RESUMEN
The current systematic review presented and discussed the most recent studies on acute cough in pediatric age. After that, the Italian Society of Pediatric Allergy and Immunology elaborated a comprehensive algorithm to guide the primary care approach to pediatric patients, such as infants, children, and adolescents, with acute cough. An acute cough is usually consequent to upper respiratory tract infections and is self-resolving within a few weeks. However, an acute cough may be bothersome, and therefore remedies are requested, mainly by the parents. An acute cough may significantly affect the quality of life of patients and their family.Several algorithms for the management of acute cough have been adopted and validated in clinical practice; however, unlike the latter, we developed an algorithm focused on pediatric age, and, also, in accordance to the Italian National Health System, which regularly follows the child from birth to all lifelong. Based on our findings, infants from 6 months, children, and adolescents with acute cough without cough pointers can be safely managed using well-known medications, preferably non-sedative agents, such as levodropropizine and/or natural compounds, including honey, glycerol, and herb-derived components.
Asunto(s)
Alergia e Inmunología/normas , Antitusígenos/uso terapéutico , Tos/tratamiento farmacológico , Guías de Práctica Clínica como Asunto , Calidad de Vida , Enfermedad Aguda/terapia , Adolescente , Apiterapia/métodos , Niño , Preescolar , Tos/complicaciones , Tos/diagnóstico , Tos/inmunología , Glicerol/uso terapéutico , Miel , Humanos , Lactante , Italia , Extractos Vegetales/uso terapéutico , Glicoles de Propileno/uso terapéutico , Sociedades Médicas/normas , Espera Vigilante/normasRESUMEN
BACKGROUND: FTY720, a sphingosine-1-phosphate (S1P) receptor agonist, possesses potent anti-inflammation capacity. We evaluated the therapeutic potentials of FTY720 against testicular injury induced by testicular torsion and/or detorsion (T/D). MATERIALS AND METHODS: Young adult male Sprague-Dawley rats were allocated to receive T/D (the T/D group) and T/D plus FTY720 (4 mg/kg, the T/D-FTY group, n = 6 in each group). To investigate the possible roles of the S1P receptors, another group of rats received T/D plus FTY720 plus the potent S1P receptor antagonist VPC23019 (1 mg/kg, the T/D-FTY-VPC group, n = 6). FTY720 was administered immediately before testicular detorsion, and VPC23019 was administered 30 min before FTY720. Another set of rats that received sham operation, immediately followed by injection of normal saline, FTY720, or FTY720 plus VPC23019, served as control groups. Sham control groups were run simultaneously. After euthanization, levels of testicular injury were measured. RESULTS: Histologic findings revealed severe testicular injury changes in both the T/D and T/D-FTY-VPC groups and moderate testicular injury changes in the T/D-FTY group. In addition, malondialdehyde activity (oxidative status), concentration of interleukin-1ß (inflammation index), myeloperoxidase activity (neutrophil infiltration index), and wet-to-dry weight ratio (tissue edema index) of both the T/D and T/D-FTY-VPC groups were significantly higher than those of the T/D-FTY group. These data confirmed the protective effects of FTY720 against testicular T/D. Moreover, antagonizing the S1P receptors could reverse the protective effects of FTY720. CONCLUSIONS: FTY720 significantly mitigated testicular injury induced by testicular T/D. The mechanisms may involve activating the S1P receptors.
Asunto(s)
Inmunosupresores/uso terapéutico , Glicoles de Propileno/uso terapéutico , Torsión del Cordón Espermático/tratamiento farmacológico , Esfingosina/análogos & derivados , Testículo/lesiones , Animales , Evaluación Preclínica de Medicamentos , Edema/tratamiento farmacológico , Clorhidrato de Fingolimod , Inmunosupresores/metabolismo , Inmunosupresores/farmacología , Inflamación/tratamiento farmacológico , Metabolismo de los Lípidos/efectos de los fármacos , Masculino , Infiltración Neutrófila/efectos de los fármacos , Glicoles de Propileno/metabolismo , Glicoles de Propileno/farmacología , Distribución Aleatoria , Ratas Sprague-Dawley , Esfingosina/metabolismo , Esfingosina/farmacología , Esfingosina/uso terapéutico , Testículo/efectos de los fármacos , Testículo/metabolismoRESUMEN
Sphingosine 1-phosphate (S1P), the natural sphingolipid ligand for a family of five G protein- coupled receptors (S1P1-S1P5Rs), regulates cell survival and lymphocyte circulation. We have shown that the pan-S1PR agonist, FTY720, attenuates kidney ischemia-reperfusion injury by directly activating S1P1 on proximal tubule (PT) cells, independent of the canonical lymphopenic effects of S1P1 activation on B and T cells. FTY720 also reduces cisplatin-induced AKI. Therefore, in this study, we used conditional PT-S1P1-null (PepckCreS1pr1(fl/fl)) and control (PepckCreS1pr1(w/wt)) mice to determine whether the protective effect of FTY720 in AKI is mediated by PT-S1P1. Cisplatin induced more renal injury in PT-S1P1-null mice than in controls. Although FTY720 produced lymphopenia in both control and PT-S1P1-null mice, it reduced injury only in control mice. Furthermore, the increase in proinflammatory cytokine (CXCL1, MCP-1, TNF-α, and IL-6) expression and infiltration of neutrophils and macrophages induced by cisplatin treatment was attenuated by FTY720 in control mice but not in PT-S1P1-null mice. Similarly, S1P1 deletion rendered cultured PT cells more susceptible to cisplatin-induced injury, whereas S1P1 overexpression protected PT cells from injury and preserved mitochondrial function. We conclude that S1P1 may have an important role in stabilizing mitochondrial function and that FTY720 administration represents a novel strategy in the prevention of cisplatin-induced AKI.
