Synergistic antibacterial effect of statins with the complex {[1-(4-bromophenyl)-3-phenyltriazene N 3 -oxide-κ 2 N 1,O 4 ](dimethylbenzylamine-κ 2 C 1, N 4 )palladium(II)}

Abstract The treatment of infections caused by resistant microorganisms represents a big challenge in healthcare due to limited treatment options. For this reason, the discovery of new active substances which are able to perform innovative and selective actions is of great impact nowadays. Statins and triazenes (TZC) have consolidated as a promising class of compounds, characterized by the expressive biological activity, especially antimicrobial activities. The aim of this study was to assess the in vitro synergistic antibacterial effect of the association of statins and a new TZC complex {[1-(4-bromophenyl)-3-phenyltriazene N 3-oxide-κ 2 N 1,O 4](dimethylbenzylamine-κ 2 C 1,N 4)palladium(II)} (Pd(DMBA)LBr) against American Type Culture Collection (ATCC) strains and clinical isolates. The complex and the statins showed bacterial activity of all tested strains and clinical isolates, evidencing that TZC complexion with metals can be promising. Simvastatin showed synergy when associated to the complex (FICI≤0.5), being the minimum inhibitory concentration (MIC) of 16 µg mL-1 found in 6 samples. Thus, it is possible to infer that the association between Pd(DMBA)LBr and simvastatin consists of an alternative to increase the pontential of these compounds, since statins have low toxicity.

Synthesis, characterization and biological activity of a gold(I) triazenide complex against chronic myeloid leukemia cells and biofilm producing microorganisms

ABSTRACT The enhancement of anti-leukemia therapy and the treatment of infections caused by multidrug-resistant pathogens are major challenges in healthcare. Although a large arsenal of drugs is available, many of these become ineffective, and as a result, the discovery of new active substances occurs. Notably, triazenes (TZCs) have been consolidated as a promising class of compounds, characterized by significant biological activity, especially antiproliferative and antimicrobial properties. The aim of this study is the synthesis and characterization of a new triazenide complex of gold (I), as well as the in vitro assessment of its antiproliferative activity against the K562 cell line (Chronic Myeloid Leukemia), and antibacterial activity against bacterial isolates of biofilm-producing coagulase-negative staphylococci. The combination of TZC with gold metal tends to have a synergistic effect against all biofilm-producing isolates, with Minimum Inhibitory Concentration values (MIC) between 32 and 64 µg mL-1. It has also shown activity against K562 cell line, getting an IC50=4.96 µM. Imatinib mesylate (Glivec) was used as reference, with IC50=3.86 µM. To the best of our knowledge, this study represents the first report of the activity of a TZC complexed with gold ion in the oxidation state (I) against microorganisms that produce biofilm and K562 cells.

Complexos triazenidos de platina (II): Avaliação in vitro da atividade antibacteriana e citotóxica frente a bactérias e células de medula óssea de pacientes leucêmicos de um hospital escola / Triazenidos complexes of platinum (II): In vitro evaluation of antibacterial and cytotoxic activity against bacteria and bone marrow cells from leukemic patients in a university hospital

