Type II Diabetes Patients under Sildenafil Citrate: Case Series Showing Benefits and a Side Effect.

BACKGROUND: Diabetes mellitus is a highly prevalent disease with rapid universal growth. In 2013, there were already 382 million people with diabetes, and it is expected that by 2035, this number will double. Chronic hyperglycemia causes a series of biochemical and structural changes, especially in the eyes, kidneys, heart, arteries, and peripheral nerves, which usually leads to the progression of microvascular disease. Several literature reports showed that the chronic use of phosphodiesterase-5 inhibitors enhances the insulin sensitivity, improves the markers of endothelial function, and helps in the treatment of severe extremity ischemia and pulmonary hypertension. We aim to test the effect of sildenafil citrate (SC) as a glucose and microcirculation regulator in diabetic patients, paying special attention to the consequences of its use in the regulation of blood glucose level. Case Presentation. Two male patients, aged 53 and 73 years, with type II diabetes, using oral hypoglycemic agents and presenting pathology associated with microcirculation alterations and ischemia, were medicated daily with SC. Both patients presented a reduction in the glycemic level, requiring lower doses or no other oral diabetes medications. Patient 1, who presented diabetic foot, was treated in the ambulatory, and patient 2, with chronic obstructive pulmonary disease and consequent mild pulmonary hypertension, was treated in the office. In addition to the clinical improvement of foot wounds and dyspnea due to the increase in microcirculatory perfusion, hypoglycemic episodes were observed in both patients under SC. The patient with pulmonary hypertension experienced one severe hypoglycemia episode and had to be taken to an emergency room. CONCLUSION: Type 2 diabetic patients may benefit from the use of a phosphodiesterase-5 inhibitor in order to improve the microcirculatory perfusion as well as glycemic control. However, adverse side effects may involve hypoglycemia. Since off-label use of SC in patients suffering from microcirculatory alterations has increased recently, our results showed that more studies are needed to verify the prevalence of hypoglycemia episodes as well as it's possible physiologic mechanism.

A new Chlorin formulation promotes efficient photodynamic action in choriocapillaris of rabbit's eyes.

Age-related macular degeneration (AMD) as well as other choroidal diseases, demand novel therapeutic methods. Photodynamic therapy (PDT), which uses light and photosensitizer (PS) to cause specific vascular occlusion in the macula, is an interesting alternative. The only drug approved for the PDT treatment of AMD (Verteporfin) has a natural tendency to aggregate, demanding an expensive separation procedure during purification. We report a novel and affordable PS that is intrinsically protected against aggregation, the Monomeric Chlorin at High Concentration (MCHC-Chlorin), whose liposomal formulation was developed to provoke effective photodynamic action on the choroidal vasculature. Our report starts by stablishing the conditions to allow the efficient synthesis of MCHC-Chlorin in high yields (92%). We then tested the light stimulated occlusion of choriocapillary vessels in rabbit's eyes induced by the two MCHC-Chlorin isomers, which are directly obtained from the synthetic route. The PS formulation was infused in the rabbit's ear vein and eyes were immediately irradiated at 650 nm. Indirect ophthalmoscopy, fundus photography, fluorescein angiography and histopathological evaluations were used to evaluate levels of photo-thrombosis and collateral damage. Choriocapillary occlusion was achieved in all treated rabbits' eyes, while retina and sclera were completely preserved. There was no photochemical reaction in none of the eyes that received LASER without PS. Both MCHC-Chlorin isomers were separately tested and exhibited similar positive results with no systemic toxicity. Therefore, PDT occurred equally well in all treated eyes and none of the controls showed any effect in the ophthalmological exams. MCHC-Chlorin offers great potential and should be further studied as an alternative drug for choroidal diseases.

Is surgical debridement necessary in the diabetic foot treated with photodynamic therapy?