Asunto(s)
Lesión Renal Aguda/prevención & control , Túbulos Renales Proximales/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Glicoles de Propileno/uso terapéutico , Receptores de Lisoesfingolípidos/agonistas , Esfingosina/análogos & derivados , Lesión Renal Aguda/inducido químicamente , Animales , Apoptosis/efectos de los fármacos , Respiración de la Célula , Cisplatino , Evaluación Preclínica de Medicamentos , Células Epiteliales/efectos de los fármacos , Clorhidrato de Fingolimod , Masculino , Ratones Endogámicos C57BL , Dinámicas Mitocondriales , Glicoles de Propileno/farmacología , Receptores de Lisoesfingolípidos/metabolismo , Esfingosina/farmacología , Esfingosina/uso terapéuticoRESUMEN
BACKGROUND: Impairment of coronary flow reserve (CFR) has been generally demonstrated in diabetic patients and animals with microvascular complications but without obvious obstructive coronary atherosclerosis. There have been few studies investigating CFR in cases of relatively well-controlled therapy. The purpose of this study is to evaluate the effect of treatment with a Sphingosine-1-phosphate (S1P) receptor potent agonist, FTY720, on early diabetic rats in terms of CFR. METHODSâANDâRESULTS: Male Sprague-Dawley (SD) rats were divided into 3 groups: (1) streptozotocin-uninjected rats (control rats); (2) streptozotocin-injected hyperglycemic rats (diabetic group); and (3) FTY720-fed and streptozotocin-injected hyperglycemic rats. FTY720 (1.25 mg/kg per day orally) was administrated for 9 weeks in SD rats (from 6 weeks old to 15 weeks old). CFR was evaluated by (13)NH3-positron emission tomography. No obvious pathological changes of macrovascular atherosclerosis were observed in each group. Diabetic rats had impaired CFR compared with the control group (1.39±0.26 vs. 1.94±0.24, P<0.05). Treatment with FTY720 for 9 weeks attenuated the heart histological changes and improved CFR in 32% of diabetic rats (1.84±0.36 vs. 1.39±0.26, P<0.05). CONCLUSIONS: In summary, long-term therapy with the Sphingosine-1-phosphate receptor agonist, FTY720, improved CFR by attenuating the heart histological changes, and it might have a beneficial effect on coronary microvascular function in diabetic rats.
Asunto(s)
Circulación Coronaria/efectos de los fármacos , Enfermedad Coronaria/tratamiento farmacológico , Diabetes Mellitus Experimental/fisiopatología , Angiopatías Diabéticas/tratamiento farmacológico , Glicoles de Propileno/uso terapéutico , Receptores de Lisoesfingolípidos/agonistas , Esfingosina/análogos & derivados , Amoníaco , Animales , Glucemia/análisis , Capilares/patología , Moléculas de Adhesión Celular/biosíntesis , Moléculas de Adhesión Celular/genética , Colágeno/biosíntesis , Colágeno/genética , Enfermedad Coronaria/diagnóstico por imagen , Enfermedad Coronaria/fisiopatología , Angiopatías Diabéticas/diagnóstico por imagen , Angiopatías Diabéticas/fisiopatología , Evaluación Preclínica de Medicamentos , Clorhidrato de Fingolimod , Regulación de la Expresión Génica/efectos de los fármacos , Interleucina-6/biosíntesis , Interleucina-6/genética , Lisofosfolípidos , Masculino , Microcirculación/efectos de los fármacos , Miocardio/química , Miocardio/patología , Radioisótopos de Nitrógeno , Tomografía de Emisión de Positrones/métodos , Glicoles de Propileno/farmacología , Ratas , Ratas Sprague-Dawley , Esfingosina/farmacología , Esfingosina/uso terapéutico , Factor de Crecimiento Transformador beta/biosíntesis , Factor de Crecimiento Transformador beta/genéticaRESUMEN
BACKGROUND: Trauma/hemorrhagic shock (T/HS) is one of the major consequences of battlefield injury as well as civilian trauma. FTY720 (sphingosine-1-phosphate agonist) has the capability to decrease the activity of the innate and adaptive immune systems and, at the same time, maintain endothelial cell barrier function and vascular homeostasis during stress. For this reason, we hypothesize that FTY720, as part of resuscitation therapy, would limit T/HS-induced multiple organ dysfunction syndrome in a rodent T/HS model. METHODS: Rats subjected to trauma/sham shock (T/SS) or T/HS (30 mm Hg × 90 min) were administered FTY720 (1 mg/kg) post-T/HS during volume resuscitation. Lung injury (permeability to Evans blue dye), polymorphonuclear leukocyte (PMN) priming (respiratory burst activity), and red blood cell (RBC) rigidity were measured. In addition, lymph duct-cannulated rats were used to quantify the effect of FTY720 on gut injury (permeability and morphology) and the biologic activity of T/HS versus T/SS lymph on PMN-RBC and RBC deformability. RESULTS: Trauma/hemorrhagic shock-induced increased lung permeability, PMN priming, and RBC rigidity were all abrogated by FTY720. The systemic protective effect of FTY720 was only partially at the gut level, because FTY720 did not prevent T/HS-induced gut injury (morphology or permeability); however, it did abrogate T/HS lymph-induced increased respiratory burst and RBC rigidity. CONCLUSIONS: FTY720 limited T/HS-induced multiple organ dysfunction syndrome (lung injury, red cell injury, and neutrophil priming) as well as T/HS lymph bioactivity, although it did not limit gut injury.