Atualmente, apesar da ampla gama de substâncias ativas existentes, progressivamente tem se limitado o arsenal terapêutico disponível na prática clínica, isto se deve, especialmente, pelo surgimento da resistência aos agentes terapêuticos utilizados no tratamento de tumores e infecções bacterianas. Em virtude das diversas propriedades farmacológicas demonstradas pelos triazenos (TZCs), avaliaram-se compostos inéditos na busca de novos agentes biologicamente ativos, estes foram denominados C1 e C2. A atividade antibacteriana foi realizada pelo método convencional da microdiluição em caldo, através da técnica da Concentração Inibitória Mínima (CIM), frente a cepas bacterianas de referência American Type Culture Collection (ATCC) e isolados clínicos com resistência múltipla as drogas (RMD). A citotoxicidade foi analisada através do ensaio colorimétrico baseado na redução do brometo de 3-(4,5-dimetiltiazol-2-il)-2,5?difeniltetrazólio frente a células da medula óssea de dois pacientes (P1 e P2) atendidos no Hospital Universitário de Santa Maria. Os dois compostos testados apresentaram atividade antibacteriana em 26,08% (6/23) das cepas testadas, sendo ativos em 38,46% (5/13) das cepas ATCC e 10% (1/10) dos isolados clínicos RMD, apenas em espécies caracterizadas como Gram positivas. Os resultados foram satisfatórios para ambos os compostos frente à amostra P2, células mononucleares de Leucemia Mielóide Crônica, pois demonstraram indução da morte celular. Pode-se concluir que os resultados obtidos desses compostos demonstraram a existência de atividade antibacteriana, bem como, atividade antileucêmica promissora. Pesquisas complementares relacionadas a esses compostos estão em andamento.(AU)

Currently, despite the wide range of existing active substances has been progressively limited therapeutic arsenal available in clinical practice, this is, in particular, the emergence of resistance to therapeutic agents used in treating tumors and bacterial infections. Because of the diverse pharmacological properties demonstrated by triazenes (TZCs) - evaluated whether unpublished compounds in the search for new biologically active agents, they were called C1 and C2. The antibacterial activity was performed by the conventional method of broth microdilution, using the technique of Minimum Inhibitory Concentration (MIC) against the bacterial strains reference American Type Culture Collection (ATCC) and clinical isolates with multiple drug resistance (MDR). Cytotoxicity was analyzed by colorimetric assay based on the reduction of the bromide of 3 - (4,5- dimethylthiazol-2- yl) -2,5- diphenyltetrazolium against bone marrow cells from two patients (P1 and P2) seen at the Hospital university of Santa Maria. The two compounds tested showed antibacterial activity in 26.08% (6/23) of the strains, being active in 38.46 % (5/13) of the ATCC strains and 10 % (1/10) of clinical isolates MDR only characterized in species such as Gram positive. The results were satisfactory for both the sample compounds front P2, mononuclear cells from chronic myeloid leukemia, as demonstrated induction of cell death. It can be concluded that the results demonstrated the existence of these compounds to antibacterial activity, as well as promising antileukemic activity. Additional research related to these compounds are in progress.(AU)

Atividade antibacteriana de um composto triazenido com ouro frente a cepas bacterianas e isolados clínicos / Actividad antibacteriana de un triazenido compuesto de oro frente a las cepas bacterianas y los aislados clínicos / Antibacterial activity of gold complexed triazenid against bacterial strains and clinical isolates

Introdução: de uma forma alarmante, estudos demonstraram que nos últimos anos ocorreu um grande aumento na resistência bacteriana frente aos antibióticos. Consequentemente, há uma grande necessidade de descoberta de novas substâncias ativas, e entre essas, os compostos triazenos vêm demonstrado-se como uma classe promissora de metalofármacos, com significativa atividade antimicrobiana. Além do mais, a associação do radical farmacofórico triazenos com metais, como o ouro, favorece a produção de moléculas com maior atividade biológica. Objetivo: avaliar a atividade antibacteriana in vitro do composto triazenos inédito complexado com ouro no estado de oxidação I {(1-(2-bromofenil)-3-(2-nitrofenil)triazenido(trifenilfosfina)ouro(I)}, frente a cepas bacterianas padrões de referência American Type Culture Collection e isolados clínicos com resistência múltipla as drogas (MDR). Métodos: a atividade antibacteriana do composto triazenos foi determinada através do método de Concentração Inibitória Mínima, baseado no Clinical and Laboratory Standards Institute de 2012. A CIM foi caracterizada visualmente, como a menor concentração que inibiu completamente o crescimento dos microrganismos nos poços de diluição. Resultados: o composto em estudo apresentou pronunciada atividade antibacteriana, sendo ativo em 43,4 por cento (10/23) das bactérias testadas, mostrando-se seletivo frente a cepas Gram positivas. Conclusão: o complexo triazenos apresentou estreito espectro de ação, sendo ativo somente frente aos microrganismos classificados como Gram positivos, demonstrando assim uma alternativa para a concepção de uma nova classe de metalofármacos com atividade antibacteriana(AU)

