Challenges and proposed framework for formative research to inform systematic intervention development in rare and unstudied conditions: The case example of Xeroderma Pigmentosum

Purpose: To outline the challenges of applying existing systematic intervention development approaches in rare diseases, and to propose a novel framework within which these challenges can be met. Background: A gap in the provision of self-management and psychosocial interventions to change behaviour and improve health in rare diseases exists, partly due to the difficulty of conducting formative research in such conditions. Challenges include heterogeneity within already small sample sizes, patient burden, and the absence of prior research to guide decision-making. XP is a very rare inherited disease (~100 UK patients), involving an inability to repair ultraviolet radiation (UVR)-induced damage and increased melanoma risk; the only treatment is complete photoprotection. No research in XP has been conducted outside of the genetic literature. Methods: Using XP and improved photoprotection as a case example, we highlight the necessity of departing from the steps outlined by three intervention development approaches (intervention mapping, UK MRC guidelines for complex interventions, behaviour change wheel), and outline a framework that can be applied to the conduct of formative research in rare diseases. The framework focuses on the sequential or parallel use of mixed-methods (e.g., n-of-1, interviews, reviews of comparable conditions) and the triangulation of gathered data, and provides solutions to challenges including patient burden and the inability to pre-test study materials or intervention content in members of the target population. Conclusions: The proposed framework offers an alternative that may overcome the limitations associated with intervention development in rare diseases, which will hopefully encourage much-needed work in this field

Ventricular arrhythmia and torsade de pointe: Dose limiting toxicities of the MDR-modulator S9788 in a phase I trial

Background: S9788 is a triazineaminopiperidine derivative capable of reversing multidrug resistance (MDR) in vitro. In preclinical models S9788 was several fold more potent MDR inhibitor than verapamil or cyclosporine. At P-glycoprotein (Pgp) blocking concentrations, S9788 appeared to have only very little toxicity. Patients and methods: In a two step phase I trial we treated 39 patients with refractory cancer with S9788 and bolus doxorubicin. The steps differed mainly in the S9788 infusion duration; in the first part 23 patients received the MDR-reversing drug S9788 over 30 minutes, in the second step of the study 16 patients were administered S9788 over 150 minutes. The doses of S9788 were escalated in cohorts of three patients up to a dose level (DL) of 96 mg/m2 on the 30 minutes infusion, and to 144 mg/m2 on the 150 minutes infusion. The pharmaco-kinetics of S9788 were determined. Results: With the 30-minute infusion schedule symptomatic cardiac arrhythmia were found to be dose limiting. In all patients at the highest DL transient cardiac repolarization prolongation with a long QT-interval on ECG was demonstrated. With the 150-minute administration schedule, S9788 could be escalated up to 144 mg/m2 without subjective toxicity. However, transient QT prolongation was present in all patients. A third degree AV-block and a QT increase of about 40% occurred at the highest DL. Asymptomatic torsade de pointe (DL 96 mg/m2) was demonstrated on Holter recording in one patient. Theses repolarization disturbances with QT increase were considered dose limiting toxicity and the trial was closed. No arrhythmia related death was noted. Pharmacokinetics were similar with both infusion schedules with a mean alpha half life of 11.3 and 13.2 minutes, for the 30-minute and 150-minute infusion, and a terminal half life of 13.5 and 15 hours, respectively. QTc prolongation duration appeared to be dose-dependent. Conclusions: With the tested infusion schedules, cardiac toxicity, in particular AV-blocks and QT prolongation, leading to ventricular arrhythmia and torsade de pointe, are the dose limiting toxicities of S9788. Our experience together with the observation of asymptomatic torsade de pointe in two other phase I trials of S9788 infused over six hours precluded the further clinical development of S978

Ultraviolet radiation exposure to the face in patients with xeroderma pigmentosum and healthy controls:applying a novel methodology to define photoprotection behaviour*

BACKGROUND: In xeroderma pigmentosum (XP), the main means of preventing skin and eye cancers is extreme protection against ultraviolet radiation (UVR). Protection is most important for the face. OBJECTIVES: We aimed to assess how well patients with XP adhere to medical advice to protect against UVR by objectively estimating the mean daily dose of UVR to the face. METHODS: We objectively estimated the UVR dose to the face in 36 patients with XP and 25 healthy individuals over 3 weeks in the summer. We used a new methodology which combined UVR dose measurements from a wrist‐worn dosimeter with an activity diary record of face photoprotection behaviour for each 15‐min period spent outside. A protection factor was associated with each behaviour, and the data were analysed using a negative binomial mixed‐effects model. RESULTS: The mean daily UVR dose (weighted for DNA damage capacity) to the face in the patients with XP was 0·13 standard erythemal doses (SEDs) (mean in healthy individuals = 0·51 SED). There was wide variation between patients (range < 0·01–0·48 SED/day). Self‐caring adult patients had a very similar UVR dose to the face as cared‐for patients (0·13 vs. 0·12 SED/day), despite photoprotecting much more poorly when outside, because the self‐caring adults were outside in daylight much less. CONCLUSIONS: Photoprotection behaviour varies widely within the XP group indicating that nonadherence to photoprotection advice is a significant issue. The timing and duration of going outside are as important as photoprotective measures taken when outside, to determine the UVR exposure to the face. This new methodology will be of value in identifying the sources of UVR exposure in other conditions in which facial UVR exposure is a key outcome, particularly in patients with multiple nonmelanoma skin cancers

Ventricular arrhythmia and torsade de pointe: dose limiting toxicities of the MDR-modulator S9788 in a phase I trial.

