Clinical and dermoscopic features of cutaneous BAP1-inactivated melanocytic tumors: Results of a multicenter case-control study by the International Dermoscopy Society.

BACKGROUND: Multiple BRCA1-associated protein 1 (BAP1)-inactivated melanocytic tumors (BIMTs) have been associated with a familial cancer syndrome involving germline mutations in BAP1. OBJECTIVES: We sought to describe the clinical and dermoscopic features of BIMTs. METHODS: This was a retrospective, multicenter, case-control study. Participating centers contributed clinical data, dermoscopic images, and histopathologic data of biopsy-proven BIMTs. We compared the dermoscopic features between BIMTs and control patients. RESULTS: The dataset consisted of 48 BIMTs from 31 patients (22 women; median age 37 years) and 80 control patients. Eleven patients had a BAP1 germline mutation. Clinically, most BIMTs presented as pink, dome-shaped papules (n = 24). Dermoscopically, we identified 5 patterns: structureless pink-to-tan with irregular eccentric dots/globules (n = 14, 29.8%); structureless pink-to-tan with peripheral vessels (n = 10, 21.3%); structureless pink-to-tan (n = 7, 14.9%); a network with raised, structureless, pink-to-tan areas (n = 7, 14.9%); and globular pattern (n = 4, 8.5%). The structureless with eccentric dots/globules pattern and network with raised structureless areas pattern were only identified in BIMT and were more common in patients with BAP1 germline mutations (P < .0001 and P = .001, respectively). LIMITATIONS: Limitations included our small sample size, retrospective design, the absence of germline genetic testing in all patients, and inclusion bias toward more atypical-looking BIMTs. CONCLUSIONS: Dome-shaped papules with pink-to-tan structureless areas and peripheral irregular dots/globules or network should raise the clinical suspicion for BIMT.

A New Class of Safe Oligosaccharide Polymer Therapy To Modify the Mucus Barrier of Chronic Respiratory Disease.

The host- and bacteria-derived extracellular polysaccharide coating of the lung is a considerable challenge in chronic respiratory disease and is a powerful barrier to effective drug delivery. A low molecular weight 12-15-mer alginate oligosaccharide (OligoG CF-5/20), derived from plant biopolymers, was shown to modulate the polyanionic components of this coating. Molecular modeling and Fourier transform infrared spectroscopy demonstrated binding between OligoG CF-5/20 and respiratory mucins. Ex vivo studies showed binding induced alterations in mucin surface charge and porosity of the three-dimensional mucin networks in cystic fibrosis (CF) sputum. Human studies showed that OligoG CF-5/20 is safe for inhalation in CF patients with effective lung deposition and modifies the viscoelasticity of CF-sputum. OligoG CF-5/20 is the first inhaled polymer therapy, represents a novel mechanism of action and therapeutic approach for the treatment of chronic respiratory disease, and is currently in Phase IIb clinical trials for the treatment of CF.

RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome.

Tylosis esophageal cancer (TOC) is an autosomal-dominant syndrome characterized by palmoplantar keratoderma, oral precursor lesions, and a high lifetime risk of esophageal cancer. We have previously localized the TOC locus to a small genomic interval within chromosomal region 17q25. Using a targeted capture array and next-generation sequencing, we have now identified missense mutations (c.557T>C [p.Ile186Thr] and c.566C>T [p.Pro189Leu] in RHBDF2, which encodes the inactive rhomboid protease RHBDF2 (also known as iRhom2), as the underlying cause of TOC. We show that the distribution of RHBDF2 in tylotic skin is altered in comparison with that in normal skin, and immortalized tylotic keratinocytes have decreased levels of total epidermal growth factor receptor (EGFR) and display an increased proliferative and migratory potential relative to normal cells, even when normal cells are stimulated with exogenous epidermal growth factor. It would thus appear that EGFR signaling is dysregulated in tylotic cells. Furthermore, we also show an altered localization of RHBDF2 in both tylotic and sporadic squamous esophageal tumors. The elucidation of a role of RHBDF2 in growth-factor signaling in esophageal cancer will help to determine whether targeting this pathway in chemotherapy for this and other squamous cell carcinomas will be effective.