Introducción: de una manera alarmante, los estudios han demostrado que en los últimos años hubo un gran aumento de la resistencia bacteriana a los antibióticos. Por consiguiente, hay una gran necesidad para el descubrimiento de nuevas sustancias activas, y entre estas, los compuestos triazenos se muestran como una clase prometedora de metalofármacos con actividad antimicrobiana significativa. Por otra parte, la asociación de triazeno farmacóforo radical con metales como el oro favorece la producción de moléculas con actividad biológica superior. Objetivo: evaluar la actividad antibacteriana in vitro del compuesto sin precedentes triazeno complejado con oro en el estado de oxidación I {(1-(2-bromofenil)-3-(2-nitrofenil)triazenido(trifenilfosfina)ouro(I)}, frente a las cepas de las normas bacterianas, cepas de referencia American Type Culture Collection y los aislados clínicos con resistencia múltiple a los medicamentos. Métodos: la actividad antibacteriana del triazeno compuesto se determinó por el método de la concentración inhibitoria mínima, sobre la base de estándares clínicos y de laboratorio de 2012. Este método se caracteriza visualmente como la menor concentración que inhibió completamente el crecimiento de microorganismos en los pocillos de dilución. Resultados: el compuesto de ensayo mostró actividad antibacteriana pronunciada, el cual fue activo en 43,4 por ciento (10/23) de las bacterias ensayadas, uy mostró ser selectivo contra las cepas grampositivas. Conclusión: el complejo triazeno mostró estrecho espectro de acción, el cual es activo solo frente a los microorganismos clasificados como grampositivos, lo que demuestra una alternativa para la concepción de una nueva clase de metalofármacos con actividad antibacteriana(AU)

Introduction: several studies have revealed that the increase of bacterial resistance to antibiotic is really alarming in the last few years. Consequently, the discovery of new active substances is a must and the triazene compounds appear as a promising class of metal drugs with significant antimicrobial action. On the other hand, the association of radical pharmacophorous triazene with metals such as gold facilitates the production of greater biological action molecules. Objective: to evaluate the in vitro antibacterial activity of this unprecedented compound called gold complexed with triazene at oxidation state I {(1-(2-bromophenyl)-3-(2-nitrophenyl)triazenide (triphenylphosphane) gold(I)} against the bacterial standard strains, American Type Culture Collection reference strains and the multiple drug resistance clinical isolates. Methods: the antibacterial activity of the compound triazene was estimated by the minimal inhibitory concentration method on the basis of the clinical and laboratory standards 2012. This method is visually characterized as the lowest concentration that fully inhibited the bacterial growth in the dilution wells. Results: the tested compound showed significant antibacterial activity, being active in 43.4 percent (10/23) of tested bacteria and selective for Gram-positive strains. Conclusions: triazene complex showed narrow action spectrum since it is only active against Gram-positive microorganisms, which is in turn an alternative for conception of a new class of metal drugs with antibacterial action(AU)

A Case of Laryngeal Mask Airway-Assisted Percutaneous Dilatational Tracheostomy / 대한구급학회지

Percutaneous dilatational tracheostomy (PDT) is a widely used method to perform tracheostomy in the critical care medicine for patients who need prolonged mechanical ventilation. Traditionally, PDT has been facilitated by bronchoscopy via the endotracheal tube. However, there are risks for blocking the view of correct puncture site on the trachea or being extubated unintentionally, which lead to loss of the airway. These complications are possibly due to insufficient bronchoscopic visualizations via endotracheal tube during the procedure. Using laryngeal mask airways (LMA) during PDT may overcome these problems and could provide a safer alternative method with superior visualizations of the trachea and larynx. We report a case of percutaneous tracheostomy being performed successfully under bronchoscopy with LMA in the intensive care unit.

