiotensin type 1 (AT1) and type 2 (AT2) receptors are present particularly in the secretory epithelium. Additionally, all the elements of a tissue renin-angiotensin system, angiotensinogen, prorenin and angiotensin-converting enzyme (ACE), are also present and distributed in different cell types in a manner suggesting a close relationship with sites of angiotensin II activity.

Eph receptors and zonation in the rat adrenal cortex.

Although the zonation of the adrenal cortex has a clear functional role, the mechanisms that maintain it remain largely conjectural. The concept that an outer proliferative layer gives rise to cells that migrate inwards, adopting sequentially the zona glomerulosa, fasciculata and reticularis phenotypes, has yet to be explained mechanistically. In other tissues, Eph receptor (EphR)/ephrin signalling provides a mechanism for cellular orientation and migration patterns.

Changes in angiotensin II type 1 receptor signalling pathways evoked by a monoclonal antibody raised to the N-terminus.

The extracellular N-terminus of G-protein-coupled receptors may be involved in signalling events. We examined this in the angiotensin II type 1 receptor (AT1-R) using monoclonal antibody 6313/G2, raised against a conserved sequence in the N-terminal domain, and found it evokes inhibitory and stimulatory responses. In rat aortic smooth muscle cell (RASMC) primary cultures, 6313/G2 (2.

Non-steroidal anti-estrogens in the treatment of breast cancer.

The non-steroidal selective estrogen receptor modulator (SERM) tamoxifen has been used as standard first-line therapy for postmenopausal breast cancer since the 1970s, during which time over 400,000 lives have been saved. Nevertheless, much attention has been paid to the side effect profile of tamoxifen, particularly in terms of cardiovascular and endometrial abnormalities. Third generation non-steroidal aromatase inhibitors, such as anastrozole and letrozole, have been approved as an alternative, although it is still too early to judge what long-term adverse effects might be associated with prolonged restriction of the supply of estrogen.

Trilostane in advanced breast cancer.

Antiestrogens, principally tamoxifen, and aromatase inhibitors have been used as the first- and second-line therapy in patients with advanced postmenopausal breast cancer for many years. However, some patients acquire resistance to these treatments and, at present, further endocrine treatment is achieved by merely substituting the current medication with a different antiestrogen or aromatase inhibitor. Trilostane offers an alternative endocrine treatment due to its unique mode of action.

Comparison of effects of 4-hydroxy tamoxifen and trilostane on oestrogen-regulated gene expression in MCF-7 cells: up-regulation of oestrogen receptor beta.

4-Hydroxy tamoxifen (OHT) and trilostane interact differently with the oestrogen receptor (ER). OHT is a competitive inhibitor whereas trilostane has direct, but non-competitive effects on ER. This study compared the effects of OHT and trilostane, in the presence of 17beta-oestradiol (E2) on gene expression in MCF-7 breast cancer cells using microarrays each representing nearly 20,000 human genes.

Design and synthesis of new tetrazolyl- and carboxy-biphenylylmethyl-quinazolin-4-one derivatives as angiotensin II AT1 receptor antagonists.

A series of novel quinazolin-4-ones was designed and their molecular modeling simulation fitting to a new HipHop 3D pharmacophore model using CATALYST was examined. Several compounds showed significant high simulation fit values. The designed compounds were synthesized and eight of them were biologically evaluated in vitro using an AT1 receptor binding assay, where compound XX competed weakly against radiolabeled Sar1Ile8-angiotensin II (Ang II) binding, compounds XIV and XXII showed moderate competition, and compound XXV showed almost equal ability to displace radiolabeled Sar1Ile8-Ang II binding to AT1 receptors as losartan.

Progress in the development of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.

Angiotensin II is a potent vasoconstrictor that stimulates aldosterone secretion. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are currently in use for the treatment of hypertension and chronic heart failure. Clinical trials show ACEIs to be effective, but with significant side effects, while ARBs provide a useful, more well-tolerated, alternative.

Synthesis and secretion of angiotensin II by the prostate gland in vitro.

The renin angiotensin system has been shown to have tissue-related functions that are distinct from its systemic roles. We showed that angiotensin II type 1 (AT1) receptors are present in mammalian sperm, and angiotensin II stimulates sperm motility and capacitation. In addition, angiotensin II is present in human seminal plasma at concentrations higher than found in blood.

Mechanism for aldosterone potentiation of angiotensin II-stimulated rat arterial smooth muscle cell proliferation.

After earlier studies in which secretion of aldosterone was demonstrated to be important in rat arterial smooth muscle cell (RASMC) proliferation in vitro, the presence of both 11beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) gene transcription were shown in these cells by real-time reverse transcription-polymerase chain reaction (RT-PCR). In proliferation studies, tritiated thymidine incorporation into RASMC and RASMC cell number were both significantly increased by angiotensin II (Ang II) (10(-7) mol/L) compared with controls (P<0.01), but this effect was inhibited by the 3beta-hydroxysteroid-dehydrogenase inhibitor trilostane (10(-6) mol/L and 10(-5) mol/L, P<0.

Role for nuclear factor-kappaB and signal transducer and activator of transcription 1/interferon regulatory factor-1 in cytokine-induced endothelin-1 release in human vascular smooth muscle cells.

Endothelin-1 (ET-1) is a potent vasoconstrictor and growth-promoting mediator that is involved in the maintenance of vascular tone within the healthy circulation. However, a pathogenic role has been implicated by its overproduction in a number of cardiovascular diseases, which include pulmonary hypertension, congestive heart failure, atherosclerosis, and coronary vasospasm. ET-1 mRNA expression and peptide production in human vascular smooth muscle cells (HVSMCs) are markedly increased by exposure to tumor necrosis factor-alpha and interferon-gamma.

Anti-estrogens in the treatment of breast cancer: current status and future directions.

For many years, the non-steroidal estrogen receptor (ER) blocker tamoxifen has been the drug of choice for the treatment of hormone-responsive breast cancer. However, deleterious effects on other tissues such as the endometrium and the frequent occurrence of relapse due to tamoxifen resistance have led to the search for alternative drugs that exhibit more favorable tissue-specific ER effects. Alongside these selective ER modulators, a new generation of aromatase inhibitors, which act by limiting the supply of local estrogen to the breast tumor, has emerged to challenge tamoxifen for supremacy.

Non-competitive steroid inhibition of oestrogen receptor functions.

Currently available antioestrogens, such as tamoxifen, are competitive inhibitors that bind to the ligand binding sites of oestrogen receptors, ERalpha and ERbeta. The search for alternative anti-hormone therapies is prompted by the need for drugs that are effective when tumours become tamoxifen resistant. The existence of different receptor isoforms also raise the possibility of improving selectivity.

Inhibitory effect of adrenomedullin on basal and tumour necrosis factor alpha-stimulated endothelin-1 synthesis in bovine aortic endothelial cells is independent of cyclic AMP.

Adrenomedullin (ADM) is a potent vasodilator and reverses the vasoconstrictor action of endothelin-1 (ET-1). These studies aimed to determine the effect of ADM on ET-1 synthesis in bovine aortic endothelial cells (BAEC) and to identify the possible mechanisms involved. In this cell model, ADM increased cyclic AMP production by BAEC with threshold concentrations of 100 pM and an EC(50) of 1 nM.