ABSTRACT
BACKGROUND: Skin lesions from patients infected with Leishmania braziliensis has been associated with inflammation induced by cytotoxic CD8+ T cells. In addition, CD8+ T cell-mediated cytotoxicity has not been linked to parasite killing. Meanwhile, the cytotoxic role played by natural killer (NK) cells in cutaneous leishmaniasis (CL) remains poorly understood. METHODS: In this study, we observed higher frequencies of NK cells in the peripheral blood of CL patients compared with healthy subjects, and that NK cells expressed more interferon-γ, tumor necrosis factor (TNF), granzyme B, and perforin than CD8+ T cells. RESULTS: We also found that most of the cytotoxic activity in CL lesions was triggered by NK cells, and that the high levels of granzyme B produced in CL lesions was associated with larger lesion size. Furthermore, an in vitro blockade of granzyme B was observed to decrease TNF production. CONCCLUSIONS: Our data, taken together, suggest an important role by NK cells in inducing inflammation in CL, thereby contributing to disease immunopathology.
Subject(s)
Gene Expression Regulation, Enzymologic/immunology , Granzymes/metabolism , Inflammation/metabolism , Killer Cells, Natural/enzymology , Leishmaniasis, Cutaneous/immunology , Leishmaniasis, Cutaneous/pathology , CD4-Positive T-Lymphocytes , Case-Control Studies , Granzymes/genetics , Humans , Interferon-gamma/genetics , Interferon-gamma/metabolism , NK Cell Lectin-Like Receptor Subfamily K/genetics , NK Cell Lectin-Like Receptor Subfamily K/metabolism , Perforin/genetics , Perforin/metabolism , T-Lymphocytes, Cytotoxic , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Pentoxifylline is a tumor necrosis factor-α (TNF-α) inhibitor that also attenuates the immune response and decreases tissue inflammation. The association of pentoxifylline with antimony improves the cure rate of mucosal and cutaneous leishmaniasis. In this randomized and double blind pilot trial, cure rate was higher, although not significant, in patients who received antimony plus pentoxifylline than in those patients receiving antimony plus placebo. A significant decrease in TNF-α and interferon-γ (IFN-γ) levels during therapy was more pronounced in the antimony plus pentoxifylline group, whereas CCL-3 (Chemokine [C-C motif] ligand 3) decreased similarly in both groups. The increased levels of CXCL-9 (Chemokine [C-X-C motif] ligand 9) during therapy were lower in the antimony plus pentoxifylline group. Therapy with pentoxifylline modifies cytokines and chemokines production, which may be associated with therapeutic outcome.
Subject(s)
Antimony/therapeutic use , Leishmaniasis, Cutaneous/drug therapy , Pentoxifylline/therapeutic use , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adult , Chemokine CCL3/immunology , Chemokine CXCL10/immunology , Chemokine CXCL9/immunology , Double-Blind Method , Drug Therapy, Combination/methods , Female , Humans , Interferon-gamma/immunology , Interleukin-10/immunology , Leishmaniasis, Cutaneous/immunology , Male , Pilot Projects , Treatment Outcome , Tumor Necrosis Factor-alpha/immunology , Young AdultABSTRACT
Amiodarone is a potent antiarrhythmic drug commonly used in the treatment of supraventricular and ventricular arrhythmias. Dronedarone is a recently developed iodine-free compound (Sanofi Recherche), structurally related to amiodarone. Amiodarone and dronedarone have shown similar long-term effects on sinoatrial node automaticity in vivo and in vitro in the rabbit heart. In the present study, we used a microelectrode technique to compare the acute in vitro electrophysiologic effects of amiodarone (100 microM) and dronedarone (100 microM) on the rabbit sinus node. Like amiodarone, dronedarone induces a marked reduction in sinus node automaticity, evidenced by decreases in spontaneous beating rate, action potential amplitude, and slope of phase 4 depolarization. Isoproterenol dose-dependently increases sinus node automaticity in the presence of either amiodarone or dronedarone. The data suggest that dronedarone may be a useful antiarrhythmic alternative to amiodarone in the treatment of supraventricular arrhythmias.
Subject(s)
Action Potentials/drug effects , Amiodarone/analogs & derivatives , Anti-Arrhythmia Agents/pharmacology , Sinoatrial Node/drug effects , Amiodarone/pharmacology , Animals , Dronedarone , Electrophysiology , In Vitro Techniques , Isoproterenol , Male , Microelectrodes , Rabbits , Tachycardia, Supraventricular/drug therapyABSTRACT
Amiodarone (AM) is an antiarrhythmic agent widely used in the treatment of ventricular and supraventricular arrhythmias. Dronedarone (DR) is a new compound with a pharmacological profile similar to that of AM, but iodine free. We previously demonstrated that chronic AM treatment reduces transmural dispersion of repolarization (TDR) in the canine heart. We used standard microelectrode technique to evaluate the effects of acute AM (100 microM) and DR (30 microM) on epicardial (EPI), endocardial (ENDO), and M region tissues obtained from the left ventricular wall of the canine heart. Amiodarone (100 microM, 120 min of exposure) produced little change in the action potential duration of ENDO and EPI tissues, but it shortened the action potential of M cells, especially at slow rates, leading to a decrease in TDR. Similar results were observed with DR. Acute AM (100 microM) and DR (30 microM) eliminated d-sotalol-induced early afterdepolarizations (EADs) and triggered activity in 3 of 3 and 2 of 6 M cell preparations, respectively. The reduction of TDR and the elimination of EAD-induced triggered activity differentiates AM and DR from other class III agents. These effects may explain the efficacy and low arrhythmogenicity of acute AM and suggest a potential safe use of DR as an antiarrhythmic agent.