Photodynamic Therapy with Ablative Carbon Dioxide Fractional Laser for Treating Bowen Disease

BACKGROUND: Topical photodynamic therapy (PDT) has been increasingly used to treat malignant skin tumors including the Bowen disease. However, patients could be displeased with the long incubation time required for conventional PDT. OBJECTIVE: We evaluated the efficacy and safety of PDT with a short incubation time of ablative CO2 fractional laser pretreatment for treating Bowen disease. METHODS: Ten patients were included. Just before applying the topical photosensitizer, all lesions were treated with ablative CO2 fractional laser, following the application of methyl aminolevulinate and irradiation with red light (Aktilite CL 128). Histological confirmation, rebiopsy, and clinical assessments were performed. Adverse events were also recorded. RESULTS: Five of the ten (50%) lesions showed a complete response (CR) within three PDT sessions. After four treatment sessions, all lesions except one penile shaft lesion (90%) achieved clinical and histological CR or clinical CR only. The average number of treatments to CR was 3.70+/-1.70. The treatments showed favorable cosmetic outcomes and no serious adverse events. CONCLUSION: The results suggest that pretreatment with an ablative fractional CO2 laser before PDT has similar treatment efficacy and requires a shorter photosensitizer incubation time compared with the conventional PDT method.

Photodynamic Therapy with Ablative Carbon Dioxide Fractional Laser for Treating Bowen Disease

BACKGROUND: Topical photodynamic therapy (PDT) has been increasingly used to treat malignant skin tumors including the Bowen disease. However, patients could be displeased with the long incubation time required for conventional PDT. OBJECTIVE: We evaluated the efficacy and safety of PDT with a short incubation time of ablative CO2 fractional laser pretreatment for treating Bowen disease. METHODS: Ten patients were included. Just before applying the topical photosensitizer, all lesions were treated with ablative CO2 fractional laser, following the application of methyl aminolevulinate and irradiation with red light (Aktilite CL 128). Histological confirmation, rebiopsy, and clinical assessments were performed. Adverse events were also recorded. RESULTS: Five of the ten (50%) lesions showed a complete response (CR) within three PDT sessions. After four treatment sessions, all lesions except one penile shaft lesion (90%) achieved clinical and histological CR or clinical CR only. The average number of treatments to CR was 3.70+/-1.70. The treatments showed favorable cosmetic outcomes and no serious adverse events. CONCLUSION: The results suggest that pretreatment with an ablative fractional CO2 laser before PDT has similar treatment efficacy and requires a shorter photosensitizer incubation time compared with the conventional PDT method.

Correlation Between Optical Coherence Tomography and Visual-Acuity in Chronic Central Serous Chorioretinopathy Treated with Half Dose Photodynamic Therapy

PURPOSE: To evaluate the results of half-dose photodynamic therapy (PDT) and determine the correlation between morphological changes measured by spectral-domain optical coherence tomography (SD-OCT) and visual acuity in patients with chronic central serous chorioretinopathy (CSC). METHODS: Twenty-five eyes of 25 patients with chronic CSC who had received half-dose verteporfin PDT were enrolled in the present study. The best-corrected visual acuity (BCVA), outer nuclear layer (ONL) thickness, and the integrity of the photoreceptor inner and outer segment junction (IS/OS) using SD-OCT were evaluated at baseline and at 3 and 6 months after treatment. RESULTS: The neurosensory retinal detachment disappeared in all eyes 6 months after treatment. The BCVA improved significantly from 0.50 +/- 0.32 to 0.31 +/- 0.29 log MAR at 6 months (p < 0.001). The average ONL thickness at the central fovea was 88.76 +/- 19.95 microm at 6 months and the ONL thickness was well correlated with the BCVA (gamma = -0.64; p = 0.001). There was no significant correlation between the status of IS/OS and the BCVA. CONCLUSIONS: Half-dose PDT is effective in treating chronic CSC resulting in visual improvement and complete resolution of neurosensory retinal detachment. The ONL thickness which was positively correlated with the BCVA could be an indicator for visual prognosis of chronic CSC.

