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Human fibrinogen concentrate (Fibryga) received temporary approval for fibrinogen replacement therapy in France (2017), with subsequent full approval for congenital and acquired hypofibrinogenemia. We evaluated real-world use for on-demand treatment of bleeding and prophylaxis to enhance our knowledge on fibrinogen concentrate as an option for fibrinogen replacement. Data were retrospectively collected from adult and pediatric patients with fibrinogen deficiency. The primary end point was indication for fibrinogen concentrate use; the secondary end point was treatment success for on-demand treatment/perioperative prophylaxis. The study included 150 adult (median age, 62 years; range, 18-94 years) and 50 pediatric (median age, 3 years; range, 0.01-17 years) patients with acquired fibrinogen deficiency. Fibrinogen concentrate was administered to 47.3% for nonsurgical bleeding, 22.7% for surgical bleeding, and 30.0% for perioperative prophylaxis in adult patients, and to 4.0% for surgical bleeding and 96.0% for perioperative prophylaxis in pediatric patients. Cardiac surgeries accounted for 79.5%/75.0% perioperative prophylaxis and 82.4%/100.0% surgical bleeding cases in adult/pediatric patients, respectively. The mean ± standard deviation (SD, median) total fibrinogen doses were 3.06 ± 1.69 g (32.61 mg/kg), 2.09 ± 1.36 g (22.99 mg/kg), and 2.36 ± 1.25 g (29.67 mg/kg) for adult nonsurgical bleeding, surgical bleeding, and perioperative prophylaxis, respectively; doses of 0.75 ± 0.35 g (47.64 mg/kg) and 0.83 ± 0.62 g (55.56 mg/kg) were used for pediatric surgical bleeding and perioperative prophylaxis, respectively. Treatment success was 85.7%/97.1/93.3% in adults and 50.0%/87.5% in pediatrics for nonsurgical bleeding (adults only), surgical bleeding, and perioperative prophylaxis, respectively. Fibrinogen concentrate demonstrated favorable effectiveness and safety across the age groups. This study contributes to evidence supporting fibrinogen concentrate for bleeding control/prevention in real-world clinical practice, particularly for patients with acquired fibrinogen deficiency.
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Reducing fuel consumption and thus CO2 emissions is one of the most urgent tasks of current research in the field of internal combustion engines. Water Injection has proven its benefits to increase power or optimize fuel consumption of passenger cars. This technology enables knock mitigation to either increase the engine power output or raise the compression ratio and efficiency while enabling λ = 1 operation in the complete engine map to meet future emission targets. Current systems have limited container capacity. It is necessary to refill the water tank regularly. This also means that we cannot get the benefits of an engine with a higher compression ratio. For this reason, the self-contained system was investigated. This article is a methodology for finding the right design of a self-contained water injection system, but also a vehicle test that proves the function.
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Gasolina , Emisiones de Vehículos , Automóviles , Gasolina/análisis , Investigación , Emisiones de Vehículos/análisis , AguaRESUMEN
BACKGROUND: The number of heart transplantations (HTs) has decreased in France since 2017 (-5%/year) despite a stable rate of patients referred on the waiting list. Ex vivo heart perfusion (EVHP) is an innovative approach for organ preservation, reducing graft ischaemic time and facilitating continuous organ monitoring before transplantation. AIM: To report our preliminary experience of seven donor hearts preserved with EVHP, including the first heart resuscitated after circulatory-determined death in France. METHODS: Seven hearts were procured from donation after brain death (DBD) for HT or donation after circulatory-determined death (DCD) for research purposes (Protocol PFS20-004, Agence de la Biomédecine, La Plaine Saint-Denis, France). All grafts were preserved using the Organ Care System® (TransMedics Inc., Andover, MA, USA) for normothermic EVHP. Perfusion parameters were adjusted to achieve stable or decreasing arterial lactate trend consistent with suitability for organ transplantation. RESULTS: Indications for EVHP were assessment of a marginal graft in four cases, prolonged preservation in two cases (anticipated duration for retrieval of recipient's heart>3hours) and resuscitation after circulatory-determined death in one case. Median duration of EVHP was 270 (interquartile range 216-343) minutes. five were transplanted, with a median ex situ preservation time (ischaemic time+EVHP time) of 334 (interquartile range 326-444) minutes. The two other grafts were discarded for HT. Three recipients had extracorporeal life support after HT, and presented complete cardiac recovery within a week after HT. One patient died at day 11 because of septic shock. The 3-month survival rate was 75% among recipients. Three months after HT, the left ventricular ejection fraction was>60% in all cases. CONCLUSIONS: EVHP enabled safe prolonged preservation and assessment of marginal grafts. This approach provides an opportunity to expand the donor pool by resuscitating grafts from donors with extended criteria, including controlled DCD.
