Efficacy and safety of Oleogel-S10 (birch triterpenes) for epidermolysis bullosa: results from the phase III randomized double-blind phase of the EASE study.

BACKGROUND: Epidermolysis bullosa (EB) is a heterogeneous group of rare, difficult-to-treat, inherited multisystem diseases affecting epithelial integrity. Patients with EB are affected by mechanical fragility of epithelial surfaces including the skin and, as a result, extensive recurrent blistering is a characteristic of the condition. Chronic wounds predispose patients with EB to the development of squamous cell carcinoma, which is a major cause of premature death. OBJECTIVES: EASE was a double-blind, randomized, vehicle-controlled, phase III study to determine the efficacy and safety of the topical gel Oleogel-S10 (birch triterpenes) in EB. EASE was funded by Amryt Research Limited. METHODS: Patients with dystrophic EB, junctional EB or Kindler EB and a target partial-thickness wound lasting ≥ 21 days and < 9 months that was 10-50 cm2, were enrolled and randomized via computer-generated allocation tables 1 : 1 to Oleogel-S10 or control gel - both with standard-of-care dressings. Study gel was applied to all wounds at least every 4 days. The primary endpoint was the proportion of patients with first complete closure of target wound within 45 days. RESULTS: A total of 223 patients were enrolled and treated (109 treated with Oleogel-S10, 114 with control gel). The primary endpoint was met; Oleogel-S10 resulted in 41·3% of patients with first complete target wound closure within 45 days, compared with 28·9% in the control gel arm (relative risk 1·44, 95% confidence interval (CI) 1·01-2·05; P = 0·013). Adverse events (AEs) occurred with similar frequency for Oleogel-S10 (81·7%) compared with control gel (80·7%). AEs were predominantly of mild-to-moderate intensity (4·6% were severe). CONCLUSIONS: Oleogel-S10 is the first therapy to demonstrate accelerated wound healing in EB. Oleogel-S10 was well -tolerated.

Treatment with amnion-derived cellular cytokine solution (ACCS) induces persistent motor improvement and ameliorates neuroinflammation in a rat model of penetrating ballistic-like brain injury.

PURPOSE: The present work compared the behavioral outcomes of ACCS therapy delivered either intravenously (i.v.) or intracerebroventricularly (i.c.v.) after penetrating ballistic-like brain injury (PBBI). Histological markers for neuroinflammation and neurodegeneration were employed to investigate the potential therapeutic mechanism of ACCS. METHODS: Experiment-1, ACCS was administered either i.v. or i.c.v. for 1 week post-PBBI. Outcome metrics included behavioral (rotarod and Morris water maze) and gross morphological assessments. Experiment-2, rats received ACCS i.c.v for either 1 or 2 weeks post-PBBI. The inflammatory response was determined by immunohistochemistry for neutrophils and microglia reactivity. Neurodegeneration was visualized using silver staining. RESULTS: Both i.v. and i.c.v. delivery of ACCS improved motor outcome but failed to improve cognitive outcome or tissue sparing. Importantly, only i.c.v. ACCS treatment produced persistent motor improvements at a later endpoint. The i.c.v. ACCS treatment significantly reduced PBBI-induced increase in myeloperoxidase (MPO) and ionized calcium binding adaptor molecule 1 (Iba1) expression. Concomitant reduction of both Iba1 and silver staining were detected in corpus callosum with i.c.v. ACCS treatment. CONCLUSIONS: ACCS, as a treatment for TBI, showed promise with regard to functional (motor) recovery and demonstrated strong capability to modulate neuroinflammatory responses that may underline functional recovery. However, the majority of beneficial effects appear restricted to the i.c.v. route of ACCS delivery, which warrants future studies examining delivery routes (e.g. intranasal delivery) which are more clinically viable for the treatment of TBI.

Correlations between blood-brain barrier disruption and neuroinflammation in an experimental model of penetrating ballistic-like brain injury.