Predictive Factors for Visual Outcome after Treatment for Myopic Choroidal Neovascularization

PURPOSE: To determine predictive factors associated with visual outcome after treatment for myopic choroidal neovascularization (mCNV). METHODS: Medical records of the patients who underwent photodynamic therapy (PDT), intravitreal anti-vascular endothelial growth factor (Anti-VEGF) injection, or combination therapy of PDT and Anti-VEGF for myopic CNV, and followed up for more than a year, were reviewed retrospectively. Multiple linear regression analyses were performed to evaluate the predictive factors significantly associated with the visual outcome at 1 year after the treatment. RESULTS: Mean best-corrected visual acuity (BCVA) of 45 eyes of 45 patients showed statistically significant improvement 1 year after the treatment with a mean of 3.5 line improvement (p < 0.01, Wilcoxon signed rank test). Age, 1-month BCVA after treatment and treatment type appeared to be associated with the 1-year visual outcome after treatment for mCNV (p = 0.033, p < 0.001, and p = 0.044, respectively, multivariate linear regression analysis). CONCLUSIONS: Younger age (less than 40 years), better 1-month BCVA after treatment, intravitreal Anti-VEGF monotherapy were associated with improved visual outcome after treatment for mCNV. In particular, 1-month BCVA after treatment is a useful indicator to predict therapeutic response after treatment for mCNV.

Comparison of Therapeutic Effect Between Half-Energy Photodynamic Therapy and Intravitreal Bevacizumab Injection in Chronic Central Serous Chorioretinopathy for 12 Months

PURPOSE: In this study we compared the effectiveness between half energy photodynamic therapy (PDT) and intravitreal bevacizumab (IVB) injection for chronic central serous chorioretinopathy (CSC). METHODS: Forty-five eyes of 42 patients diagnosed as chronic CSC from March 2008 to April 2011 were treated with half energy PDT or IVB injection. The subjects were chosen for a retrospective study and analysis was performed on changes in best corrected visual acuity and existence of subretinal fluid, recurrence rate and changes in central macular thickness. RESULTS: Similar improvement of visual acuity was observed in both treatment groups 1 month after treatment and no meaningful difference was found in each stage for both groups (p = 0.001, p = 0.0012, respectively). However, 6 to 12 months after the treatment, the half energy PDT group showed more improvement in visual acuity compared to the IVB injection group (p = 0.019, p = 0.043, respectively). Nineteen out of 21 cases showed full recovery of subretinal fluid in the half energy PDT group with an average treatment period of 1.3 +/- 0.8 months and 7 out of 24 cases showed full recovery in the IVB injection group with an average treatment period of 3.2 +/- 2.8 months. There was a single case of recurrence in the half energy PDT group and 4 in the IVB injection group. The half energy PDT group showed a meaningful decline in central macular thickness at 1, 3, and 6 months after treatment (p = 0.001, p = 0.005, p = 0.007, respectively) compared to the IVB injection group and showed numerous cases with decline in central macular thickness below the 2 standard deviation from normal values (p = 0.002). CONCLUSIONS: Both half energy PDT and IVB injection were effective for the treatment of chronic central serous chorioretinopathy. However, the half energy PDT group comparatively showed better anatomical and functional outcomes. The thinning of central macular thickness below normal value was also observed, thus careful choice of treatment is necessary for patients with chronic central serous chorioretinopathy.