Background: Diabetic patients are susceptible to developing foot ulcers with serious complications such as osteomyelitis and amputations. Treatment approaches are still empirical and the benefit of usual procedures such as surgical debridement has not been properly evaluated. Photodynamic Therapy (PDT) is a non-invasive and highly efficient method for the treatment of the diabetic foot, being able to eradicate the infection and to stimulate healing, decreasing considerably the amputation risk. In the day-to-day practice of our service, we have been faced with the question whether debridement is necessary before PDT. In here, we designed a study to answer that question. Methods: Patients were divided in two groups: In one of the groups (n = 17), debridement was performed before PDT and in the other (n = 40) only PDT treatment was performed. PDT sessions were performed once a week in all patients until healing was achieved, as indicated by visual inspection as well as by radiographic and laboratory exams. At the start of the study, the two groups had no statistical differences concerning their clinical features: average age, gender, insulin use, diabetes mellitus onset time and previous amputations. Results: PDT was effective in the treatment of 100% of the patients showing no relapses after one year of follow up. The group submitted to PDT without previous debridement had a statistically significant (p = 0.036, Mann-Whitney) shorter cure time (29 days, ~27%). Conclusion: Our data indicates that debridement is not necessary in the treatment of diabetic foot in patients that have enough peripheral arterial perfusion. In addition, we reproduced previous studies confirming that PDT is an efficient, safe, simple and affordable treatment method for the diabetic foot.

Therapeutic comparison between treatments for Vulvar Lichen Sclerosus: study protocol of a randomized prospective and controlled trial.

BACKGROUND: Vulvar lichen sclerosus (VLS) is a lymphocyte-mediated disease of unknown etiology that can cause intense itching as well stenosis, hindering the evacuation and urination. It can also limit the sex life due to severe local pruritus, pain and dyspareunia (pain during sexual intercourse). The standard treatment for this disease is the use of topical corticosteroids to reduce the clinical symptoms and to try to increase disease-free intervals. Photodynamic therapy (PDT), a treatment that associates a light radiation with a photosensitizing agent and photobiomodulation (PBM) are therapies that can promote effective immunomodulatory responses at the application site by means of photophysical and photochemical phenomena from the molecular to the systemic level, which promote their use in chronic dermatoses. The aim is to compare the effects of PDT, PBM, and topical corticosteroid in VLS evaluating clinical, histological, immunohistochemical and spectroscopic responses. METHODS: The study is prospective, randomized and controlled, in a population of 60 women with histological diagnoses of VLS. There will be 3 treatments groups: PDT, PBM and topical corticosteroid (control group), where will be allocated by randomization 20 patients in each one. The clinical course will be monitored by measuring local temperature, itching, atrophy, and the area of the lesion. Histologically, the slides will be classified and will have the ordering of collagen fibers quantified. Immunohistochemical analysis will be done using the markers IFN-γ, TGF-ß, CD4, CD8, IL-1, p53 and Ki-67. Finally, the spectroscopic evaluation will be done by reflectance. Descriptive and inferential statistical analyses will be conducted to compare the groups and make associations between different responses. The study is an open-label for patients with active symptomatic disease with a period of 1 year follow-up to determine the rate of recurrence in each groups. DISCUSSION: The immunological effects of PDT and PBM are described by several authors in inflammatory skin diseases, stimulating the production and organization of the associated collagen. Thus, it is reasonable to determine the efficacy and safety of these new treatments in VLS, in comparison to the control group, analyzing the recurrence time, the impact on the optical properties of the skin, and the benefit to patients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02416531 .

Development of the Tardivo Algorithm to Predict Amputation Risk of Diabetic Foot.

Diabetes is a chronic disease that affects almost 19% of the elderly population in Brazil and similar percentages around the world. Amputation of lower limbs in diabetic patients who present foot complications is a common occurrence with a significant reduction of life quality, and heavy costs on the health system. Unfortunately, there is no easy protocol to define the conditions that should be considered to proceed to amputation. The main objective of the present study is to create a simple prognostic score to evaluate the diabetic foot, which is called Tardivo Algorithm. Calculation of the score is based on three main factors: Wagner classification, signs of peripheral arterial disease (PAD), which is evaluated by using Peripheral Arterial Disease Classification, and the location of ulcers. The final score is obtained by multiplying the value of the individual factors. Patients with good peripheral vascularization received a value of 1, while clinical signs of ischemia received a value of 2 (PAD 2). Ulcer location was defined as forefoot, midfoot and hind foot. The conservative treatment used in patients with scores below 12 was based on a recently developed Photodynamic Therapy (PDT) protocol. 85.5% of these patients presented a good outcome and avoided amputation. The results showed that scores 12 or higher represented a significantly higher probability of amputation (Odds ratio and logistic regression-IC 95%, 12.2-1886.5). The Tardivo algorithm is a simple prognostic score for the diabetic foot, easily accessible by physicians. It helps to determine the amputation risk and the best treatment, whether it is conservative or surgical management.