Comparison of the in vitro release characteristics of mucosal freeze-dried wafers and solvent-cast films containing an insoluble drug.

Drug release characteristics of freeze-dried wafers and solvent-cast films prepared from sodium carboxymethylcellulose have been investigated and compared. In vitro drug dissolution studies were performed using an exchange cell and drug release was measured by UV spectroscopy at 272 nm using distilled water. The dissolution profiles of hydrochlorothiazide from the wafers and films were compared by determining the rates of drug release, estimated from the % release versus time profiles and calculating their difference (f(1)) and similarity (f(2)) factors. The effects of drug loading, polymer content and amount of glycerol (GLY) (films) on the drug release characteristics of both formulations were investigated. Both the wafers and films showed sustained type release profiles that were best explained by the Korsmeyer-Peppas equation. Changes in the concentration of drug and GLY (films) did not significantly alter the release profiles whilst increasing polymer content significantly decreased the rate of drug release from both formulations. The rate of release was faster from the wafers than the corresponding films which could be attributed to differences in the physical microstructure. The results show the potential of employing both formulations in various mucosal drug delivery applications.

Correlation between in vitro and in vivo erosion behaviour of erodible tablets using gamma scintigraphy.

In vitro and in vivo erosion behaviour of erodible tablets consisting of glyceryl behenate and low-substituted hydroxypropylcellulose manufactured using three different methods: direct compression (DC), melt granulation (MG) and direct solidification (DS) was investigated. In vitro erosion behaviour was studied using gravimetric and scintigraphic methods. For scintigraphic investigations, the radiolabel was adsorbed onto activated charcoal and incorporated into tablets at a concentration that did not affect the erosion profile. A clinical study was carried out in six healthy volunteers using gamma scintigraphy. Tablet erosion was affected by the preparation method and was found to decrease in the order of preparation method, DC>MG>DS tablets. The mean in vivo onset time for all tablets (DC: 6.7±3.8 min, MG: 18.3±8.1 min, DS: 67±18.9 min) did not differ significantly from in vitro onset time (DC: 5.3±1 min, MG: 16.8±3.9 min, DS: 61.8±4.7 min). The mean in vivo completion times were found to be 36.6±9.7 (DC tablets), 70±18.3 min (MG tablets) and 192.5±39.9 min (DS tablets). Among the three different erodible tablets, MG tablets showed the highest correlation between in vitro and in vivo mean erosion profile and suggested a potential platform to deliver controlled release of water-insoluble compounds.

In-vitro and in-vivo erosion profiles of hydroxypropylmethylcellulose (HPMC) matrix tablets.

The purpose of this study was to evaluate and compare the in-vitro and in-vivo erosion profiles of two tablet formulations primarily consisting of hydroxypropylmethylcellulose (HPMC) and lactose. HPMC was used at concentrations below and above the reported values for polymer percolation threshold in controlled release matrix formulations: 20 and 40% (w/w) HPMC. In-vitro erosion behaviour was studied using traditional gravimetric and scintigraphic methods, with radiolabelled charcoal used as a marker to quantify erosion profiles in scintigraphic studies. Six healthy male subjects participated in a randomised crossover scintigraphic erosion study. Both in-vitro and in-vivo erosion profiles determined using the gravimetric and/or scintigraphic method for matrix tablets were dependent upon the concentration of HPMC, and erosion was faster for tablets containing 20% (w/w) HPMC than those containing 40% (w/w) HPMC. Good correlation was found between in-vitro gravimetric and scintigraphic erosion profiles for both tablets. Tablets containing 40% (w/w) HPMC (polymer level above percolation threshold) demonstrated robust in-vivo performance and showed stronger correlation with in-vitro erosion profiles. The study demonstrated that a matrix formulation with a lower concentration of HPMC and higher lactose concentration is more likely to perform poorly in the in-vivo environment.

