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Aims Novel low toxicity formulations using biomaterial (i.e. gelatin) for triggered release and controlled manner of formulated therapeutic agent for treatment of immuno-inflammatory disease on the skin were studied in the PhD project. It is a challenging concept because of difficulties in targeting and controlling for the releases that is tailored to disease severity or lesional inflammation extent. Background Psoriasis is a complicated disease with multi-factorial pathogenesis. Potent anti-psoriatic drugs are available but for managing the symptoms of the disease. Due to the toxicity of the therapeutic agents, different strategies have been suggested to avoid severe side effects from long term or high dose usage. Psoriasis is an optimal representative for this investigation in terms of the toxicities of recognized drugs, unpredictable or relapsed nature of the disease or even life threatening developments if generalised symptoms develop as they can in some types. Method Using the rheometry in temperature sweep mode, a series of concentrations of pure gelatin and gelatin mixture were developed. In addition, using tryptic enzyme, their action was studied rheologically. A Petri dish observational method was used to investigate the permeability of formulations chosen on the basis of the rheometric performance. Then, combining the Copley diffusion cell kit and UV/VIS spectrophotometer, the release of the model drug was investigated in porous artificial membranes and porcine skin for one or more of the formulations. The preliminary part using porous artificial membranes was to investigate the amount of the release of tartrazine from a candidate gel into the circulation system. In this part, alternatives were considered for dealing with gelatin or gelatin/carbomer swelling by using mechanical stress approach or changing to octanol solvent. For the latter a dye, rhodamine, which would partition into octanol had to be substituted for tartrazine (which has iv negligible organic solubility). In the final part, using skin membrane, the amount of the release tartrazine to the skin was measured because in this, skin staining, rather than partition was needed. Results Promising results were observed in each stage. The rheological investigation on the developed gelatin/water system and gelatin/carbomer intimate system in absence and presence of tryptic enzyme showed that a responsive but convenient formulation was possible and was independent of the presence of tartrazine. Analysis of these resulting rheological profiles suggested a prediction for the best gelatin/carbomer formulations to select for the permeability tests. The latter used Petri dishes to compare differential diffusion of these candidates showed the carbomer was able to stop three-dimensional spreading of the dye through the pure gelatin or its residue (after enzyme action). The drug release studies using artificial porous membranes for preliminary work showed significant differential release between enzyme free and enzyme treated versions of the 20% gelatin/0.9% carbomer formulation. The final success was the in vitro skin experiment in which the result was obtained for the pure gelatin and shown to deliver very substantially more to areas with applied enzyme s a simulated lesion.

Thesis (doctoral)--Karolinska Institutet, Stockholm, 1983. / Extra t.p. with thesis statement inserted. Includes the author's seven published papers. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Use of ontology is an approach to overcome the &ldquo / search-on-the-net&rdquo / problem. An ontology based web information retrieval system requires a topical web crawler to construct a high quality document collection. This thesis focuses on implementing a topical web crawler with medical domain ontology in order to find out the advantages of ontological information in web crawling. Crawler is implemented with Best-First search algorithm. Design of the crawler is optimized to UMLS ontology. Crawler is tested with Harvest Rate and Target Recall Metrics and compared to a non-ontology based Best-First Crawler. Performed test results proved that ontology use in crawler URL selection algorithm improved the crawler performance by 76%.