Chlorophyllin-M: A new substance for photodynamic therapy in the retina and choroid.

BACKGROUND AND OBJECTIVE: Chlorophyllin-M is a new chlorophyll-based derivative photosensitive compound developed by our research group with easy laboratorial synthesis and ideal properties for photodynamic therapy (PDT). It is intended for clinical treatments with simple and low cost techniques and reagents. The objective of this study is to evaluate if intravenous chlorophyllin-M is able to deliver a photosensitizer to rabbit retina and rabbit choroid and promote PDT after ocular irradiation with a 660 nm LASER. METHODS: This is a pre-clinical study. Ten eyes of five pigmented Californian rabbits were included in the study. The right eyes served as the treatment group, and the left eyes served as the control group. All eyes had been ophthalmologically evaluated and were considered normal. RESULTS: Ophthalmic exam with anterior biomicroscopy, dilated fundus examination, and fluorescein angiography after the LASER procedure revealed normal anterior segment, retinal and choroid vessels occlusion, lumen narrowing, and capillary non-perfusion in the treated areas, indicating that PDT was successful in the treatment eyes group. CONCLUSION: The results of this pre-clinical study encourage future studies with this new compound. Chlorophyllin-M may become a new cost-effective agent in the retinal therapeutic arsenal.

Small scale trial of photodynamic treatment of onychomycosis in São Paulo.

The use of methylene blue and toluidine blue in the photodynamic treatment of onychomycosis at an ambulatory clinic in São Paulo, Brazil is reported. Local application and illumination of infected nails produced a response in 53 of 62 patients, without any pain or burning associated with the therapy.

A clinical trial testing the efficacy of PDT in preventing amputation in diabetic patients.

The feet of diabetic patients continue to be an unsolved problem in medicine. Uncontrolled neuropathy, ulceration and infection usually lead to amputation and presently there is no effective and reliable method that can be used to provide an efficient cure. Overall improvement in the salvage strategies, based on comprehensive pre-clinical evaluation, debridement, antibiotic therapy and follow up, has shown improvements in certain hospital settings, but the general picture for patients with diabetic foot is to have some sort of amputation, especially in underserved populations. It is clearly necessary to develop novel treatment strategies for this worldwide health problem. Photodynamic therapy (PDT) is a treatment modality that uses light to generate in situ reactive oxygen species, which can cause cell death. PDT can be used to treat several diseases, including foot infections that do not respond well to antibiotic therapy. There are several characteristics of PDT that make it potentially ideal to treat diabetic feet: the photosensitizer is non-toxic in the dark, but after illumination it becomes a very efficient antimicrobial agent with topical use, and it can regenerate small bones, such as the phalanges. However, PDT is still not used in clinical practice to treat diabetic feet. Therefore, we decided to perform a clinical study to prove that PDT is an effective method to avoid amputation of infected diabetic feet. An inexpensive PDT protocol was developed and applied to 18 patients with osteomyelitis, classified as Grade 3 on the Wagner scale. Only one of these patients suffered amputation. At least two of them were cured from resistant bacteria strains without intravenous antibiotic therapy. In the control group of 16 patients, all of them ended up suffering amputation. The rate of amputation in the PDT group was 0.029 times the rate in the control group and the difference is clearly statistically significant (p=0.002).

Local clinical phototreatment of herpes infection in São Paulo.

