Influence of Formulation Factors on PpIX Production and Photodynamic Action of Novel ALA-loaded Microparticles

A novel 5-aminolevulinic acid (ALA)-containing microparticulate system was produced recently, based on incorporation of ALA into particles prepared from a suppository base that maintains drug stability during storage and melts at skin temperature to release its drug payload. The novel particulate system was applied to the skin of living animals, followed by study of protoporphyrin IX (PpIX) production. The effect of formulating the microparticles in different vehicles was investigated and also the phototoxicity of the PpIX produced using a model tumour. Particles formulated in propylene glycol gels (10% w/w ALA loading) generated the highest peak PpIX fluorescence levels in normal mouse skin. Peak PpIX levels induced in skin overlying subcutaneously implanted WiDr tumours were significantly lower than in normal skin for both the 10% w/w ALA microparticles alone and the 10% w/w ALA microparticles in propylene glycol gels during continuous 12 h applications. Tumours not treated with photodynamic therapy continued to grow over the 17 days of the anti-tumour study. However, those treated with 12 h applications of either the 10% w/w ALA microparticles alone or the 10% w/w ALA microparticles in propylene glycol gel followed by a single laser irradiation showed no growth. The gel formulation performed slightly better once again, reducing the tumour growth rate by approximately 105%, compared with the 89% reduction achieved using particles alone. Following the promising results obtained in this study, work is now going on to prepare particle-loaded gels under GMP conditions with the aim of initiating an exploratory clinical trial.

Aminolevulinic acid-loaded Witepsol microparticles manufactured using a spray congealing procedure: implications for topical photodynamic therapy

Objectives The aim was to enhance aminolevulinic acid (ALA) stability by incorporation into low-melting microparticles prepared using a spray congealing procedure and to evaluate temperature-triggered release, allowing topical bioavailability following melting at skin temperature.

Rheological, mechanical and membrane penetration properties of novel dual drug systems for percutaneous delivery

In this study it has been demonstrated that mixtures of two solid drugs, ibuprofen and methyl nicotinate, with different but complementary pharmacological activities and which exist as a single liquid phase over a wide composition range at skin temperature, can be formulated as o/w emulsions without the use of an additional hydrophobic carrier. These novel dual drug systems provided significantly enhanced in vitro penetration rates through a model lipophilic barrier membrane compared to conventional individual formulations of each active. Thus, for ibuprofen, drug penetration flux enhancements of three- and 10-fold were observed when compared to an aqueous ibuprofen suspension and a commercial alcohol-based ibuprofen formulation, respectively. Methyl nicotinate penetration rates were shown to be similar for aqueous gels and emulsified systems. Mechanisms explaining these observations are proposed. Novel dual drug formulations of ibuprofen and methyl nicotinate, formulated within the liquid range at skin temperature, were investigated by oscillatory rheology and texture profile analysis. demonstrating the effects of drug and viscosity enhancer concentrations, and disperse phase type upon the rheological, mechanical and drug penetration properties of these systems. (C) 2000 Elsevier Science B.V. All rights reserved.

A double-blind cross-over study of nifedipine retard in patients with Raynaud's phenomenon

The effectiveness of nifedipine retard as a treatment for Raynaud's phenomenon was assessed in 15 patients in a placebo controlled double blind study. An associated connective tissue disease was evident in 7 patients. Changes in finger and forearm blood flow (venous occlusion plethysmography), digital skin temperature and digital systolic pressure were measured acutely before and after a 2-week treatment period. Subjective assessment of efficacy was based on patient diary data. In addition alpha 2-adrenoceptor density on platelets was measured before and after chronic nifedipine therapy in both the patient group and in an age-and-sex-matched control group. No significant haemodynamic changes were observed. Nifedipine retard significantly reduced the frequency (p less than 0.05) with no change in either the duration or severity of vasospastic attacks. Side effects were common following nifedipine retard. A reduction in alpha 2-adrenoceptor density on platelets was observed in patients compared to a control group (p less than 0.05). Alpha 2-adrenoceptor density was unchanged following a 2-week treatment period with nifedipine retard. This study concludes that nifedipine retard is not effective in the treatment of Raynaud's phenomenon over a short time course. Patients with Raynaud's phenomenon have reduced alpha 2-adrenoceptor densities on their platelets.

The sympathetic release test: a test used to assess thermoregulation and autonomic control of blood flow

When a subject is heated, the stimulation of temperature-sensitive nerve endings in the skin, and the raising of the central body temperature, results in the reflex release of sympathetic vasoconstrictor tone in the skin of the extremities, causing a measurable temperature increase at the site of release. In the sympathetic release test, the subject is gently heated by placing the feet and calves in a commercially available foot warming pouch or immersing the feet and calves in warm water and wrapping the subject in blankets. Skin blood flow is estimated from measurements of skin temperature in the fingers. Normally skin temperature of the fingers is 65-75 degrees F in cool conditions (environmental temperature: 59-68 degrees F) and rises to 85-95 degrees F during body heating. Deviations in this pattern may mean that there is abnormal sympathetic vasoconstrictor control of skin blood flow. Abnormal skin blood flow can substantially impair an individual's ability to thermoregulate and has important clinical implications. During whole body heating, the skin temperature from three different skin sites is monitored and oral temperature is monitored as an index of core temperature. Students determine the fingertip temperature at which the reflex release of sympathetic activity occurs and its maximal attainment, which reflects the vasodilating capacity of this cutaneous vascular bed. Students should interpret typical sample data for certain clinical conditions (Raynaud's disease, peripheral vascular disease, and postsympathectomy) and explain why there may be altered skin blood flow in these disorders.