The increasing spread of antibiotic resistance among bacteria poses a major threat to the public health. There is an urge for the development of innovative formulations of existing and new antibiotics. One area of interest is in wound care, where two interesting antimicrobials are the conventional antibiotic amoxicillin and the antimicrobial peptide AP114. The objective of this work was to systemically evaluate topical gel formulations of these APIs by following a Quality by Design approach. A short excipient compatibility study was performed and the thickening agents poloxamer 407 and HPMC were chosen to be included in the following Design of Experiment (DoE) study of formulation composition and storage climate. The DoE set up was generated by the software MODDE Pro® and a short stability study of four weeks was performed, including analysis of the apparent pH, rheology stability, appearance, BCA assay, UV-Vis and FTIR spectroscopy and Franz cell diffusion. The results showed that AP114 formulations stored at 2-8˚C with poloxamer 407 should be with buffer pH 5-6 and 5-15 wt% organic phase to maximize stability, while HPMC based AP114 gels should be with buffer pH 6-8 and 10-40 wt% organic phase. Poloxamer 407 was not preferrable for amoxicillin formulations. The optimal HPMC based amoxicillin formulations included the storage temperature 25˚C, a buffer pH 7-8 and 40-60 wt% organic phase. HPMC based amoxicillin gels stored at 2-8˚C should be composed with buffer pH 6-8 and 10-40 wt% organic phase.

Purpose: The purposes of this study were four-fold: 1) to determine the types and effectiveness of various topical anesthetics being used among dentists currently treating children, 2) to determine the types of procedures for which topical anesthetics are being used among children, 3) to understand the awareness and use of a relatively newer compounded topical gel Oraqix (Dentsply Caulk) among children, 4) to understand the adverse reactions to topical anesthesia that are seen among children. Methods: A cross sectional survey was designed, regarding the type, procedural use, effectiveness, and adverse reactions noted among children to various topical anesthetics. The survey sampled n=4933 actively practicing member dentists from a database of willing survey participants obtained from the American Academy of Pediatric Dentistry. The survey consisted of 14-items in multiple choice/answer format. The survey was pilot tested by a committee of faculty, and attached via e-mail with a cover letter containing a direct survey link for the study participants. Surveys were collected, posted, and managed through www.surveymonkey.com. Results: The study received 1255 responses from practitioners who are actively treating children giving an effective response rate of 25%. Of those that participated 94% are Pediatric dentists, 6% General dentists or “Other” specialists who treat children. The majority of respondents (95%) routinely use topical anesthetic, rating it as effective or very effective clinically. The most commonly used topical was 20%-Benzocaine gel with a reported 96% effective rate. The most common procedures topical anesthetics are being used for are pre-injection of local anesthetic and extraction of exfoliating deciduous teeth. Very few of the responding practitioners have ever heard of or used Oraqix gel prior to this survey. Many though, would consider using Oraqix if proven effective. Only 10% of respondents reported an adverse reaction to topical anesthetics, the most common being contact dermatitis or tissue sloughing from prolonged contact, followed by an allergic or aversive reaction to the dyes or flavoring in the topical anesthetic. Conclusions: The overwhelming majority of dentists treating children routinely use topical anesthetics to reduce pain response among children. 20%-Benzocaine gel is the most widely used topical anesthetic being used for dental procedures on children. Adverse reactions to topical anesthetic noted among practitioners treating children are very low but must still be strongly considered as potential life threatening risks if not used appropriately. Many practitioners treating children are still looking for the “ideal” topical anesthetic with improvements in taste, the ability to stay localized, the method of delivery, and improved effectiveness being key areas for future research.