Asunto(s)
Inmunosupresores/uso terapéutico , Insuficiencia Multiorgánica/prevención & control , Glicoles de Propileno/uso terapéutico , Choque Hemorrágico/tratamiento farmacológico , Esfingosina/análogos & derivados , Lesión Pulmonar Aguda/etiología , Lesión Pulmonar Aguda/prevención & control , Animales , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Deformación Eritrocítica/efectos de los fármacos , Deformación Eritrocítica/fisiología , Clorhidrato de Fingolimod , Inmunosupresores/administración & dosificación , Masculino , Insuficiencia Multiorgánica/sangre , Insuficiencia Multiorgánica/etiología , Activación Neutrófila/efectos de los fármacos , Glicoles de Propileno/administración & dosificación , Ratas Sprague-Dawley , Estallido Respiratorio/efectos de los fármacos , Choque Hemorrágico/sangre , Choque Hemorrágico/complicaciones , Esfingosina/administración & dosificación , Esfingosina/uso terapéuticoAsunto(s)
Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Medicina Tradicional , Farmacología/tendencias , Preparaciones de Plantas/química , Preparaciones de Plantas/farmacología , Plantas Medicinales , Animales , Curcumina/farmacología , Curcumina/uso terapéutico , Diosgenina/farmacología , Diosgenina/uso terapéutico , Descubrimiento de Drogas , Medicamentos Herbarios Chinos/uso terapéutico , Clorhidrato de Fingolimod , Ácido Glicirrínico/farmacología , Ácido Glicirrínico/uso terapéutico , Humanos , Terapia Molecular Dirigida , Farmacología/métodos , Fitoterapia , Preparaciones de Plantas/uso terapéutico , Glicoles de Propileno/farmacología , Glicoles de Propileno/uso terapéutico , Esfingosina/análogos & derivados , Esfingosina/farmacología , Esfingosina/uso terapéuticoRESUMEN
BACKGROUND: Increased vascular leakage leading to hypovolaemia and tissue oedema is common in severe sepsis. Hypovolaemia together with oedema formation may contribute to hypoxia and result in multiorgan failure and death. To improve treatment during sepsis, a potential therapeutic target may be to reduce the vascular leakage. Substances affecting the endothelial barrier are interesting in this respect, as it is suggested that increase in vascular leakage depends on reorganisation of the endothelial cells and breakdown of the endothelial barrier. The agonist of the bioactive lipid sphingosine-1-phosphate, FTY720, has been shown to modulate the integrity of the endothelium and reduce permeability both in vitro and in vivo. The aim of the present study was to determine if FTY720 could reduce the loss of plasma volume during experimental sepsis in rats. METHODS: Sepsis was induced by ligation and incision of the caecum in the rat. Plasma volume was determined before and 4.5 h after induction of sepsis by a dilution technique using (125) I-labelled albumin. RESULTS: FTY720 in a dose of 0.2 mg/kg reduced the loss of plasma during sepsis by approximately 30% compared with vehicle, without any adverse effects on haemodynamic and physiological parameters. The increase in hematocrit and haemoglobin concentration was also found to be higher in the vehicle group. CONCLUSION: FTY720 in a dose without haemodynamic side effects reduces loss of plasma volume during experimental sepsis most likely because of reduction in permeability and may therefore be beneficial in sepsis.