Clinical Manifestation of Retinal Pigment Epithelial Tear after Treatment of Age-Related Macular Degeneration

PURPOSE: To determine the risk factors of retinal pigment epithelial (RPE) tears developed after treatment of exudative age-related macular degeneration (AMD) and to report its clinical manifestations. METHODS: A retrospective, consecutive chart review was performed for all patients with exudative AMD treated with intravitreal anti-vascular endothelial growth factor (VEGF) antibody or photodynamic therapy (PDT) between March 2010 and January 2013. The main outcome measures were the time from first injection to development of the RPE tear and pre- and post-RPE tear visual acuity. The visual acuity conservational interval was defined between the time the RPE tear occurred and the time visual acuity decreased 5 letters or more from pre-RPE tear visual acuity. RESULTS: A total of 219 eyes were treated with intravitreal bevacizumab, ranibizumab or PDT. Ten eyes from 10 patients developed a RPE tear (4.6%); 7 were occult choroidal neovasculization (CNV) and 3 were polypoidal choroidal vasculopathy (PCV). The average age of the RPE tear patients was 75.4 years which is statistically greater than the others (65.7) (p = 0.001). Ninety percent (9/10) of the RPE tears occurred within the first 12 weeks after treatment started. Five patients conserved their visual acuity for approximately 4 months after the RPE tear occurred. However, all 10 patients had poor visual acuity within 1 year of the follow-up period. CONCLUSIONS: RPE tears occur after intravitreal anti-VEGF antibody or PDT treatments for exudative AMD in elderly patients. Visual acuity could be conserved in the early period after a RPE tear occurred but decreased within the next year.

Bevacizumab Monotherapy Versus Combined Therapy with Photodynamic Therapy for Occult Choroidal Neovascularization in Age-Related Macular Degeneration

PURPOSE: To compare clinical outcomes between intravitreal bevacizumab (IVB) monotherapy and combined therapy with half-fluence rate verteporfin photodynamic therapy (PDT) for occult choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). METHODS: Medical records were reviewed in consecutive patients who underwent IVB monotherapy or combined therapy with PDT for occult CNV secondary to AMD and had a 12-month follow-up period. After 3 consecutive monthly IVB injections, both groups were eligible for additional IVB injections when necessary. Best-corrected visual acuity (BCVA), central macular thickness (CMT), and number of additional IVB injections were compared between the groups. RESULTS: Thirty-nine eyes underwent IVB monotherapy (IVB group) and 25 eyes underwent combined therapy (PDT+IVB group). Mean BCVA improved significantly in the PDT+IVB group (p = 0.046) and not in IVB group (p = 0.213). A significant reduction in mean CMT occurred in both groups (p < 0.001). The mean number of additional IVB injections was 1.6 +/- 1.33 in the IVB group and 0.5 +/- 1.01 in the PDT+IVB group (p = 0.001). There were no serious complications. CONCLUSIONS: Combined therapy with half-fluence rate PDT improved BCVA and reduced the number of additional IVB injections in the eyes with occult CNV secondary to AMD.

Photodynamic Therapy with Ablative Carbon Dioxide Fractional Laser in Treatment of Actinic Keratosis

BACKGROUND: Recently, photodynamic therapy (PDT) has been shown to be an effective first-line treatment for actinic keratosis (AK). However, a major limitation of PDT is the long incubation time required to allow penetration of the photosensitizer. OBJECTIVE: The aim of this study was to assess if pretreatment with an ablative carbon dioxide (CO2) fractional laser can reduce the incubation time of the photosensitizer. METHODS: Initially, 29 patients with a total of 34 AK lesions were treated with an ablative CO2 fractional laser at Ajou University Hospital between January and December 2010. Immediately after the laser treatment, topical 20% 5-aminolevulinic acid or methyl-aminolevulinate was applied to the AK lesions and incubated for 70 to 90 minutes. Then, the treated areas were illuminated with a red light source. Improvement was clinically or histologically assessed eight weeks after the treatment. RESULTS: In spite of the short incubation time, 24 lesions (70.6%) showed a complete response (CR) within three sessions of PDT (10 lesions a clinical CR and 14 lesions a clinical/histological CR). There were no significant side effects associated with the combination of ablative CO2 fractional laser and PDT. CONCLUSION: Ablative CO2 fractional laser may be considered an additional treatment option for reducing the incubation time of the photosensitizer in PDT.