Abstract Blood-brain barrier (BBB) disruption is a pathological hallmark of severe traumatic brain injury (TBI) and is associated with neuroinflammatory events contributing to brain edema and cell death. The goal of this study was to elucidate the profile of BBB disruption after penetrating ballistic-like brain injury (PBBI) in conjunction with changes in neuroinflammatory markers. Brain uptake of biotin-dextran amine (BDA; 3 kDa) and horseradish peroxidase (HRP; 44 kDa) was evaluated in rats at 4 h, 24 h, 48 h, 72 h, and 7 days post-PBBI and compared with the histopathologic and molecular profiles for inflammatory markers. BDA and HRP both displayed a uniphasic profile of extravasation, greatest at 24 h post-injury and which remained evident out to 48 h for HRP and 7 days for BDA. This profile was most closely associated with markers for adhesion (mRNA for intercellular adhesion molecule-1) and infiltration of peripheral granulocytes (mRNA for matrix metalloproteinase-9 [MMP-9] and myeloperoxidase staining). Improvement of BBB dysfunction coincided with increased expression of markers implicated in tissue remodeling and repair. The results of this study reveal a uniphasic and gradient opening of the BBB after PBBI and suggest MMP-9 and resident inflammatory cell activation as candidates for future neurotherapeutic intervention after PBBI.

Similarities and differences of acute nonconvulsive seizures and other epileptic activities following penetrating and ischemic brain injuries in rats.

The similarities and differences between acute nonconvulsive seizures (NCS) and other epileptic events, for example, periodic epileptiform discharges (PED) and intermittent rhythmic delta activities (IRDA), were characterized in rat models of penetrating and ischemic brain injuries. The NCS were spontaneously induced by either unilateral frontal penetrating ballistic-like brain injury (PBBI) or permanent middle cerebral artery occlusion (pMCAO), and were detected by continuous electroencephalogram (EEG) monitoring begun immediately after the injury and continued for 72 h or 24 h, respectively. Analysis of NCS profiles (incidence, frequency, duration, and time distribution) revealed a high NCS incidence in both injury models. The EEG waveform expressions of NCS and PED exhibited intrinsic variations that resembled human electrographic manifestations of post-traumatic and post-ischemic ictal and inter-ictal events, but these waveform variations were not distinguishable between the two types of brain injury. However, the NCS after pMCAO occurred more acutely and intensely (latency=0.6 h, frequency=25 episodes/rat) compared with the PBBI-induced NCS (latency=24 h, frequency=10 episodes/rat), such that the most salient features differentiating post-traumatic and post-ischemic NCS were the intensity and time distribution of the NCS profiles. After pMCAO, nearly 50% of the seizures occurred within the first 2 h of injury, whereas after PBBI, NCS occurred sporadically (0-5%/h) throughout the 72 h recording period. The PED were episodically associated with NCS. By contrast, the IRDA appeared to be independent of other epileptic events. This study provided comprehensive comparisons of post-traumatic and post-ischemic epileptic profiles. The identification of the similarities and differences across a broad spectrum of epileptic events may lead to differential strategies for post-traumatic and post-stroke seizure interventions.

Temozolomide treatment for aggressive pituitary tumors: correlation of clinical outcome with O(6)-methylguanine methyltransferase (MGMT) promoter methylation and expression.

CONTEXT: The typically indolent behavior of pituitary tumors is juxtaposed with high rates of tumor cell invasion into adjacent dural structures, and occasional aggressive behavior. Although clinically significant invasion and malignant transformation remain uncommon, there are limited treatment options available for the management of these aggressive tumors. Recently, case reports have described efficacy of temozolomide for the treatment of aggressive pituitary tumors. DESIGN: Seven patients with aggressive pituitary tumors have been treated with temozolomide. We compared O(6)-methylguanine methyltransferase (MGMT) promoter methylation and MGMT expression in 14 surgical specimens from these seven patients and correlated these molecular features with the clinical response to temozolomide. RESULTS: Significant tumor regression was seen in two patients (29%), a 20% reduction in tumor volume with subsequent stable tumor size was noted in one patient, arrest of tumor growth occurred in three patients, and progressive metastatic disease developed during treatment in one patient. The DNA promoter site for MGMT was unmethylated in all 14 adequate specimens, and variable MGMT expression was seen in all 14 cases. There was no correlation between MGMT expression and clinical outcomes. CONCLUSIONS: We conclude that medical therapy with temozolomide can be helpful in the management of life-threatening pituitary tumors that have failed to respond to conventional treatments. The optimal duration of treatment in patients with stabilization or reduction of tumor size has not been established, and long-term follow up studies are needed.