Asunto(s)
Lisofosfolípidos/agonistas , Volumen Plasmático/efectos de los fármacos , Glicoles de Propileno/uso terapéutico , Sepsis/fisiopatología , Esfingosina/análogos & derivados , Animales , Síndrome de Fuga Capilar/tratamiento farmacológico , Síndrome de Fuga Capilar/etiología , Permeabilidad Capilar/efectos de los fármacos , Ciego/lesiones , Modelos Animales de Enfermedad , Diuresis/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Edema/etiología , Edema/prevención & control , Endotelio Vascular/efectos de los fármacos , Clorhidrato de Fingolimod , Hematócrito , Hemodinámica/efectos de los fármacos , Hemoglobinas/análisis , Perforación Intestinal/complicaciones , Masculino , Glicoles de Propileno/farmacología , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Sepsis/sangre , Sepsis/etiología , Esfingosina/agonistas , Esfingosina/farmacología , Esfingosina/uso terapéuticoRESUMEN
BACKGROUND: Multiple sclerosis patients who discontinue using natalizumab are at risk of a rebound in disease activity. However, the optimal alternative therapy is not currently known. AIMS OF THE STUDY: We report on clinical and MRI data and patient safety in a group of relapsing-remitting multiple sclerosis patients who tested seropositive for the JC virus and who have switched from natalizumab to fingolimod because of concerns regarding PML risks. METHODS: The test for JC virus antibodies was performed in 18 relapsing-remitting multiple sclerosis patients who were being treated with natalizumab for more than 1 year. Eight seropositive patients switched to fingolimod while the seronegative patients continued with natalizumab. RESULTS: After switching to fingolimod, five of eight patients (63%) experienced clinical relapses, and MRI activity was detected in six of eight patients (75%). Neither clinical relapses nor MRI activity was observed in the patients who continued with natalizumab. No serious adverse effects were detected. CONCLUSIONS: Natalizumab is an effective treatment for relapsing-remitting multiple sclerosis, but its discontinuation continues to be a complex problem. All of the therapies tried thus far, including fingolimod, have been unable to control the reactivation of the disease. Further studies addressing alternative therapies after natalizumab discontinuation are necessary.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Sustitución de Medicamentos , Inmunosupresores/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Glicoles de Propileno/uso terapéutico , Esfingosina/análogos & derivados , Adulto , Femenino , Clorhidrato de Fingolimod , Humanos , Interferón beta/inmunología , Virus JC/inmunología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Natalizumab , Observación , Esfingosina/uso terapéutico , Resultado del Tratamiento , Adulto JovenRESUMEN
T-lymphocytes promote cerebral inflammation, thus aggravating neuronal injury after stroke. Fingolimod, a sphingosine 1-phosphate receptor analog, prevents the egress of lymphocytes from primary and secondary lymphoid organs. Based on these findings, we hypothesized fingolimod treatment would reduce the number of T-lymphocytes migrating into the brain, thereby ameliorating cerebral inflammation following experimental intracerebral hemorrhage (ICH). We investigated the effects of fingolimod in two well-established murine models of ICH, implementing intrastriatal infusions of either bacterial collagenase (cICH) or autologous blood (bICH). Furthermore, we tested the long term neurological improvements by Fingolimod in a collagenase-induced rat model of ICH. Fingolimod, in contrast to vehicle administration alone, improved neurological functions and reduced brain edema at 24 and 72 h following experimental ICH in CD-1 mice (n=103; p<0.05). Significantly fewer lymphocytes were found in blood and brain samples of treated animals when compared to the vehicle group (p<0.05). Moreover, fingolimod treatment significantly reduced the expression of intercellular adhesion molecule-1 (ICAM-1), interferon-γ (INF-γ), and interleukin-17 (IL-17) in the mouse brain at 72 h post-cICH (p<0.05 compared to vehicle). Long-term neurocognitive performance and histopathological analysis were evaluated in Sprague-Dawley rats between 8 and 10 weeks post-cICH (n=28). Treated rats showed reduced spatial and motor learning deficits, along with significantly reduced brain atrophy and neuronal cell loss within the basal ganglia (p<0.05 compared to vehicle). We conclude that fingolimod treatment ameliorated cerebral inflammation, at least to some extent, by reducing the availability and subsequent brain infiltration of T-lymphocytes, which improved the short and long-term sequelae after experimental ICH in rodents.
Asunto(s)
Corteza Cerebral/patología , Hemorragia Cerebral/tratamiento farmacológico , Hemorragia Cerebral/patología , Inmunosupresores/uso terapéutico , Linfocitos/efectos de los fármacos , Glicoles de Propileno/uso terapéutico , Esfingosina/análogos & derivados , Análisis de Varianza , Animales , Ganglios Basales/patología , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Transfusión de Sangre Autóloga/efectos adversos , Edema Encefálico/etiología , Edema Encefálico/prevención & control , Complejo CD3/metabolismo , Recuento de Células , Hemorragia Cerebral/inducido químicamente , Hemorragia Cerebral/complicaciones , Hemorragia Cerebral/etiología , Hemorragia Cerebral/inmunología , Colagenasas/toxicidad , Modelos Animales de Enfermedad , Clorhidrato de Fingolimod , Miembro Anterior/fisiopatología , Lateralidad Funcional/efectos de los fármacos , Molécula 1 de Adhesión Intercelular/metabolismo , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Leucocitos/efectos de los fármacos , Linfocitos/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/prevención & control , Glicoles de Propileno/farmacología , Trastornos Psicomotores/tratamiento farmacológico , Trastornos Psicomotores/etiología , Ratas , Ratas Sprague-Dawley , Percepción Espacial/efectos de los fármacos , Esfingosina/farmacología , Esfingosina/uso terapéutico , Factores de TiempoRESUMEN
The therapeutic efficacy of the novel immunomodulator FTY720 (Fingolimod), alone and in combination with betamethasone ointment, was examined in the NC/Nga mouse model of spontaneous steroid-resistant dermatitis. Male NC/Nga mice which had developed severe dermatitis were divided into six groups: 1) a biweekly betamethasone group (betamethasone ointment, twice a week), 2) a daily betamethasone group (betamethasone ointment, six times a week), 3) an FTY720 group (FTY720, orally, three times a week), 4) a biweekly combination group (oral FTY720 plus betamethasone ointment, twice a week), 5) a daily combination group (oral FTY720 plus betamethasone ointment, six times a week) and 6) a placebo group (vehicle alone). The therapeutic efficacy was evaluated in terms of severity of dermatitis, epidermal hypertrophy, accumulation and degranulation of mast cells and infiltrated CD3+ T cells into the dermis after 4 weeks of treatment. Biweekly and daily betamethasone treatments had little effect, confirming that the dermatitis was steroid-resistant. In the FTY720 and biweekly combination groups, the dermatitis showed no marked improvement. In the daily combination group, the dermatitis was significantly (p<0.05, Mann-Whitney U-test) improved as compared with the FTY720 group, biweekly and daily betamethasone groups and placebo group. Further, epidermal hypertrophy and accumulation of mast cells were suppressed. Therefore, combination therapy with FTY720 and daily betamethasone ointment is a promising candidate for treatment of steroid-resistant atopic dermatitis.