The clinical use of topical photodynamic therapy in herpes simplex lesions in São Paulo is presented and discussed. Although previous attempts utilising this type of approach in the USA were discontinued in the early 1970s due to several presentations of post-treatment Bowen's disease, none of the cases from the clinic presented here have displayed any complications on follow-up. In addition, lesion recrudescence periods are generally much longer than with conventional approaches. This is thought to be due to improvements in the treatment protocol, viz. use of the non-toxic photosensitisers methylene blue and Hypericum perforatum extract in place of proflavine and neutral red in the original trials, differences in photosensitisation pathway and illumination of the treatment site with red rather than fluorescent/UV light. Post-treatment cosmesis is also excellent.

Photodynamic therapy using methylene blue to treat cutaneous leishmaniasis.

OBJECTIVE: The purpose of this study was to show the efficiency and underlying mechanism of action of photodynamic therapy (PDT) using methylene blue (MB) and non-coherent light sources to treat cutaneous leishmaniasis (CL). BACKGROUND DATA: Systemic treatment can cause severe side effects, and PDT using porphyrin precursors as sensitizers has been used as an alternative to treat CL. MB has been used under illumination or in the dark to treat a wide range of medical conditions, and it exhibits antimicrobial activity against protozoa and viruses. METHODS: In in vitro tests, the cell viability (via a MTT colorimetric assay) of Leishmania amazonensis parasites was evaluated as a function of MB concentration. In in vivo experiments, we analyzed the treatment of two lesions from a patient with leishmaniasis. The patient received a low dose of pentavalent antimony (SbV), and one lesion was treated with PDT. RESULTS: We observed IC(50) decreases from 100 to 20 µM in response to PDT when MB was used in different concentrations in in vitro tests. Use of SbV in combination with the PDT protocol produced faster wound recovery when compared with the use of SbV alone. CONCLUSIONS: The in vitro experiments and the results from the clinical case suggest that the inexpensive PDT protocol that is based on MB and RL50® may be used to treat CL caused by L. amazonensis.

Methylene blue in photodynamic therapy: From basic mechanisms to clinical applications.

Methylene blue (MB) is a molecule that has been playing important roles in microbiology and pharmacology for some time. It has been widely used to stain living organisms, to treat methemoglobinemia, and lately it has been considered as a drug for photodynamic therapy (PDT). In this review, we start from the fundamental photophysical, photochemical and photobiological characteristics of this molecule and evolved to show in vitro and in vivo applications related to PDT. The clinical cases shown include treatments of basal cell carcinoma, Kaposi's Sarcoma, melanoma, virus and fungal infections. We concluded that used together with a recently developed continuous light source (RL50(®)), MB has the potential to treat a variety of cancerous and non-cancerous diseases, with low toxicity and no side effects.

Aspectos morfológicos e histométricos da reparaçäo tecidual das feridas cutâneas de ratos após irradiaçäo com o laser de hélio-neônio / Morphological and histometric aspects of tissue healing of skin wounds in rats after irradiation with the helium-neon laser

O objetivo foi avaliar a reparaçäo tecidual das feridas cutâneas de ratos após irradiaçäo com o Laser de Hélio-Neônio (He-Ne). Utilizamos 18 ratos machos, da linhagem Wistar. Dividimos os animais em 3 grupos de 6 animais: G1, G2, G3. Realizamos, em cada animal, duas feridas circulares de 1 cm na regiäo dorsal, sendo uma irradiada com o Laser de He-Ne na dose diária de 2,7 Joules/10 minutos, e a outra observada como controle. No 7§, 14§ e 21 dias as feridas foram analisadas quanto aos aspectos morfológicos e histométricos. Os resultados obtidos mostraram uma epitelizaçäo e contraçäo mais precoce das feridas irradiadas. A proporçäo de fibras colágenas foi maior nas feridas irradiadas nas 3 fases estudadas. A proporçäo de fibroblastos foi maior no grupo irradiadas nas 3 fases estudadas. A proporçäo de fibroblastos foi maior no grupo irradiado apenas no 7§ P. O. Concluímos que o processo de reparaçäo evoluiu de forma mais rápida nas feridas irradiadas em relaçäo ao controle