Patients are happy to be informed of their final non-melanoma skin cancer results by post.

During the past year, because of increasing pressure to see more patients, we have started to write to our patients informing them in a letter of their final skin cancer histology results following surgery for non-melanoma skin cancers: basal cell carcinoma and squamous cell carcinoma only. A questionnaire-based study was carried out to assess whether patients were happy to receive information concerning their non-melanoma skin cancer diagnosis in a carefully worded letter. One-hundred fifty patients were involved with a diagnosis of "completely excised non-melanoma skin cancer (NMSC)" that had previously received their final diagnosis by post. Seventy-seven (51.3%) patients responded to the questionnaire. Eighty-seven percent felt that they had been given the cancer diagnosis in an appropriate manner; 90 percent reported that they had understood the explanation about their skin cancer. In addition, 81 percent stated that they had been sufficiently involved in the discussion about their skin cancer and its treatment. Patients gave an average rating of 7.76 (1 = poor and 10 = excellent) for the overall experience of care that they had received. By writing to the patient with their final histology results, we have reduced the number of follow-up appointments without reducing the quality of patient care.

Characterisation of freeze-dried wafers and solvent evaporated films as potential drug delivery systems to mucosal surfaces.

Freeze-dried (lyophilised) wafers and solvent cast films from sodium alginate (ALG) and sodium carboxymethylcellulose (CMC) have been developed as potential drug delivery systems for mucosal surfaces including wounds. The wafers (ALG, CMC) and films (CMC) were prepared by freeze-drying and drying in air (solvent evaporation) respectively, aqueous gels of the polymers containing paracetamol as a model drug. Microscopic architecture was examined using scanning electron microscopy, hydration characteristics with confocal laser scanning microscopy and dynamic vapour sorption. Texture analysis was employed to investigate mechanical characteristics of the wafers during compression. Differential scanning calorimetry was used to investigate polymorphic changes of paracetamol occurring during formulation of the wafers and films. The porous freeze-dried wafers exhibited higher drug loading and water absorption capacity than the corresponding solvent evaporated films. Moisture absorption, ease of hydration and mechanical behaviour were affected by the polymer and drug concentration. Two polymorphs of paracetamol were observed in the wafers and films, due to partial conversion of the original monoclinic to the orthorhombic polymorph during the formulation process. The results showed the potential of employing the freeze-dried wafers and solvent evaporated films in diverse mucosal applications due to their ease of hydration and based on different physical mechanical properties exhibited by both type of formulations.

Assessing gastrointestinal motility and disintegration profiles of magnetic tablets by a novel magnetic imaging device and gamma scintigraphy.

PURPOSE: To validate Magnetic Moment Imaging (MMI) for the investigation of gastrointestinal transit and disintegration of solid dosage forms and to correlate the MMI findings with the corresponding gamma scintigraphic data. MATERIALS AND METHODS: Three magnetic tablets (MTs) were investigated using in vitro and in vivo tests. The clinical study was a four-way, crossover study with the following arms: (a) immediate-release tablets administered in fasted state; (b) immediate-release tablets administered after 400mL of Clinutren ISO; (c) enteric-coated tablets administered in the fasted state; and (d) non-disintegrating tablets studied in the lightly fed state (100mL of Clinutren ISO). RESULTS: In both the in vitro and in vivo studies, tablets were detected successfully by MMI and scintigraphy. There was a good correlation between gastric residence times and positional data (in the x, y and y, z-axes). In addition, MMI revealed early swelling behaviour of the tablet matrix. There was excellent agreement for the disintegration times of MT(A) in the fasted arm (scintigraphy 12.0+/-4.4min, MMI 11.8+/-4.4min). In the MT(A)-fed arm, onset times determined by scintigraphy were delayed in three subjects when compared to the corresponding MMI results. Delayed disintegration was observed with MT(A) administered after food (p<0.01) in both the techniques. CONCLUSION: The MMI device is a reliable imaging tool for tracking the transit and disintegration of a magnetic tablet through the gastrointestinal tract.