Asunto(s)
Betametasona/uso terapéutico , Dermatitis/tratamiento farmacológico , Resistencia a Medicamentos/efectos de los fármacos , Epidermis/efectos de los fármacos , Glucocorticoides/uso terapéutico , Factores Inmunológicos/uso terapéutico , Glicoles de Propileno/uso terapéutico , Esfingosina/análogos & derivados , Animales , Ascomicetos/química , Betametasona/administración & dosificación , Betametasona/farmacología , Productos Biológicos/administración & dosificación , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Dermatitis/inmunología , Dermatitis/patología , Epidermis/inmunología , Epidermis/patología , Clorhidrato de Fingolimod , Glucocorticoides/administración & dosificación , Glucocorticoides/farmacología , Hipertrofia/tratamiento farmacológico , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/farmacología , Masculino , Mastocitos/metabolismo , Ratones , Ratones Endogámicos , Fitoterapia , Glicoles de Propileno/administración & dosificación , Glicoles de Propileno/farmacología , Esfingosina/administración & dosificación , Esfingosina/farmacología , Esfingosina/uso terapéutico , Esteroides , Resultado del TratamientoRESUMEN
INTRODUCTION: Fingolimod has recently been approved for the therapy of relapsing multiple sclerosis. This drug binds to different sphingosine-1-phosphate receptors. AIM: To analyze basic mechanisms of action that can account for the efficacy of this drug in multiple sclerosis. DEVELOPMENT: Fingolimod acts as an inverse agonist on sphingosine-1-phosphate receptors, inducing degradation of receptors. On lymphoid circulation, this effect causes retention in lymph nodes of naive and central memory T cells, including Th17 T lymphocytes, bearing CCR7 and CD62L receptors. As a result, the level of circulating T cells is markedly decreased. B ell circulation is impaired and complex effects on other immune cells are also induced. Fingolimod enters the central nervous system and binds to receptors on glial cells and neurons. In experimental autoimmune encephalomyelitis, the therapeutic efficacy of fingolimod is not only associated with a reduced entry of inflammatory cells into the nervous system, but also with a direct effect mostly on astroglial cells. CONCLUSIONS: In multiple sclerosis patients, the available evidence indicates that fingolimod efficacy is directly associated with impairment of circulation of several T cell subsets and possibly B cells. Animal studies raise the possibility that an additional effect on glial cells might also contribute to the clinical efficacy.
Asunto(s)
Linfocitos B/efectos de los fármacos , Inmunosupresores/farmacología , Esclerosis Múltiple/tratamiento farmacológico , Glicoles de Propileno/farmacología , Receptores de Lisoesfingolípidos/agonistas , Esfingosina/análogos & derivados , Células Th17/efectos de los fármacos , Animales , Atrofia , Linfocitos B/inmunología , Encéfalo/inmunología , Encéfalo/patología , Movimiento Celular , Evaluación Preclínica de Medicamentos , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Clorhidrato de Fingolimod , Humanos , Inmunosupresores/química , Inmunosupresores/uso terapéutico , Selectina L/análisis , Lisofosfolípidos/fisiología , Ratones , Estructura Molecular , Esclerosis Múltiple/inmunología , Neuroglía/efectos de los fármacos , Neuroglía/inmunología , Glicoles de Propileno/química , Glicoles de Propileno/uso terapéutico , Ratas , Receptores CCR7/análisis , Esfingosina/química , Esfingosina/farmacología , Esfingosina/fisiología , Esfingosina/uso terapéutico , Subgrupos de Linfocitos T/inmunología , Células Th17/inmunologíaRESUMEN
Spinal cord injury (SCI) is an incapacitating injury that can result in limited functional recovery. We have previously shown increases in the lysophospholipid mediator, sphingosine-1-phosphate (S1P), in the spinal cord after contusion injury. To apply S1P receptor modulation to the treatment of SCI, we examined the therapeutic effects of FTY720, an S1P receptor agonist, on locomotor recovery after SCI in mice. Oral administration of FTY720 shortly after contusion SCI significantly improved motor function recovery, as assessed by both Basso Mouse Scale scores and Rotarod Performance test results. FTY720 induced lymphopenia and reduced T-cell infiltration in the spinal cord after SCI but did not affect the early infiltration of neutrophils and the activation of microglia. In addition, plasma levels and mRNA expression of inflammatory cytokines in the spinal cord after SCI were not attenuated by FTY720. Vascular permeability and astrocyte accumulation were both decreased by FTY720 in the injured spinal cord. The therapeutic effects of FTY720 were not solely dependent on immune modulation, as confirmed by the demonstration that FTY720 also ameliorated motor function after SCI in mice with severe combined immunodeficiency. Finally, the S1P(1) receptor agonist, SEW2871, partly mimicked the therapeutic effect of FTY720. Our data highlight the importance of immune-independent functions of FTY720 in decreasing vascular permeability and astrogliosis in the injured spinal cord and promoting locomotor function recovery after SCI.