Fimose, definida como a dificuldade em retrair o prepúcio para expor a glande, devido à presença de um anel fibroso, tem sido tradicionalmente tratada por meio da circuncisão. Durante a última década, no entanto, a corticoterapia foi proposta como tratamento clínico da fimose. Apresentamos um estudo duplo cego, para tratamento clínico de fimose em crianças, comparando um creme de furoato de mometasona 0,1%, aplicado topicamente, com um creme hidratante. Crianças de 2 a 13 anos de idade (n=110) apresentando fimose grau 5 de acordo com a escala de retratibilidade de Kikiros et al, todas previamente agendadas para cirurgia, foram incluídas neste trabalho. Após oito semanas de tratamento tópico, tanto com o creme hidratante quanto com o corticóide, os pacientes foram reavaliados e os que não responderam ao tratamento, antes da abertura do estudo duplo cego, foram submetidos a um adicional tratamento com corticóide, por mais oito semanas. No grupo dos pacientes tratados com corticóide, o anel fimótico desapareceu e a glande foi exposta em quarenta e nove pacientes (88%). No grupo placebo, o mesmo aconteceu 28 pacientes (52%) (*p <0,05). Dos 7 pacientes que não responderam ao tratamento inicial, com corticóide, 5 apresentaram boa resposta, ao tratamento adicional, enquanto que dos 26 pacientes do grupo placebo, 22 apresentaram exposição da glande, após o tratamento adicional (*p <0,05). Dois meninos, do grupo tratado com corticóide e quatro do grupo placebo, ainda continuaram com o anel fimótico, mesmo após o tratamento adicional com corticóide, e foram submetidos à postectomia. Concluímos que o uso de corticóide tópico, durante oito semanas, representa uma boa opção para o tratamento da fimose, principalmente na idade pré-escolar. / Phimosis, defined as the inability to retract the prepuce in order to expose the glans, due to the presence of a preputial fibrotic ring, is surgically treated in 1% of children. During the last decade, however, topical steroid treatment was proposed for phimosis. We herein present a double blind study comparing 0,1% mometasone furoate topical cream vs moisturizing cream (placebo) treatment for phimosis. Children aged 2 to 13 year old (n=110) presenting with phimosis (retractability grade 5 Kikiro´s classification) and scheduled for circumcision were included in this trial. The patients were evaluated after eight weeks topical treatment with moisturizing cream (n=54) or steroid cream (n=56). In the steroid group, the ring disappeared and glans was exposure obtained in forty nine patients (87,5%) vs twenty eight patients (52%) in the placebo group (*p<0,05). Non responders from both groups received an additional eight weeks steroid cream treatment. In the steroid group, five of seven patients were finally cured vs twenty two out of twenty six in the placebo group (*p<0,05). Two children with persisting phimosis (Kikiro´s retractability grade 5 and appearance grade 3 in the steroid group (4%) vs four children in the placebo group (7%) ended up receiving circumcision. We conclude that eight weeks topical steroid cream treatment represents a very good option for phimosis management in this age group.

A Terapia Fotodinâmica (TFD) é uma modalidade terapêutica inovadora para o tratamento de tumores cutâneos. As ftalocianinas têm sido utilizadas como fotossensibilizantes sistêmicos devido à sua alta afinidade ao tecido tumoral e seu efeito acentuado quando irradiadas com luz. No entanto, a lipossolubilidade e o baixo coeficiente de partilha óleo/água dessas substâncias dificultam sua aplicação tópica, levando ao desenvolvimento de derivados carregados, como a zinco ftalocianina tetrassulfonada (ZnPcS4) na tentativa de aumentar sua solubilidade em água, bem como melhorar sua captação pelas células tumorais. Entretanto, moléculas carregadas têm dificuldades em atravessar o estrato córneo (EC), a principal barreira da pele. Como a iontoforese é uma técnica não-invasiva capaz de aumentar e controlar a penetração de moléculas carregadas na pele, ela parece ser uma alternativa para aumentar a penetração cutânea da ZnPcS4 nas camadas da pele onde os tumores estão presentes. Dessa forma, foram realizados experimentos in vitro de iontoforese de um gel hidrofílico da ZnPcS4 aplicado topicamente na presença e ausência de NaCl. Estudos de iontoforese in vivo também foram realizados, empregando ratos Wistar como modelo animal, bem como experimentos em cultura de células tumorais para avaliar a citotoxicidade do fármaco em estudo. O método analítico para