In vitro drug release studies of polymeric freeze-dried wafers and solvent-cast films using paracetamol as a model soluble drug.

Drug dissolution and release characteristics from freeze-dried wafers and solvent-cast films prepared from sodium carboxymethylcellulose (CMC) have been investigated to determine the mechanisms of drug release from the two systems. The formulations were prepared by freeze-drying (wafers) or drying in air (films), the hydrated gel of the polymer containing paracetamol as a model soluble drug. Scanning electron microscopy (SEM) was used to examine differences between the physical structure of the wafers and films. Dissolution studies were performed using an exchange cell and drug release was measured by UV spectroscopy at 242 nm. The effects of drug loading, polymer content and amount of glycerol (films) on the release characteristics of paracetamol were investigated. The release profiles of paracetamol from the wafers and films were also compared. A digital camera was used to observe the times to complete hydration and dissolution of the wafers containing different amounts of CMC and how that impacts on drug release rates. Both formulations showed sustained type drug release that was modelled by the Korsmeyer-Peppas equation. Changes in the concentration of drug and glycerol (films) did not significantly alter the rate of drug release while increasing polymer content significantly decreased the rate of drug release from both formulations. The results show that the rate of paracetamol release was faster from the wafers than the corresponding films due to differences in their physical structures. The wafers which formed a porous network, hydrated faster than the more dense and continuous, (non-porous) sheet-like structure of the films.

A pharmacoscintigraphic study of three time-delayed capsule formulations in healthy male volunteers.

Three time-delayed capsule (TDC) formulations were investigated in a pharmacoscintigraphic study, using a three-way crossover design in eight healthy male volunteers. Additionally, the pulsed release of a TDC was investigated with time-lapse photography, using a nondisintegrating riboflavin tablet. The photographic study indicated how the release characteristics of the TDC relied on the erosion of a tablet containing hypromellose (HPMC). Each TDC was duel radio labelled with indium-111 and technetium-99 m DTPA complexes, to observe drug release scintigraphically (theophylline was a marker compound). Three formulations, having in vitro dissolution release times of 1.8, 2.9 or 4.0 h were shown to compare favourably with mean in vivo scintigraphic release times of 2.7, 3.0 and 4.0 h for each formulation containing 20, 24 or 35% (w/w) HPMC concentrations respectively. An increase in HPMC concentration was associated with a delayed technetium release time, and followed the same rank order as the in vitro dissolution study. Observed radiolabel dispersion always occurred in the small intestine. In conclusion, the study established that the TDC performs and demonstrates an in vitro-in vivo correlation. Additionally, time and site of release were accurately visualized by gamma scintigraphy, and confirmed with determination of theophylline absorption.

Development and mechanical characterization of solvent-cast polymeric films as potential drug delivery systems to mucosal surfaces.

Solvent-cast films from three polymers, carboxymethylcellulose (CMC), sodium alginate (SA), and xanthan gum, were prepared by drying the polymeric gels in air. Three methods, (a) passive hydration, (b) vortex hydration with heating, and (c) cold hydration, were investigated to determine the most effective means of preparing gels for each of the three polymers. Different drying conditions [relative humidity - RH (6-52%) and temperature (3-45 degrees C)] were investigated to determine the effect of drying rate on the films prepared by drying the polymeric gels. The tensile properties of the CMC films were determined by stretching dumbbell-shaped films to breaking point, using a Texture Analyser. Glycerol was used as a plasticizer, and its effects on the drying rate, physical appearance, and tensile properties of the resulting films were investigated. Vortex hydration with heating was the method of choice for preparing gels of SA and CMC, and cold hydration for xanthan gels. Drying rates increased with low glycerol content, high temperature, and low relative humidity. The residual water content of the films increased with increasing glycerol content and high relative humidity and decreased at higher temperatures. Generally, temperature affected the drying rate to a greater extent than relative humidity. Glycerol significantly affected the toughness (increased) and rigidity (decreased) of CMC films. CMC films prepared at 45 degrees C and 6% RH produced suitable films at the fastest rate while films containing equal quantities of glycerol and CMC possessed an ideal balance between flexibility and rigidity.