BACKGROUND: S9788 is a triazineaminopiperidine derivative capable of reversing multidrug resistance (MDR) in vitro. In preclinical models S9788 was several fold more potent MDR inhibitor than verapamil or cyclosporine. At P-glycoprotein (Pgp) blocking concentrations, S9788 appeared to have only very little toxicity. PATIENTS AND METHODS: In a two step phase I trial we treated 39 patients with refractory cancer with S9788 and bolus doxorubicin. The steps differed mainly in the S9788 infusion duration; in the first part 23 patients received the MDR-reversing drug S9788 over 30 minutes, in the second step of the study 16 patients were administered S9788 over 150 minutes. The doses of S9788 were escalated in cohorts of three patients up to a dose level (DL) of 96 mg/m2 on the 30 minutes infusion, and to 144 mg/m2 on the 150 minutes infusion. The pharmacokinetics of S9788 were determined. RESULTS: With the 30-minute infusion schedule symptomatic cardiac arrhythmia were found to be dose limiting. In all patients at the highest DL transient cardiac repolarization prolongation with a long QT-interval on ECG was demonstrated. With the 150-minute administration schedule, S9788 could be escalated up to 144 mg/m2 without subjective toxicity. However, transient QT prolongation was present in all patients. A third degree AV-block and a QT increase of about 40% occurred at the highest DL. Asymptomatic torsade de pointe (DL 96 mg/m2) was demonstrated on Holter recording in one patient. Theses repolarization disturbances with QT increase were considered dose limiting toxicity and the trial was closed. No arrhythmia related death was noted. Pharmacokinetics were similar with both infusion schedules with a mean alpha half life of 11.3 and 13.2 minutes, for the 30-minute and 150-minute infusion, and a terminal half life of 13.5 and 15 hours, respectively. QTc prolongation duration appeared to be dose-dependent. CONCLUSIONS: With the tested infusion schedules, cardiac toxicity, in particular AV-blocks and QT prolongation, leading to ventricular arrhythmia and torsade de pointe, are the dose limiting toxicities of S9788. Our experience together with the observation of asymptomatic torsade de pointe in two other phase 1 trials of S9788 infused over six hours precluded the further clinical development of S9788

An overview of the cutaneous porphyrias

This is an overview of the cutaneous porphyrias. It is a narrative review based on the published literature and my personal experience; it is not based on a formal systematic search of the literature. The cutaneous porphyrias are a diverse group of conditions due to inherited or acquired enzyme defects in the porphyrin–haem biosynthetic pathway. All the cutaneous porphyrias can have (either as a consequence of the porphyria or as part of the cause of the porphyria) involvement of other organs as well as the skin. The single commonest cutaneous porphyria in most parts of the world is acquired porphyria cutanea tarda, which is usually due to chronic liver disease and liver iron overload. The next most common cutaneous porphyria, erythropoietic protoporphyria, is an inherited disorder in which the accumulation of bile-excreted protoporphyrin can cause gallstones and, rarely, liver disease. Some of the porphyrias that cause blistering (usually bullae) and fragility (clinically and histologically identical to porphyria cutanea tarda) can also be associated with acute neurovisceral porphyria attacks, particularly variegate porphyria and hereditary coproporphyria. Management of porphyria cutanea tarda mainly consists of visible-light photoprotection measures while awaiting the effects of treating the underlying liver disease (if possible) and treatments to reduce serum iron and porphyrin levels. In erythropoietic protoporphyria, the underlying cause can be resolved only with a bone marrow transplant (which is rarely justifiable in this condition), so management consists particularly of visible-light photoprotection and, in some countries, narrowband ultraviolet B phototherapy. Afamelanotide is a promising and newly available treatment for erythropoietic protoporphyria and has been approved in Europe since 2014

Effect of Particle Size and Support Type on Pd Catalysts for 1,3-Butadiene Hydrogenation

Pd nanoparticles supported on SiO 2 , Si 3 N 4 and Al 2 O 3 were studied to examine the effect of particle size and support type on the hydrogenation of 1,3-butadiene. Pd nanoparticles were produced using a reverse micelle method resulting in particles with a remarkably small particle size distribution (σ < < 1 nm). The support type and particle size were observed to affect both catalytic activity and product selectivity. All catalysts showed a decrease of their activity with time on stream, paired with an increase in selectivity to butenes (1-butene and cis/trans-2-butene) from a product stream initially dominated by n-butane. In situ XAFS demonstrated a correlation between the formation of palladium hydride and n-butane production in the early stages (~ 1 h) of reaction. The extent of palladium hydride formation, as well as its depletion with time on stream, was dependent on both particle size and support type. Metallic Pd was identified as the species selective towards the production of butenes