Kirste Mellish

In Vitro Photodynamic Activity of a Series of Methylene Blue Analogues

We have synthesized a series of symmetrical phenothiazines in which the methyl groups of methylene blue have been substituted by longer alkyl chains. Intrinsic photosensitizing ability was not altered by increasing the chain length. However, in vitro phototoxicity after 2 h incubation of RIF‐1 murine fibrosarcoma cells followed the order n‐propyl > n‐pentyl > n‐butyl > n‐hexyl > ethyl > methyl, with ethyl and n‐propyl analogues being 14‐ and 130‐fold more phototoxic than methylene blue, respectively. All analogues also had an improved ratio of phototoxicity : dark toxicity (4:1 to 27:1) compared with methylene blue (3:1). Phototoxicity did not correlate with cellular phenothiazine levels, suggesting that the site of subcellular localization may be more important. After 2 h incubation of RIF‐1 cells with the phototoxicity LD50 concentration, methylene blue and all analogues were observed to be localized in the lysosomes by fluorescence microscopy. On exposure to light, methylene blue relocalized to the nucleus, the ethyl analogue did not relocalize, whereas the more phototoxic n‐propyl –n‐hexyl analogues relocalized to the mitochondria. Relocalization to the mitochondria was associated with an octanol : buffer partition coefficient ≥ 1. Therefore, the longer‐chain analogues of methylene blue show significantly improved phototoxicity in vitro and, in addition, are expected to avoid the problems of mutagenicity associated with the nuclear localization of methylene blue.

Verteporfin: a milestone in opthalmology and photodynamic therapy.

During the past year, a photosensitiser named benzoporphyrin derivative (BPD) has been approved in 26 countries under the generic name verteporfin (Visudyne™, Novartis), for the treatment of patients with a certain type of the wet form of age-related macular degeneration (AMD) by photodynamic therapy (PDT). AMD is the leading cause of blindness in the developed world, with approximately half a million new cases of the wet form per year. The approval of Visudyne™ therapy represents a major milestone in ophthalmology since AMD was previously untreatable by any modality which would preserve existing vision. It was also a milestone in the development of PDT, not only because it represented the first breakthrough in the use of PDT to treat an otherwise untreatable condition, but also because it represented the first mass market for a PDT treatment where prospects of a substantial financial return on many years of investment appear to be likely. In this article, we look at the background to the development of BPD, primarily for its use in AMD, but also in other applications.

Cluster Randomized Controlled Trial: Clinical and Cost-Effectiveness of a System of Longer-Term Stroke Care

Background and Purpose— We developed a new postdischarge system of care comprising a structured assessment covering longer-term problems experienced by patients with stroke and their carers, linked to evidence-based treatment algorithms and reference guides (the longer-term stroke care system of care) to address the poor longer-term recovery experienced by many patients with stroke. Methods— A pragmatic, multicentre, cluster randomized controlled trial of this system of care. Eligible patients referred to community-based Stroke Care Coordinators were randomized to receive the new system of care or usual practice. The primary outcome was improved patient psychological well-being (General Health Questionnaire-12) at 6 months; secondary outcomes included functional outcomes for patients, carer outcomes, and cost-effectiveness. Follow-up was through self-completed postal questionnaires at 6 and 12 months. Results— Thirty-two stroke services were randomized (29 participated); 800 patients (399 control; 401 intervention) and 208 carers (100 control; 108 intervention) were recruited. In intention to treat analysis, the adjusted difference in patient General Health Questionnaire-12 mean scores at 6 months was −0.6 points (95% confidence interval, −1.8 to 0.7; P=0.394) indicating no evidence of statistically significant difference between the groups. Costs of Stroke Care Coordinator inputs, total health and social care costs, and quality-adjusted life year gains at 6 months, 12 months, and over the year were similar between the groups. Conclusions— This robust trial demonstrated no benefit in clinical or cost-effectiveness outcomes associated with the new system of care compared with usual Stroke Care Coordinator practice. Clinical Trial Registration— URL: http://www.controlled-trials.com. Unique identifier: ISRCTN 67932305.

Protocol of a cluster randomized trial evaluation of a patient and carer-centered system of longer-term stroke care (LoTS care)

Rationale Despite recognition of the importance of the longer-term consequences of stroke, services addressing these needs remain poorly developed. There are persuasive arguments that a community-based orientation to poststroke care, to assess, support, and coordinate relevant services, might be more helpful in minimizing longer-term stroke morbidity. To address this, an evidence-based system of care has been developed that aims to meet the longer-term needs for stroke survivors and their carers living at home in the community. Aims The study aims to evaluate the clinical and cost-effectiveness of a purposely developed system of care for stroke patients and their carers living in the community. Design This is a cluster randomized, controlled trial. The trial aimed to recruit 800 patients (and their carers, if appropriate) in 32 stroke services across the United Kingdom. The system of care is delivered by health professionals undertaking a community-based liaison or coordinating role for stroke patients (termed ‘stroke care coordinators’). Stroke care coordinators in stroke services randomized to the intervention group were trained to deliver the system of care, while those randomised to the control group continued to deliver current practice. Study outcomes The primary outcome is patient emotional health measured using the General Health Questionnaire 12 at six-months after recruitment. Secondary outcomes include cost-effectiveness, patient functional health and carer emotional health, with final follow-up at 12 months. Current status Thirty-two stroke services were randomized and 800 patients and 208 carers were recruited from 29 services. Follow-up is ongoing, and trial results are expected in early 2013.

Poststroke Trajectories: The Process of Recovery Over the Longer Term Following Stroke

We adopted a grounded theory approach to explore the process of recovery experienced by stroke survivors over the longer term who were living in the community in the United Kingdom, and the interacting factors that are understood to have shaped their recovery trajectories. We used a combination of qualitative methods. From the accounts of 22 purposively sampled stroke survivors, four different recovery trajectories were evident: (a) meaningful recovery, (b) cycles of recovery and decline, (c) ongoing disruption, (d) gradual, ongoing decline. Building on the concept of the illness trajectory, our findings demonstrate how multiple, interacting factors shape the process and meaning of recovery over time. Such factors included conception of recovery and meanings given to the changing self, the meanings and consequences of health and illness experiences across the life course, loss, sense of agency, and enacting relationships. Awareness of the process of recovery will help professionals better support stroke survivors.

Economic evaluation of a patient and carer centred system of longer-term stroke care from a cluster randomised trial (the LoTS care trial)

Materials and methods A pragmatic cluster, randomised, controlled trial compared the system of care against usual care. Randomisation was at the level of stroke service. Participants’ use of health/social care services and informal care were measured by self-complete questionnaires at baseline, 6 and 12 months. From these, we estimated and compared individual-level total costs from health/social care and societal perspectives at 6 months, 12 months and over 1 year. Costs were combined with the primary outcome, psychological health (General Health Questionnaire 12; GHQ12), and quality-adjusted life years (QALYs; based on the EQ-5D) to examine cost-effectiveness at 6 months. Costeffectiveness acceptability curves based on the net benefit approach and bootstrapping techniques were used to estimate the probability of cost-effectiveness.