Asymptotic Expansions for Stationary Distributions of Perturbed Semi-Markov Processes

New algorithms for computing of asymptotic expansions for stationary distributions of nonlinearly perturbed semi-Markov processes are presented. The algorithms are based on special techniques of sequential phase space reduction, which can be applied to processes with asymptotically coupled and uncoupled finite phase spaces.Comment: 83 page

Developing Transdermal Applications of Ketorolac Tromethamine Entrapped in Stimuli Sensitive Block Copolymer Hydrogels

Purpose: In order to obtain dermal vehicles of ketorolac tromethamine (KT) for the local treatment of inflammation and restrict undesirable side effects of systemic levels hydrogels (HGs) of poloxamer and carbomer were developed. / Methods: KT poloxamer based HG (KT-P407-HG) and KT carbomer based HG (KT-C940-HG) were elaborated and characterized in terms of swelling, degradation, porosity, rheology, stability, in vitro release, ex vivo permeation and distribution skin layers. Finally, in vivo anti-inflammatory efficacy and skin tolerance were also assessed. / Results: HGs were transparent and kept stable after 3 months exhibiting biocompatible near neutral pH values. Rheological patterns fitted to Herschel-Bulkley for KT-C940-HG and Newton for KT-P407-HG due to its low viscosity at 25°C. Rapid release profiles were observed through first order kinetics. Following the surface the highest concentration of KT from C940-HG was found in the epidermis and the stratum corneum for P407-HG. Relevant anti-inflammatory efficacy of KT-P407-HG revealed enough ability to provide sufficient bioavailability KT to reach easily the site of action. The application of developed formulations in volunteers did not induce any visual skin irritation. / Conclusions: KT-P407-HG was proposed as suitable formulation for anti-inflammatory local treatment without theoretical systemic side effect

Stratum corneum lipids liposomes for the topical delivery of 5-aminolevulinic acid in photodynamic therapy of skin cancer: preparation and in vitro permeation study

BACKGROUND: Photodynamic therapy (PDT) using 5-aminolevulinic acid (5-ALA) is a skin cancer therapy that still has limitations due to the low penetration of this drug into the skin. We have proposed in this work a delivery system for 5-ALA based on liposomes having lipid composition similar to the mammalian stratum corneum (SCLLs) in order to optimize its skin delivery in Photodynamic Therapy (PDT) of skin cancers. METHODS: SCLLs were obtained by reverse phase evaporation technique and size distribution of the vesicles was determinated by photon correlation spectroscopy. In vitro permeation profile was characterized using hairless mouse skin mounted in modified Franz diffusion cell. RESULTS: Size exclusion chromatography on gel filtration confirmed vesicle formation. SCLLs obtained by presented a degree of encapsulation of 5-ALA around 5.7%. A distribution of vesicle size centering at around 500 nm and 400 nm respectively for SCLLs and SCLLs containing 5-ALA was found. In vitro 5-ALA permeation study showed that SCLLs preparations presented higher skin retention significantly (p < 0.05) on the epidermis without SC + dermis, with a decreasing of skin permeation compared to aqueous solution. CONCLUSIONS: The in vitro delivery performance provided by SCLLs lead to consider this systems adequate for the 5-ALA-PDT of skin cancer, since SCLLs have delivered 5-ALA to the target skin layers (viable epidermis + dermis) to be treated by topical PDT of skin cancer

Measurement of health-related quality by multimorbidity groups in primary health care