Advance in Photosensitizers and Light Delivery for Photodynamic Therapy

The brief history of photodynamic therapy (PDT) research has been focused on photosensitizers (PSs) and light delivery was introduced recently. The appropriate PSs were developed from the first generation PS Photofrin (QLT) to the second (chlorins or bacteriochlorins derivatives) and third (conjugated PSs on carrier) generations PSs to overcome undesired disadvantages, and to increase selective tumor accumulation and excellent targeting. For the synthesis of new chlorin PSs chlorophyll a is isolated from natural plants or algae, and converted to methyl pheophorbide a (MPa) as an important starting material for further synthesis. MPa has various active functional groups easily modified for the preparation of different kinds of PSs, such as methyl pyropheophorbide a, purpurin-18, purpurinimide, and chlorin e6 derivatives. Combination therapy, such as chemotherapy and photothermal therapy with PDT, is shortly described here. Advanced light delivery system is shown to establish successful clinical applications of PDT. Phtodynamic efficiency of the PSs with light delivery was investigated in vitro and/or in vivo.

Photodynamic Therapy (PDT): PDT Mechanisms

Photodynamic therapy (PDT) is a light based therapy used to ablate tumors. As practiced in oncology a photosensitizing agent is applied and then activated by a specific wavelength and energy of light. This light energy in the presence of oxygen will lead to the creation of the photodynamic reaction which is cyto and vasculo toxic. This paper will review the mechanisms of action of PDT and how they may be manipulated to improve clinical outcome in cancer patients.

Photodynamic Therapy for Barrett's Esophagus and Esophageal Carcinoma

This paper reviews the use of photodynamic therapy (PDT) in patients with Barrett's esophagus and esophageal carcinoma. We describe the history of PDT, mechanics, photosensitizers for PDT in patients with esophageal disease. Finally, we discuss its utility and limitations in this setting.

Current Status of Photodynamic Therapy for Bile Duct Cancer

The most common form in bile duct cancers is a highly desmoplastic cancer with a growth pattern characterized by periductal extension and infiltration. The prognosis of bile duct cancers, especially hilar cholangiocarcinoma, is limited by tumor spread along the biliary tree leading to refractory obstructive cholestasis, cholangitis, and liver failure. Although biliary endoprosthesis improves occlusion rates and reduces the number of therapeutic interventions, median survival time is not ameliorated. Photodynamic therapy (PDT) is a local photochemical tumor treatment that consists of a photosensitizing agent in combination with laser irradiation of a distinct wavelength. Tumor ablation with PDT combined with biliary stenting reduces cholestasis and significantly improves median survival time in selected patients with bile duct cancers.

Photodynamic Therapy in Unresectable Cholangiocarcinoma: Not for the Uncommitted

BACKGROUND/AIMS: Photodynamic therapy (PDT) in unresectable cholangiocarcinoma has been associated with improved survival. We report a single tertiary care center experience over the past 6 years. METHODS: Fifty-five patients with unresectable cholangiocarcinoma received PDT between 2004 and 2010. Plastic stents were placed after PDT to prevent cholangitis. RESULTS: Twenty-seven patients (49%) showed Bismuth type IV, 22 (41%) showed Bismuth type III, and six (10%) showed Bismuth type I and II. Twenty patients (37%) received chemotherapy and radiation therapy, five (9%) received chemotherapy only; and one (2%) received radiation therapy only. Mean number of PDT sessions was 1.9+/-1.5 sessions (range, 1 to 9). Mean survival duration was 293+/-266 days (median, 190; range, 25 to 1,332). PDT related complications included three (5%) facial burn, three (5%) photosensitivity, and two (3%) rash. Kaplan-Meier analysis comparing the survival means of patients who received PDT and chemotherapy/radiation therapy (median survival 257 days; 95% confidence interval [CI], 166 to 528) versus who received PDT only (median survival 183 days; 95% CI, 129 to 224) showed no significant difference (log-rank p=0.20). CONCLUSIONS: PDT has a measurable impact on survival in unresectable cholangiocarcinoma but requires aggressive stenting posttherapy.