An unusual presentation of a common disease.

We present a case of perforating granuloma annulare (PGA), in which we show the natural history of lesions and outline the different clinical types. Our patient responded well to intralesional triamcinolone acetonide 10mg/ml injections. Although she was otherwise well, PGA can be associated with diabetes mellitus in up to 17 percent of cases. Differential clinico-histopathological diagnosis, specifically in relation to necrobiosis lipoidica diabeticorum is being discussed. Treatment for PGA is difficult; apart from topical and/or intralesional steroids (clearance up to 54% in one case series), other options include Psoralen plus UVA (PUVA), systemic isotretinoin, chloroquine or hydroxylchloroquine, sulphapyridine, dapsone, topical application of imidazole creams, and liquid nitrogen. Spontaneous remission has also been reported in up to 77 percent in one case series.

In vivo performance of an oral MR matrix tablet formulation in the beagle dog in the fed and fasted state: assessment of mechanical weakness.

PURPOSE: To evaluate the behaviour of an oral matrix modified release formulation in the canine gastrointestinal tract, and establish if a mechanical weakness previously observed in clinical studies would have been identified in the dog model. MATERIALS AND METHODS: In vitro release profiles were obtained for two modified release matrix tablets containing UK-294,315, designed to release over either 6 (formulation A) or 18 (formulation B) hours. Tablets were labelled with (153)samarium and in vivo pharmacoscintigraphy studies were performed in four beagle dogs in the fasted state for both formulations, and following ingestion of an FDA high fat meal for formulation B. RESULTS: The matrix tablet formulations displayed significantly different in vitro release profiles (F (2) < 50), with time to 80% release for formulation A and B of 406 and 987 min respectively. Complete in vivo disintegration occurred at 339 +/- 181 and 229 +/- 171 for formulation A and B respectively in the fasted state, and at 207 +/- 154 min for formulation B in the fed state, in disagreement with in vitro release. CONCLUSION: The fed/fasted dog model would have predicted a lack of physical robustness in the matrix tablet formulation B, however it would not have predicted the clear fed/fasted effects on performance observed previously in man.

Wound healing dressings and drug delivery systems: a review.

The variety of wound types has resulted in a wide range of wound dressings with new products frequently introduced to target different aspects of the wound healing process. The ideal dressing should achieve rapid healing at reasonable cost with minimal inconvenience to the patient. This article offers a review of the common wound management dressings and emerging technologies for achieving improved wound healing. It also reviews many of the dressings and novel polymers used for the delivery of drugs to acute, chronic and other types of wound. These include hydrocolloids, alginates, hydrogels, polyurethane, collagen, chitosan, pectin and hyaluronic acid. There is also a brief section on the use of biological polymers as tissue engineered scaffolds and skin grafts. Pharmacological agents such as antibiotics, vitamins, minerals, growth factors and other wound healing accelerators that take active part in the healing process are discussed. Direct delivery of these agents to the wound site is desirable, particularly when systemic delivery could cause organ damage due to toxicological concerns associated with the preferred agents. This review concerns the requirement for formulations with improved properties for effective and accurate delivery of the required therapeutic agents. General formulation approaches towards achieving optimum physical properties and controlled delivery characteristics for an active wound healing dosage form are also considered briefly.

Evaluation of the clearance of a sublingual buprenorphine spray in the beagle dog using gamma scintigraphy.