Asunto(s)
Glicoles de Propileno/uso terapéutico , Esfingosina/análogos & derivados , Traumatismos de la Médula Espinal/tratamiento farmacológico , Animales , Astrocitos/efectos de los fármacos , Permeabilidad Capilar/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Citocinas/biosíntesis , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Femenino , Clorhidrato de Fingolimod , Inmunosupresores/administración & dosificación , Inmunosupresores/uso terapéutico , Inflamación/tratamiento farmacológico , Inflamación/etiología , Mediadores de Inflamación/metabolismo , Locomoción/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones SCID , Microglía/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Glicoles de Propileno/administración & dosificación , Receptores de Lisoesfingolípidos/agonistas , Recuperación de la Función/efectos de los fármacos , Esfingosina/administración & dosificación , Esfingosina/uso terapéutico , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/inmunología , Traumatismos de la Médula Espinal/fisiopatología , Linfocitos T/efectos de los fármacos , Resultado del TratamientoRESUMEN
A novel PCD/CUR self-assembly approach for improved curcumin delivery to prostate cancer cells is described. The formation of PCD/CUR was confirmed using FTIR, DSC, TGA, and SEM/TEM, and their stability and solubility under physiological conditions was demonstrated. A mechanism for self-assembly is proposed. Intracellular uptake of the self-assemblies was studied by flow cytometry and immunofluorescence microscopy. The therapeutic efficacy was determined by cell proliferation and colony formation assays using C4-2, DU145 and PC3 prostate cancer cells. The results suggest that the PCD/CUR formulation could be a useful system for improving curcumin delivery and its therapeutic efficacy in prostate cancer.
Asunto(s)
Antineoplásicos , Curcumina , Neoplasias de la Próstata/tratamiento farmacológico , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Curcumina/administración & dosificación , Curcumina/química , Curcumina/uso terapéutico , Sistemas de Liberación de Medicamentos , Humanos , Masculino , Modelos Moleculares , Glicoles de Propileno/administración & dosificación , Glicoles de Propileno/química , Glicoles de Propileno/uso terapéutico , beta-Ciclodextrinas/administración & dosificación , beta-Ciclodextrinas/química , beta-Ciclodextrinas/uso terapéuticoRESUMEN
The prevention of diabetes by the immunomodulatory agent FTY720 (fingolimod) was studied in the LEW.1AR1-iddm (IDDM) rat, an animal model of human type 1 diabetes. Immune cell subtypes and cytokine profiles in pancreatic islets, secondary lymphoid tissue, and serum were analyzed for signs of immune cell activation. Animals were treated with FTY720 (1 mg/kg body weight) for 40 d starting on d 50 of life. Changes in gene and protein expression of cytokines, CD8 markers, monocyte chemoattractant protein-1, inducible NO synthase, and caspase 3 were evaluated. Treatment with FTY720 prevented diabetes manifestation and islet infiltration around d 60 of life, the usual time of spontaneous diabetes development. On d 120, 30 d after the end of FTY720 therapy, diabetes prevention persisted. However, six of 12 treated animals showed increased gene expression of IL-1beta, TNF-alpha, and CD8 markers in pancreas-draining lymph nodes, indicating immune cell activation. In parallel, serum concentrations of these proinflammatory cytokines were increased. These six animals also showed macrophage infiltration without proinflammatory cytokine expression in a small minority (2-3%) of islets. Interestingly, regulatory T lymphocytes were significantly increased in the efferent vessels of the pancreas-draining lymph nodes only in animals without signs of immune cell activation but not in the rats with immune cell activation. This provides an indication for a lack of protective capacity in the animals with activated immune cells. Thus, FTY720 treatment prevented the manifestation of diabetes by promoting the retention of activated immune cells in the lymph nodes, thereby avoiding islet infiltration and beta-cell destruction by proinflammatory cytokines.