quantificação do fármaco na pele foi validado quanto à linearidade, precisão, exatidão, sensibilidade e seletividade. A iontoforese catódica promoveu um aumento significativo da retenção da ZnPcS4 tanto no EC como na epiderme viável nos experimentos realizados na presença e ausência de NaCl em relação à aplicação passiva da formulação e de iontoforese anódica, sendo que ocorreu um aumento da quantidade do fármaco retido nas diferentes camadas da pele quando o sal foi retirado da formulação. Os estudos in vivo com a formulação também mostraram que a corrente elétrica aumentou a penetração do fármaco para as camadas mais profundas da pele em relação aos experimentos passivos de permeação, o que foi evidenciado pela intensidade de fluorescência do fármaco visualizada por microscopia confocal e pela quantidade de fármaco retido nas diferentes camadas da pele. Resultados em cultura de células tumorais A431 sugerem que a concentração de fármaco que chega à epiderme viável após experimentos de iontoforese catódica é capaz de matar mais de 90% dessas células tumorais quando a dose de irradiação de 5 J/cm2 é aplicada. Além disso, quando a corrente elétrica é aplicada em cultura celular, não foi observado nenhum aumento significativo da citotoxicidade da ZnPcS4, demonstrando que a aplicação de corrente elétrica não fez com que a entrada do fármaco para o interior das células tumorais aumentasse. Não restam dúvidas, no entanto, que a corrente elétrica aumentou a penetração do fármaco nas camadas profundas da pele, além de levar a uma distribuição homogênea da ZnPcS4 nessas camadas após 15 minutos de aplicação. / Photodynamic therapy (PDT) is an innovative therapeutic modality for the treatment of cutaneous tumors. The phthalocyanines have been used as systemic photosensitizing agents due to its high affinity to tumor tissues and its accentuated effect when irradiated with light. However, the lipophilicity and the low partition coefficient oil/water of these substances difficult its topical application, leading to the development of charged derivatives, such as the zinc phthalocyanine tetrasulfonated (ZnPcS4) in an attempt to increase the water solubility, as well as improve the drug uptake by tumor cells. However, charged molecules have difficulties to cross the stratum corneum (SC), the main barrier of the skin. As iontophoresis is a noninvasive technique able to improve and control the penetration of charged molecules through the skin, it seems to be an alternative for enhancing ZnPcS4 penetration into the deep layers of the skin, where cutaneous tumors reside. This way, in vitro iontophoresis experiments of a hydrophilic gel containing ZnPcS4 applied topically in the presence and absence of NaCl were performed. In vivo iontophoresis studies were also carried out employing Wistar rats as animal model, as well as experiments in culture of tumour cells to evaluate the cytotoxicity of the drug. The analytical method for the quantification of the drug in the skin was validated considering the parameters of linearity, precision, accuracy, sensitivity and selectivity. The cathodal iontophoresis promoted a significant increase in retention of ZnPcS4 in both SC and viable epidermis in the experiments conducted in the presence and absence of NaCl in relation to the formulation applied passively or by anodal iontophoresis. Therefore, there was an increase in the amount of the drug retained in different layers of the skin when salt was removed from the formulation in the cathodal iontophoresis. In vivo studies also demonstrated that the electrical current increased penetration of the drug to the deeper layers of the skin in relation to passive experiments, evidenced by the fluorescence intensity of the drug showed by confocal microscopy and by the amount of drug retained in the different layers of the skin. Results with A431 tumor cells suggest that the concentration of the drug that reaches the viable epidermis after cathodal iontophoresis is able to kill more than 90% of these tumor cells when the radiation dose of 5 J/cm² was applied. In addition, when the electric current was applied to the cells, it was not observed any significant increase of cytotoxicity, demonstrating that the electric current application did not increased the uptake of the ZnPcS4 by the tumor cells. There are no doubts, however, that the electric current increased the ZnPcS4 penetration to the deep layers of the skin and lead to a homogeneous distribution of ZnPcS4 in these layers after 15 minutes of application.

