Day: 09/16/2010

Cyanine dyes in optical imaging of tumours

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Near-infrared imaging holds promise for in-vivo cancer detection because of flow tissue autofluorescence and high tissue penetration depth. Cyanine dyes have shown much potential as non-targeting contrast agents for optical imaging; in particular, indocyanine green has long been implemented in clinical use. To improve targeting selectivity and delivery efficiency, common strategies with activatable technology need the chemical conjugation of suitable near-infrared emission range agents with tumour-specific ligands such as antibodies.1 Although these conjugated agents with tumour-specific antibodies or other ligands have shown promising efficacy in preclinical and clinical trials compared with conventional chemotherapy drugs, limitations in their delivery and specificity remain. For example, in-vivo studies have shown that only one to ten parts per 100 000 of intravenously administered monoclonal antibodies, of therapeutic or imaging agents, can reach their parenchymal targets, and only to specific tumour types.2 Furthermore, the chemical conjugation might affect the specificity, affinity, and distribution of the agents in cells and tissues.

To overcome these limitations, a rational strategy is to develop near-infrared dyes with native tumour targeting properties. With this hypothesis, our research has identified a group of heptamethine cyanine dyes with improved near-infrared fluorescence emission profiles and active tumour targeting properties that do not require chemical conjugation. These cyanine dyes are lipophilic cations at 780 nm, and preferentially accumulate in the mitochondria of viable tumour cells because of their higher mitochondrial membrane potential, compared with normal cells, to reach a significant signal contrast for in-vivo tumour imaging.3, 4 The accumulation of these cyanine dyes is via an energy-dependent pathway (only by viable tumour cells), and can be distinguished from dead or apoptotic cells.
These cyanine dyes have superior optical properties for tumour imaging owing to a rigid cyclohexenyl ring in the heptamethine chain with a central chlorine atom that maintains photostability, increases quantum yield, and decreases photobleaching. The dyes have superb biocompatible, pharmacokinetic, and retention properties. They can persist in tumours over 2 weeks for repeated imaging, but free dyes in circulation can be excreted rapidly from the interstitial fluid, resulting in no apparent acute toxic effect and improved signal contrast of tumours. The cyanine dyes can reach a contrast index value up to 20, whereas previously, a contrast index in a tumour of more than 2·5 times compared with that in its surrounding tissue was regarded as substantial accumulation.5 Additionally, the fluorescence of these dyes was stable after formalin fixation, which raised the possibility of developing new and sensitive means of detecting tumours in harvested surgical specimens.6
Most human tumours have been identified with higher mitochondrial membrane potentials than normal cells, making these dyes attractive imaging agents for cancer detection.7 Therefore, cyanine dyes can be used non-invasively to detect tumour and tumour metastases in vivo, cancer cells in pathological specimens, and circulating cancer cells in blood to improve cancer detection, prognosis, and treatment.
CS initially made the concept and identified these heptamethine cyanine dyes with native tumour targeting and near-infrared imaging properties. CS is also an inventor on the pending patents for these cyanine dyes as tumour imaging agents. CZ, YS, and TC declared no conflicts of interest.
source: Lancet oncology

Effect of palliative oxygen versus room air in relief of breathlessness in patients with refractory dyspnoea

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Palliative oxygen therapy is widely used for treatment of dyspnoea in individuals with life-limiting illness who are ineligible for long-term oxygen therapy. We assessed the effectiveness of oxygen compared with room air delivered by nasal cannula for relief of breathlessness in this population of patients.

Methods

Adults from outpatient clinics at nine sites in Australia, the USA, and the UK were eligible for enrolment in this double-blind, randomised controlled trial if they had life-limiting illness, refractory dyspnoea, and partial pressure of oxygen in arterial blood (PaO2) more than 7·3 kPa. Participants were randomly assigned in a 1:1 ratio by a central computer-generated system to receive oxygen or room air via a concentrator through a nasal cannula at 2 L per min for 7 days. Participants were instructed to use the concentrator for at least 15 h per day. The randomisation sequence was stratified by baseline PaO2 with balanced blocks of four patients. The primary outcome measure was breathlessness (0—10 numerical rating scale [NRS]), measured twice a day (morning and evening). All randomised patients who completed an assessment were included in the primary analysis for that data point (no data were imputed). This study is registered, numbers NCT00327873 and ISRCTN67448752.

Findings

239 participants were randomly assigned to treatment (oxygen, n=120; room air, n=119). 112 (93%) patients assigned to receive oxygen and 99 (83%) assigned to receive room air completed all 7 days of assessments. From baseline to day 6, mean morning breathlessness changed by −0·9 points (95% CI −1·3 to −0·5) in patients assigned to receive oxygen and by −0·7 points (−1·2 to −0·2) in patients assigned to receive room air (p=0·504). Mean evening breathlessness changed by −0·3 points (−0·7 to 0·1) in the oxygen group and by −0·5 (−0·9 to −0·1) in the room air group (p=0·554). The frequency of side-effects did not differ between groups. Extreme drowsiness was reported by 12 (10%) of 116 patients assigned to receive oxygen compared with 14 (13%) of 108 patients assigned to receive room air. Two (2%) patients in the oxygen group reported extreme symptoms of nasal irritation compared with seven (6%) in the room air group. One patient reported an extremely troublesome nose bleed (oxygen group).

Interpretation

Since oxygen delivered by a nasal cannula provides no additional symptomatic benefit for relief of refractory dyspnoea in patients with life-limiting illness compared with room air, less burdensome strategies should be considered after brief assessment of the effect of oxygen therapy on the individual patient.
source:Lancet

Nutraceuticals in Diabetes and Metabolic Syndrome

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Davì G et al. – Metabolic syndrome represents a clustering of risk factors related to an elevated risk of cardiovascular disease and type 2 diabetes. Several nutraceuticals used in clinical practice have been shown to target the pathogenesis of diabetes mellitus, metabolic syndrome and their complications and to favorably modulate a number of biochemical and clinical endpoints. These compounds include antioxidant vitamins, such as vitamins C and E, flavonoids, vitamin D, conjugated linoleic acid, omega–3 fatty acids, minerals such as chromium and magnesium, (alpha)–lipoic acid, phytoestrogens, and dietary fibers. Several areas of concern exist regarding the use of dietary supplements and nutraceuticals in this setting, including product standardization, definition of optimal dosing regimen, potential side effects, drug interactions, and need for evidence–based indications.