Asunto(s)
Diabetes Mellitus Experimental/inmunología , Diabetes Mellitus Experimental/prevención & control , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/prevención & control , Sistema Inmunológico/efectos de los fármacos , Glicoles de Propileno/uso terapéutico , Esfingosina/análogos & derivados , Animales , Antígenos CD8/metabolismo , Citocinas/genética , Citocinas/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patología , Evaluación Preclínica de Medicamentos , Femenino , Clorhidrato de Fingolimod , Regulación de la Expresión Génica/efectos de los fármacos , Sistema Inmunológico/inmunología , Inmunomodulación , Inmunosupresores/uso terapéutico , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/patología , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/genética , Masculino , Páncreas/efectos de los fármacos , Páncreas/metabolismo , Páncreas/patología , Ratas , Esfingosina/uso terapéuticoRESUMEN
BACKGROUND: This study evaluates the eye drop delivery of genes with cornea-specific promoters, i.e., keratin 12 (K12) and keratocan (Kera3.2) promoters, by non-ionic poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) polymeric micelles (PM) to mouse and rabbit eyes, and investigates the underlying mechanisms. METHODS: Three PM-formulated plasmids (pCMV-Lac Z, pK12-Lac Z and pKera3.2-Lac Z) containing the Lac Z gene for beta-galactosidase (beta-Gal) whose expression was driven by the promoter of either the cytomegalovirus early gene, the keratin 12 gene or the keratocan gene, were characterized by critical micelle concentration (CMC), dynamic light scattering (DLS), and atomic force microscopy (AFM). Transgene expression in ocular tissue after gene delivery was analyzed by 5-bromo-4-chloro-3-indolyl-beta-D-galactoside (X-Gal) color staining, 1,2-dioxetane beta-Gal enzymatic activity measurement, and real-time polymerase chain reaction (PCR) analysis. The delivery mechanisms of plasmid-PM on mouse and rabbit corneas were evaluated by EDTA and RGD (arginine-glycine-aspartic acid) peptide. RESULTS: The sizes of the three plasmid-PM complexes were around 150-200 nm with unimodal distribution. Enhanced stability was found for three plasmid-PM formulations after DNase I treatment. After six doses of eye drop delivery of pK12-Lac Z-PM three times a day, beta-Gal activity was significantly increased in both mouse and rabbit corneas. Stroma-specific Lac Z expression was only found in pKera3.2-Lac Z-PM-treated animals with pretreatment by 5 mM EDTA, an opener of junctions. Lac Z gene expression in both pK12-Lac Z-PM and pKera3.2-Lac Z-PM delivery groups was decreased by RGD peptide pretreatment. CONCLUSIONS: Cornea epithelium- and stroma-specific gene expression could be achieved using cornea-specific promoters of keratin 12 and keratocan genes, and the gene was delivered with PM formulation through non-invasive, eye drop in mice and rabbits. The transfection mechanism of plasmid-PM may involve endocytosis and particle size dependent paracellular transport.
Asunto(s)
Córnea/metabolismo , Sistemas de Liberación de Medicamentos/métodos , Micelas , Nanopartículas/uso terapéutico , Soluciones Oftálmicas/química , Animales , Enfermedades de la Córnea/terapia , Expresión Génica , Vectores Genéticos , Queratina-12/administración & dosificación , Queratina-12/genética , Ratones , Nanopartículas/química , Polietilenglicoles/uso terapéutico , Regiones Promotoras Genéticas , Glicoles de Propileno/uso terapéutico , Proteoglicanos/administración & dosificación , Proteoglicanos/genética , Conejos , TransgenesRESUMEN
PEO-PPO-PEO/PEG shell cross-linked nanocapsules encapsulating an oil phase in their nanoreservoir structure was developed as a target-specific carrier for a water-insoluble drug, paclitaxel. Oil-encapsulating PEO-PPO-PEO/PEG composite nanocapsules were synthesized by dissolving an oil (Lipiodol) and an amine-reactive PEO-PPO-PEO derivative in dichloromethane and subsequently dispersing in an aqueous solution containing amine-functionalized six-arm-branched poly(ethylene glycol) by ultrasonication. The resultant shell cross-linked nanocapsules had a unique core/shell architecture with an average size of 110.7 +/- 9.9 nm at 37 degrees C, as determined by dynamic light scattering and transmission electron microscopy. Paclitaxel could be effectively solubilized in the inner Lipiodol phase surrounded by a cross-linked PEO-PPO-PEO/PEG shell layer. The paclitaxel-loaded nanocapsules were further conjugated with folic acid to achieve folate receptor targeted delivery. Confocal microscopy and flow cytometric analysis revealed that folate-mediated targeting significantly enhanced the cellular uptake and apoptotic effect against folate receptor overexpressing cancer cells. The present study suggested that these novel nanomaterials encapsulating an oil reservoir could be potentially applied for cancer cell targeted delivery of various water-insoluble therapeutic and diagnostic agents.
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Nanocápsulas/química , Paclitaxel/administración & dosificación , Polietilenglicoles/uso terapéutico , Glicoles de Propileno/uso terapéutico , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Apoptosis/efectos de los fármacos , Proteínas Portadoras/metabolismo , Línea Celular Tumoral , Reactivos de Enlaces Cruzados , Receptores de Folato Anclados a GPI , Ácido Fólico/química , Humanos , Aceite Yodado , Aceites , Paclitaxel/farmacocinética , Polietilenglicoles/farmacocinética , Glicoles de Propileno/farmacocinética , Receptores de Superficie Celular/metabolismo , SolubilidadRESUMEN
Renal involvement in systemic lupus erythematosus is a common complication that significantly worsens morbidity and mortality. Although treatment with corticosteroids and cytotoxic drugs may be useful in many cases, morbidity associated with these drugs and the relapsing nature of the disease make it necessary to develop new treatment strategies. Five-month old female NZB/W F1 mice were divided into the following groups: CYP group (n = 10), cyclophosphamide (CYP) 50 mg/kg intraperitoneally every 10 days; RAPA 1 group (n = 10) oral daily sirolimus (SRL), 1 mg/kg; RAPA 12 group (n = 13), oral daily SRL, 12mg/kg; FTY group (n = 10), oral fingolimod (FTY720), 2 mg/kg three times per week. An additional group of 13 non-treated mice were used as a control (control group). Follow-up was performed over four months. Animal survival, body weight, anti-DNA antibodies and proteinuria were determined. Kidneys were processed for conventional histology and immunofluorescence for IgG and complement. Total histological score (HS) was the sum of mesangial expansion, endocapillary proliferation glomerular deposits, extracapillary proliferation, interstitial infiltrates, tubular atrophy and interstitial fibrosis. All treated groups had lower proteinuria at the end of the follow-up with respect to the control group (P < 0.0001). Serum anti-DNA antibodies were appropriately controlled in RAPA 1 and CYP groups, but not in FTY or RAPA 12 groups. SRL and CYP arrested, and perhaps reversed almost all histological lesions. FTY720 ameliorated histological lesions but did not control mesangial expansion or interstitial infiltrates. SRL produces great improvement in murine lupus nephritis, while FTY720 seems a promising alternative if used in appropriate doses.