Photoallergic contact dermatitis (PACD) is a clinical problem that has often been poorly understood and neglected by dermatologists over recent years. This can be partly attributed to its investigation by photopatch testing (PPT) falling between the expertise of photobiologists and contact dermatitis clinicians. One result of this situation was that no European Baseline PPT series had been agreed on. To redress this, the European multi centre photopatch test study (EMCPPTS) was conceived to provide up to date information on which photoallergens are of greatest clinical relevance. Its conduct and results form the core research project of this thesis. To enable the EMCPPTS to proceed and its results to be viewed in a wider context, the other Chapters of this thesis explore important related aspects of PACD and PPT in Europe. The introduction examines the nature of PACD and PPT and reviews current photoallergens. Then, the investigation of the two photoallergens carprofen and chlorproethazine by PPT is recounted. These studies highlight deficiencies within the current European regulatory system for preventing photoallergens from reaching the marketplace, as well as providing templates for the investigation of new photoallergens in the human environment. This is followed by a pilot PPT study which provides new information on the optimum non-irritating concentration of the 19 ultraviolet sunscreen absorbers to be used in the EMCPPTS. The issue of attempting to determine the photoallergenic potential of the EMCPPTS agents with respect to exposure patterns is addressed by conducting a sunscreen survey in the UK. The EMCPPTS itself is then detailed, as well as the difficulties that can be encountered when conducting a large clinical study of this nature. The results from the EMCPPTS and other presented studies were shown to be of importance in deciding upon a new European Baseline PPT series. The process involved in deciding this series, as well as its content are described before overall conclusions and possible future studies in the domain of PACD and PPT are discussed.

Infantile hemangiomas (IHs), benign vascular lesions present on the surface of the skin of children, are treated with systemic or topical beta-adrenergic antagonists (known as “beta-blockers”). However, systemic beta-blocker therapy is associated with serious adverse events in pediatric patients, and there are currently no topical formulations optimized for the skin. The objectives of this work were to 1) evaluate the local skin concentrations and drug permeation through the skin using novel beta-blocker formulations, and 2) characterize the epidermal properties and skin surface inflammatory mediators of IH skin. Skin concentrations and drug permeation through the skin from current topical treatment options were quantified in vitro; these data served as benchmarks to which other treatment paradigms in later studies were compared. Microneedle (MN)-mediated delivery of two beta-blockers, propranolol and timolol, was evaluated in vitro using solid MNs and two dissolving MN array formulations. Solid MNs increased skin concentrations of timolol compared to intact skin, while producing similar skin concentrations of propranolol. Drug permeation through the skin was increased for both drugs after MN pretreatment. Both formulations of dissolving MN arrays were ineffective at increasing local skin concentrations compared to intact skin. This was likely due to the small loading capacity of drug into the array. Drug-loaded microemulsions (ME) of varying composition were formulated and characterized. All ME formulations had solubilization properties, and water rich MEs had the greatest cumulative release through a homogenous membrane compared to surfactant rich MEs. Drug-loaded MEs did not increase local skin concentrations in vitro compared to a drug solution; however, water rich ME formulations produced greater skin-to-receiver ratio of drug concentration, indicating their potential for skin accumulation. MN pretreatment increased the skin-to-receiver ratios for surfactant rich formulations but not for water rich formulations, indicating this enhancement in skin retention after MN pretreatment is formulation dependent. These results demonstrate the potential for topical treatment of IHs upon further optimization of delivery and formulation parameters. The epidermal properties and skin surface mediators of IH skin were compared to normal, unaffected skin. Significant differences in barrier function and color, as well as chemokine and growth factor concentrations, were observed between the two sites. These results provide a greater understanding of the IH properties that have previously not been quantified. Similar changes in lesion color, which correlate to efficacy, were observed after beginning treatment with oral propranolol or topical timolol, while changes in barrier function were similar between the two treatment groups. These results indicate topical timolol may be a safe alternative for systemic treatment for superficial IHs without a loss of efficacy.