Comparison of Very Low Fluence and Low Fluence Photodynamic Therapy in Chronic Central Serous Chorioretinopathy

PURPOSE: To investigate the safe, effective light dose for photodynamic therapy (PDT) in the treatment of chronic central serous chorioretinopathy (CSC). METHODS: Thirty-eight eyes of 37 patients with chronic CSC were recruited for this study. From November 2009 to July 2010 and from April 2011 to February 2012, PDT was performed using 50% and 25% of the full light dose in 27 eyes of 27 patients (group I) and 11 eyes of 10 patients (group II), respectively. The minimum follow-up period was 6 months. Mean change in best corrected visual acuity (BCVA) and central retinal thickness, hyperpermeability change from abnormal choriocapillaris, success rate, recurrence rate, and complications were analyzed. RESULTS: Group I showed that BCVA (log MAR) improved significantly from 0.33 +/- 0.17 to 0.14 +/- 0.15 at 6 months (p < 0.001). However, there was no significant improvement of BCVA (p = 0.050) in group II. One eye out of 27 eyes (3.7%) in group I and 5 eyes out of 11 eyes (45.5%) in group II showed recurrence at the 6-month follow-up (p = 0.016). After initial PDT, hyperpermeability from abnormal choriocapillaris reduced or disappeared at 95.5% in group I and 54.5% in group II at month 3 (p = 0.016). No patient in either group experienced severe adverse events. CONCLUSIONS: PDT performed with 50% of the full light dose appears to be a more useful method in the treatment of chronic CSC, with less frequent recurrence, than PDT using 25% of the full light dose.

Contrasting effects of nitric oxide and corticotropin- releasing factor within the dorsal periaqueductal gray on defensive behavior and nociception in mice

The anxiogenic and antinociceptive effects produced by glutamate N-methyl-D-aspartate receptor activation within the dorsal periaqueductal gray (dPAG) matter have been related to nitric oxide (NO) production, since injection of NO synthase (NOS) inhibitors reverses these effects. dPAG corticotropin-releasing factor receptor (CRFr) activation also induces anxiety-like behavior and antinociception, which, in turn, are selectively blocked by local infusion of the CRF type 1 receptor (CRFr1) antagonist, NBI 27914 [5-chloro-4-(N-(cyclopropyl)methyl-N-propylamino)-2-methyl-6-(2,4,6-trichlorophenyl)aminopyridine]. Here, we determined whether i) the blockade of the dPAG by CRFr1 attenuates the anxiogenic/antinociceptive effects induced by local infusion of the NO donor, NOC-9 [6-(2-hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-hexanamine], and ii) the anxiogenic/antinociceptive effects induced by intra-dPAG CRF are prevented by local infusion of Nω-propyl-L-arginine (NPLA), a neuronal NOS inhibitor, in mice. Male Swiss mice (12 weeks old, 25-35 g, N = 8-14/group) were stereotaxically implanted with a 7-mm cannula aimed at the dPAG. Intra-dPAG NOC-9 (75 nmol) produced defensive-like behavior (jumping and running) and antinociception (assessed by the formalin test). Both effects were reversed by prior local infusion of NBI 27914 (2 nmol). Conversely, intra-dPAG NPLA (0.4 nmol) did not modify the anxiogenic/antinociceptive effects of CRF (150 pmol). These results suggest that CRFr1 plays an important role in the defensive behavior and antinociception produced by NO within the dPAG. In contrast, the anxiogenic and antinociceptive effects produced by intra-dPAG CRF are not related to NO synthesis in this limbic midbrain structure.