Asunto(s)
Inmunosupresores/uso terapéutico , Nefritis Lúpica/tratamiento farmacológico , Glicoles de Propileno/uso terapéutico , Sirolimus/uso terapéutico , Esfingosina/análogos & derivados , Administración Oral , Animales , Anticuerpos Antinucleares/sangre , Apoptosis/inmunología , Autoantígenos/inmunología , Movimiento Celular/efectos de los fármacos , Cromatina/inmunología , Complemento C3/análisis , Factor Nefrítico del Complemento 3/análisis , Ciclofosfamida/administración & dosificación , Ciclofosfamida/uso terapéutico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Femenino , Clorhidrato de Fingolimod , Mesangio Glomerular/patología , Inmunoglobulina G/análisis , Inmunosupresores/farmacología , Inyecciones Intraperitoneales , Glomérulos Renales/inmunología , Glomérulos Renales/patología , Nefritis Lúpica/genética , Nefritis Lúpica/inmunología , Nefritis Lúpica/patología , Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos NZB , Nucleosomas/inmunología , Glicoles de Propileno/administración & dosificación , Glicoles de Propileno/farmacología , Proteinuria/etiología , Receptores de Lisoesfingolípidos/efectos de los fármacos , Sirolimus/administración & dosificación , Sirolimus/farmacología , Esfingosina/administración & dosificación , Esfingosina/farmacología , Esfingosina/uso terapéuticoAsunto(s)
Adhesivos , Utilización de Medicamentos/estadística & datos numéricos , Solventes/uso terapéutico , Acetatos/uso terapéutico , Vendajes , Ciclohexenos , Éter/efectos adversos , Éter/uso terapéutico , Incendios/prevención & control , Francia , Hospitales Pediátricos , Hospitales Públicos , Hospitales Urbanos , Humanos , Limoneno , Selección de Paciente , Guías de Práctica Clínica como Asunto , Glicoles de Propileno/uso terapéutico , Factores de Riesgo , Administración de la Seguridad , Soluciones , Solventes/provisión & distribución , Encuestas y Cuestionarios , Terpenos/uso terapéuticoRESUMEN
Mitsubishi Pharma Corp and Novartis AG are developing fingolimod, an orally active immunosuppressant affecting lymphocyte re-circulation, for the potential prevention of transplant rejection and the treatment of autoimmune diseases, including multiple sclerosis. Fingolimodis a synthetic sphingosine analog that becomes phosphorylated in vivo and acts as a sphingosine-1-phosphate receptor agonist.
Asunto(s)
Inmunosupresores/uso terapéutico , Glicoles de Propileno/uso terapéutico , Esfingosina/análogos & derivados , Administración Oral , Animales , Ensayos Clínicos como Asunto , Evaluación Preclínica de Medicamentos/métodos , Clorhidrato de Fingolimod , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/química , Metaanálisis como Asunto , Glicoles de Propileno/administración & dosificación , Glicoles de Propileno/química , Esfingosina/administración & dosificación , Esfingosina/química , Esfingosina/uso terapéuticoRESUMEN
BACKGROUND: A novel immunomodulator, KRP-203, the molecular structure of which has some similarity to FTY720, has been developed for use in organ transplantation. The present study was designed to investigate the potency and safety of KRP-203 on allograft survival against both acute and chronic rejection in rat skin and heart transplantation. METHODS AND RESULTS: KRP-203 significantly prolonged skin or heart allograft survival of a minor histocompatibility complex (mHC)-disparate (LEW to F344) rat combination. Histopathological and immunohistochemical analysis at 100 days after mHC-disparate rat heart transplantation revealed that KRP-203 treatment significantly inhibited infiltration of inflammatory cells, including macrophages and T cells; expression of endothelin-1 and transforming growth factor-beta1; and IgG deposition and eventually attenuated neointimal formation and myocardial fibrosis. KRP-203 also prolonged heart allograft survival in a major histocompatibility complex (MHC)-incompatible (DA to LEW) rat combination, but the efficacy was not as significant. However, KRP-203 combined with a subtherapeutic dose of cyclosporin A synergistically prolonged the heart allograft survival. Flow cytometric analysis demonstrated that KRP-203 reduced the number of peripheral blood mononuclear cells (lymphocytes and monocytes) but not granulocytes and enhanced lymphocyte homing into peripheral lymph nodes. The influence of KRP-203 on heart rate changes in Hartley guinea pigs was examined. KRP-203 had less of a tendency to cause bradycardia than FTY720. CONCLUSIONS: These findings demonstrated that KRP-203 prolonged skin and heart allograft survival and significantly attenuated chronic rejection and bradycardia as an adverse effect. Therefore, KRP-203 offers considerable potential as a novel therapeutic immunosuppressant in patients with organ transplantation.