[EN] Background: Increased life expectancy in Western societies does not necessarily mean better quality of life. To improve resources management, management systems have been set up in health systems to stratify patients according to morbidity, such as Clinical Risk Groups (CRG). The main objective of this study was to evaluate the effect of multimorbidity on health-related quality of life (HRQL) in primary care. Methods: An observational cross-sectional study, based on a representative random sample (n = 306) of adults from a health district (N = 32,667) in east Spain (Valencian Community), was conducted in 2013. Multimorbidity was measured by stratifying the population with the CRG system into nine mean health statuses (MHS). HRQL was assessed by EQ-5D dimensions and the EQ Visual Analogue Scale (EQ VAS). The effect of the CRG system, age and gender on the utility value and VAS was analysed by multiple linear regression. A predictive analysis was run by binary logistic regression with all the sample groups classified according to the CRG system into the five HRQL dimensions by taking the ¿healthy¿ group as a reference. Multivariate logistic regression studied the joint influence of the nine CRG system MHS, age and gender on the five EQ-5D dimensions. Results: Of the 306 subjects, 165 were female (mean age of 53). The most affected dimension was pain/discomfort (53%), followed by anxiety/depression (42%). The EQ-5D utility value and EQ VAS progressively lowered for the MHS with higher morbidity, except for MHS 6, more affected in the five dimensions, save self-care, which exceeded MHS 7 patients who were older, and MHS 8 and 9 patients, whose condition was more serious. The CRG system alone was the variable that best explained health problems in HRQL with 17%, which rose to 21% when associated with female gender. Age explained only 4%. Conclusions: This work demonstrates that the multimorbidity groups obtained by the CRG classification system can be used as an overall indicator of HRQL. These utility values can be employed for health policy decisions based on cost-effectiveness to estimate incremental quality-adjusted life years (QALY) with routinely e-health data. Patients under 65 years with multimorbidity perceived worse HRQL than older patients or disease severity. Knowledge of multimorbidity with a stronger impact can help primary healthcare doctors to pay attention to these population groups.The authors would like to thank the Conselleria de Sanitat Universal i Sanitat Pública of the Generalitat Valenciana (the Regional Valencian Health Government) for providing the study data. We would also like to thank Helen Warbuton for editing the English.Milá-Perseguer, M.; Guadalajara Olmeda, MN.; Vivas-Consuelo, D.; Usó-Talamantes, R. (2019). 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Safety and effectiveness of vinflunine in patients with metastatic transitional cell carcinoma of the urothelial tract after failure of one platinum-based systemic therapy in clinical practice

BACKGROUND: Patients with transitional cell carcinoma of the urothelial tract (TCCU) who fail initial platinum-based chemotherapy for advanced disease represent a challenge in daily clinical practice. Vinflunine is approved by the European Medicine Agency (EMA) but, up to now, limited experience has been reported outside clinical trials. METHODS: We assessed the efficacy and safety of vinflunine in an unselected group of 102 consecutive patients with metastatic TCCU. RESULTS: The median age was 67 years (range 45–83). Among the most common comorbidities that patients presented at baseline were hypertension (50.5%) and diabetes (20.7%). Distant metastases were present in retroperitoneal nodes (58%), lung (29.3%), and bone (20.2%). The ECOG 0, 1 and 2 performance status at the start of vinflunine were 31.3%, 60.6% and 8.1%, respectively. The most commonly reported adverse events of any grade were constipation 70.6% (5.9% grade 3–4), vomiting 49.1% (2% grade 3–4), neutropenia 48.1% (12.8% grade 3–4) and abdominal pain 34.3% (4.9% grade 3–4). A median of 4 cycles of vinflunine was administered per patient (range 1–18). Median progression free and overall survival for all patients (N = 102) were 3.9 months (2.3-5.5) and 10 months (7.3-12.8), respectively. Time to tumor progression was 4.3 months (2.6-5.9). Two patients (2%) achieved CR, 23 (22.5%) patients had PR, and 42 (41.2%) presented SD as best response. The clinical benefit rate with vinflunine was 65.7%. CONCLUSIONS: Our results show that the behavior of vinflunine in routine clinical practice resembles that of the pivotal phase III randomized study

In vivo and in vitro evaluation of topical formulations containing physiological lipid mixture for replacement of skin barrier function.

AIM: The aim of the study was to describe a new in vivo and in vitro approach of the efficacy evaluation of cosmetic emollients to better understand the link between the formulation and the activity of cosmetic products. METHODS: Two long term in vivo studies were carried out on nine healthy Caucasian volunteers mean age 4012 years to evaluate the protecting and repairing effects of the two different barrier repair cosmetic formulations. The application of the formulations was repeated once a day during 7 days and biophysical parameters (TEWL and Skin Hydration) were measured before and after Sodium laureth sulphate exposure The in vitro study was carried out by freeze substitution transmission electron microscopy (FSTEM) on stratum corneum samples obtained by sections of fresh skin from young pigs, depleted with a solvent mixture and treated with the two products RESULTS: The in vivo results demonstrated that daily product application provided a reinforcement of the skin barrier with protecting and repairing effects from chemical injuries the extent of which was dependent on the formulation features (product A>product B) The role of the technical form on the lipid availability was confirmed by the in vitro evaluation tests. CONCLUSION: The results point out that a daily application of physiological lipid mixture containing emulsion can protect healthy skin and promote the reparing effect on unpaired barrier skin, reducing TEWL and maintaining hydration of the stratum corneum. The efficacy degree is higher when the cosmetic form promotes the availability of active ingredients increasing the product performance