Elements of the granular gland peptidome and transcriptome persist in air-dried skin of the South American orange-legged leaf frog, Phyllomedusa hypocondrialis.

The defensive strategy of amphibians against predator attack relies heavily on the secretion of noxious/toxic chemical cocktails from specialized skin granular glands. Bioactive peptides constitute a major component of secretions in many species and the most complex are produced by neotropical leaf frogs of the sub-family Phyllomedusinae. We recently reported that these skin secretions contain elements of both the granular gland peptidome and transcriptome and that polyadenylated mRNAs constituting the latter are protected from degradation by interactions with endogenous amphipathic peptides. This thus permits parallel amino acid sequencing of peptides and nucleic acid sequencing of cloned precursor transcripts from single lyophilized samples of secretion. Here we report that the protection afforded is sufficiently robust to permit transcriptome studies by cloning of full-length polyadenylated peptide precursor encoding mRNAs from libraries constructed using ambient temperature air-dried skin from recently deceased specimens as source material. The technique was sufficiently sensitive to permit the identification of cDNAs encoding antimicrobial peptides constituted by six different isoforms of phylloseptin and two dermaseptins. Also, for the first time, establishment of the nucleic acid and amino acid sequence of the precursor encoding the phyllomedusine frog skin bradykinin-related peptide, phyllokinin, from cloned cDNA, was achieved. These data unequivocally demonstrate that the granular gland transcriptome persists in air-dried amphibian skin—a finding that may have fundamental implications in the study of archived materials but also in the wider field of molecular biology.

Periodontal Manifestations of Chronic Atypical Neutrophilic Dermatosis With Lipodystrophy and Elevated Temperature (CANDLE) Syndrome in an 11 Year Old Patient

Introduction: Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) is an auto inflammatory syndrome caused by an autosomal recessive gene mutation. This very rare syndrome has been reported in only 14 patients worldwide. A number of clinical signs have been reported including joint contractures, muscle atrophy, microcytic anaemia, and panniculitis-induced childhood lipodystrophy. Further symptoms include recurrent fevers, purpuric skin lesions, periorbital erythema and failure to thrive. This is the first reported case of periodontal manifestations associated with CANDLE syndrome. 
Case Presentation: An 11 year old boy was referred to Cork University Dental School and Hospital with evidence of severe periodontal destruction. The patient’s medical condition was managed in Great Ormond Street Children’s Hospital, London. The patient’s dental management included initial treatment to remove teeth of hopeless prognosis followed by prosthodontic rehabilitation using removable partial dentures. This was followed by further non-surgical periodontal treatment and maintenance. In the long term, the potential definitive restorative options, including dental implants, will be evaluated in discussion with the patient’s medical team.
Conclusion: Periodontitis as a manifestation of systemic disease is one of seven categories of periodontitis as defined by the American Academy of Periodontology 1999 classification system. A number of systemic diseases have been associated with advanced periodontal destruction including Diabetes Mellitus, Leukaemia and Papillon-Lefevre Syndrome. In the case described, treatment necessitated a multidisciplinary approach with input from medical and dental specialities for a young patient with severe periodontal destruction associated with CANDLE syndrome.

Assessment of the double-skin façade passive thermal buffer effect.

Double Skin Façades (DSFs) are becoming increasingly popular architecture for commercial office buildings. Although DSFs are widely accepted to have the capacity to offer significant passive benefits and enable low energy building performance, there remains a paucity of knowledge with regard to their operation. Identification of the most determinant architectural parameters of DSFs is the focus of ongoing research. This paper presents an experimental and simulation study of a DSF installed on a commercial building in Dublin, Ireland. The DSF is south facing and acts to buffer the building from winter heat losses, but risks enhancing over-heating on sunny days. The façade is extensively monitored during winter months. Computational Fluid Dynamic (CFD) models are used to simulate the convective operation of the DSF. This research concludes DSFs as suited for passive, low energy architecture in temperature climates such as Ireland but identifies issues requiring attention in DSF design.

Experimental analysis of air flow profiles in a double skin facade in a maritime climate

Glazed Double Skin Facades (DSF) offer the potential to improve the performance of all-glass building skins, common to commercial office buildings in which full facade glazing has almost become the standard. Single skin glazing results in increased heating and cooling costs over opaque walls, due to lower thermal resistance of glass, and the increased impact of solar gain through it. However, the performance benefit of DSF technology continues to be questioned and its operation poorly understood, particularly the nature of airflow through the cavity. This paper deals specifically with the experimental analysis of the air flow characteristics in an automated double skin façade. The benefit of the DSF as a thermal buffer, and to limit overheating is evaluated through analysis of an extensive set of parameters including air and surface temperatures at each level in the DSF, airflow readings in the cavity and at the inlet and outlet, solar and wind data, and analytically derived pressure differentials. The temperature and air-flow are monitored in the cavity of a DSF using wireless sensors and hot wire anemometers respectively. Automated louvre operation and building set-points are monitored via the BMS. Thermal stratification and air flow variation during changing weather conditions are shown to effect the performance of the DSF considerably and hence the energy performance of the building. The relative pressure effects due to buoyancy and wind are analysed and quantified. This research aims to developed and validate models of DSFs in the maritime climate, using multi-season data from experimental monitoring. This extensive experimental study provides data for training and validation of models.