PURPOSE: The aim of this study was to evaluate clearance from the buccal cavity and pharmacokinetic profiles of a sublingual spray formulation in the dog, to assist in interpretation of future pharmacokinetic studies. METHODS: Radiolabelled buprenorphine in a spray formulation (400 microg/100 microl in 30% ethanol) was administered sublingually to four beagle dogs, and the residence in the oral cavity was determined using gamma scintigraphy. Pharmacokinetic sampling was performed to facilitate correlation of location of dose with significant pharmacokinetic events. RESULTS: Scintigraphic imaging revealed that clearance of the formulation from the oral cavity was rapid, with a mean T 50% clearance of 0.86 +/- 0.46 min, and T 80% clearance of 2.75 +/- 1.52 min. In comparison, absorption of buprenorphine was relatively slow, with a T max of 0.56 +/- 0.13 h. Good buccal absorption despite short residence time can be explained by lipophilicity of buprenorphine enabling rapid sequestration into the oral mucosa, prior to diffusion and absorption directly into systemic circulation. CONCLUSION: This study demonstrated rapid clearance of a sublingual solution from the canine oral cavity, with T 50% similar to results previously reported in man, providing initial confidence in using a conscious dog model to achieve representative residence times for a sublingual solution.

The use of simple dynamic mucosal models and confocal microscopy for the evaluation of lyophilised nasal formulations.

A range of methods is reported in the literature for assessing hydration and adhesion parameters in the performance of nasal bioadhesive formulations; however, these tests do not always represent the dynamic conditions in the nasal cavity. Lyophilised formulations intended for nasal administration were evaluated using in-vitro tests designed in an attempt to mimic relevant processes in the nasal cavity, and intended to discriminate between different formulations. Initial investigative studies using scanning electron microscopy revealed that the lyophilisate had a highly porous internal structure, expected to provide an ideal porous pathway for re-hydration. Vapour sorption analysis demonstrated substantial weight gain of the lyophilisates on exposure to 95% relative humidity, ranging from 38% to 66%. Agar was used as a synthetic mucosal model designed to provide a standardised quantity of water available for rehydration of the formulations in in-vitro tests. A dynamic adhesion test and a texture analyser sliding test were designed to quantify different aspects of the spreading and adhesion of the hydrating formulations on the synthetic mucosal surface. Examination of the lyophilised formulations using confocal microscopy allowed visualisation and quantification of the initial rate of water ingress into the lyophilisates, which was found to consist of an initial rapid phase, followed by a slower steady-state phase. The results demonstrated that the use of a combination of methods representing the dynamic conditions of the nasal cavity is advisable in order to evaluate a formulation fully and to avoid misleading conclusions.

In-vitro/in-vivo correlation of pulsatile drug release from press-coated tablet formulations: a pharmacoscintigraphic study in the beagle dog.

The aim of the current study was to investigate the in-vitro and in-vivo performance of a press-coated tablet (PCT) intended for time delayed drug release, consisting of a rapidly disintegrating theophylline core tablet, press-coated with barrier granules containing glyceryl behenate (GB) and low-substituted hydroxypropylcellulose (L-HPC). The PCTs showed pulsatile release with a lag time dependent upon the GB and L-HPC composition of the barrier layer. In-vivo gamma-scintigraphic studies were carried out for PCTs containing GB:L-HPC at 65:35 w/w and 75:25 w/w in the barrier layer in four beagle dogs, in either the fed or fasted state. The in-vivo lag time in both the fed and fasted states did not differ significantly (p>0.05) from the in-vitro lag time. Additionally, no significant difference (p<0.05) between in-vivo fed and fasted disintegration times was observed, demonstrating that in-vivo performance of the PCT was not influenced by the presence or absence of food in the gastrointestinal tract. A distinct lag time was obtained prior to the appearance of drug in plasma and correlated (R2=0.98) with disintegration time observed from scintigraphic images. However, following disintegration, no difference in pharmacokinetic parameters (AUC(0-6 dis), K(el), Cmax) was observed. The current study highlighted the potential use of these formulations for chronopharmaceutical drug delivery.