Subject(s)
Amiodarone/analogs & derivatives , Amiodarone/pharmacology , Anti-Arrhythmia Agents/pharmacology , Endocardium/drug effects , Myocardium/cytology , Pericardium/drug effects , Action Potentials/drug effects , Amiodarone/administration & dosage , Amiodarone/pharmacokinetics , Analysis of Variance , Animals , Anti-Arrhythmia Agents/administration & dosage , Anti-Arrhythmia Agents/pharmacokinetics , Dogs , Dronedarone , Endocardium/physiology , Heart Ventricles/cytology , In Vitro Techniques , Male , Pericardium/physiology , Sotalol/pharmacology , Ventricular Function, Left/drug effectsABSTRACT
La amiodarona es un agente antiarrítmico de gran eficacia en el tratamiento de las arritmias supraventriculares y ventriculares. La dronedarona es un nuevo derivado de la amiodarona libre de yodo con un perfil farmacológico similar. En este estudio se comparan los efectos electrofisiológicos in vitro de la amiodarona y la dronedarona sobre preparados de nódulo sinusal del corazón de conejo. La amiodarona (30 µM) y la dronedarona (10µM) prolongaron la longitud del ciclo espontánea y disminuyeron la amplitud del potencial de acción y la pendiente de la fase 4. En este modelo, la presencia de dronedarona no modificó la intensidad de la respuesta automática ante la exposición a isoproterenol. La dronedarona, como la amiodarona, deprime el automatismo sinusal, debido probablemente a un mecanismo de bloqueo cálcico
Subject(s)
Animals , Rabbits , Amiodarone , Arrhythmias, Cardiac , Heart Rate , Sinoatrial Node , Sinoatrial Node/physiology , Sinoatrial Node/physiopathology , Anti-Arrhythmia Agents/pharmacology , Anti-Arrhythmia Agents/therapeutic use , Depression, Chemical , ElectrophysiologyABSTRACT
La amiodarona y la dronedarona, in vitro, desarrollan efectos electrofisiológicos similares entre sí y con el tratamiento crónico de amiodarona. Disminuyen la dispersión de la refractariedad ventricular, acortando principalmente el potencial de acción de las células M prolongándolo levemente en el endocardio y el epicardio e inhibiendo y revirtiendo el aumento desproporcionado de la duración del potencial de las células M y las posdespolarizaciones precoces inducidas por el d-sotalol. No se observó un efecto depresor de la Vmáx en estas células con ninguna de las dos drogas. La dronedarona parece ser más potente, ya que con concentraciones menores se alcanzaron resultados similares a la amiodarona
Subject(s)
Animals , Dogs , Amiodarone , Arrhythmias, Cardiac , Heart Ventricles , Anti-Arrhythmia Agents/administration & dosage , Anti-Arrhythmia Agents/therapeutic use , Depression, Chemical , ElectrophysiologyABSTRACT
La amiodarona es un agente antiarrítmico de gran eficacia en el tratamiento de las arritmias supraventriculares y ventriculares. La dronedarona es un nuevo derivado de la amiodarona libre de yodo con un perfil farmacológico similar. En este estudio se comparan los efectos electrofisiológicos in vitro de la amiodarona y la dronedarona sobre preparados de nódulo sinusal del corazón de conejo. La amiodarona (30 AM) y la dronedarona (10AM) prolongaron la longitud del ciclo espontánea y disminuyeron la amplitud del potencial de acción y la pendiente de la fase 4. En este modelo, la presencia de dronedarona no modificó la intensidad de la respuesta automática ante la exposición a isoproterenol. La dronedarona, como la amiodarona, deprime el automatismo sinusal, debido probablemente a un mecanismo de bloqueo cálcico (AU)
Subject(s)
Animals , Comparative Study , Rabbits , Sinoatrial Node/drug effects , Sinoatrial Node/physiology , Sinoatrial Node/physiopathology , Heart Rate/drug effects , Amiodarone/therapeutic use , Amiodarone/administration & dosage , Amiodarone/pharmacology , Arrhythmias, Cardiac/therapy , Anti-Arrhythmia Agents/pharmacology , Anti-Arrhythmia Agents/therapeutic use , Electrophysiology , Depression, ChemicalABSTRACT
La amiodarona y la dronedarona, in vitro, desarrollan efectos electrofisiológicos similares entre sí y con el tratamiento crónico de amiodarona. Disminuyen la dispersión de la refractariedad ventricular, acortando principalmente el potencial de acción de las células M prolongándolo levemente en el endocardio y el epicardio e inhibiendo y revirtiendo el aumento desproporcionado de la duración del potencial de las células M y las posdespolarizaciones precoces inducidas por el d-sotalol. No se observó un efecto depresor de la Vmáx en estas células con ninguna de las dos drogas. La dronedarona parece ser más potente, ya que con concentraciones menores se alcanzaron resultados similares a la amiodarona (AU)