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Trasplante de Corazón , Trasplante de Corazón/efectos adversos , Humanos , Perfusión , Volumen Sistólico , Donantes de Tejidos , Función Ventricular IzquierdaRESUMEN
AIMS: Although right ventricular (RV) function is an important determinant of morbidity and mortality in patients with pulmonary arterial hypertension (PAH), there is no treatment targeting directly the RV. We evaluate the efficacy of sacubitril/valsartan (LCZ 696) as add-on therapy to bosentan in rats with severe pulmonary hypertension (PH). METHODS AND RESULTS: Combination therapy of LCZ 696 and bosentan has additive vascular protective effects against the pulmonary vascular remodelling and PH in two preclinical models of severe PH. Compared with monotherapy, co-treatment of LCZ 696 (30 or 68 mg/kg/day for 2 weeks, per os) and bosentan (100 mg/kg/day for 2 weeks, per os) started 7 days after monocrotaline (MCT) injection substantially reduces pulmonary pressures, vascular remodelling, and RV hypertrophy and fibrosis in rats. Consistent with these observations, co-treatment of rats with established PH induced by sugen/hypoxia (SuHx) with LCZ 696 (30 mg/kg/day for 3 weeks, per os) and bosentan (100 mg/kg/day for 3 weeks, per os) started 5 weeks after Sugen injection partially attenuate total pulmonary vascular resistance and cardiovascular structures. We also obtained evidence showing that LCZ 696 has anti-proliferative effect on cultured human pulmonary artery smooth muscle cells derived from patients with idiopathic PAH, an effect that is more pronounced in presence of bosentan. Finally, we found that the plasma levels of atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP) are higher in rats co-treated with LCZ 696 (30 mg/kg/day) and bosentan (100 mg/kg/day) than in MCT and SuHx rats treated with vehicle. CONCLUSION: Dual therapy with LCZ 696 plus bosentan proved significantly superior beneficial effect to LCZ 696 or bosentan alone on vascular remodelling and severity of experimental PH.
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Aminobutiratos/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Compuestos de Bifenilo/farmacología , Bosentán/farmacología , Antagonistas de los Receptores de Endotelina/farmacología , Inhibidores de Proteasas/farmacología , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Arteria Pulmonar/efectos de los fármacos , Valsartán/farmacología , Remodelación Vascular/efectos de los fármacos , Animales , Factor Natriurético Atrial/sangre , Proliferación Celular/efectos de los fármacos , Células Cultivadas , GMP Cíclico/sangre , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Combinación de Medicamentos , Quimioterapia Combinada , Hipertensión Pulmonar Primaria Familiar/tratamiento farmacológico , Hipertensión Pulmonar Primaria Familiar/metabolismo , Hipertensión Pulmonar Primaria Familiar/fisiopatología , Humanos , Masculino , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Neprilisina/antagonistas & inhibidores , Hipertensión Arterial Pulmonar/metabolismo , Hipertensión Arterial Pulmonar/fisiopatología , Arteria Pulmonar/metabolismo , Arteria Pulmonar/fisiopatología , Ratas WistarRESUMEN
Functional constipation (FC) is a chronic constipation for which no physiological, anatomical or iatrogenic origin can be evidenced. This condition has a high impact on a patient's quality of life and healthcare costs. Since FC is frequently associated with low physical activity and a diet low in fiber and/or water, first-line recommendations focus on sufficient activity, and sufficient fiber and water intake. In case of inefficacy of these measures, numerous drug treatments are available, either over the counter or on prescription. Magnesium sulfate has a long history in the treatment of FC, and magnesium sulfate-rich mineral waters have been used for centuries for their laxative properties. The laxative effect of magnesium and sulfate has since been widely demonstrated. Nevertheless, it appears that no clinical studies aiming at demonstrating their efficacy in FC had been conducted before the 21st century. In this paper, we reviewed the clinical data reporting the efficacy of magnesium sulfate-rich natural mineral waters. In view of their reported efficacy and safety, magnesium sulfate-rich natural mineral waters may represent a natural treatment for FC.
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Estreñimiento/terapia , Laxativos/administración & dosificación , Sulfato de Magnesio/administración & dosificación , Aguas Minerales/administración & dosificación , Defecación , Fibras de la Dieta/administración & dosificación , Femenino , Humanos , Óxido de Magnesio/administración & dosificación , Masculino , Probióticos/administración & dosificación , Calidad de VidaRESUMEN
OBJECTIVES: First-line recommendations for the management of functional constipation include nutritional-hygienic measures. We previously showed that a natural mineral water rich in sulphates and magnesium (Hépar) is efficient in the treatment of functional constipation. The aim of this study was to consolidate those first results and determine a precise time to respond to Hépar. METHODS: This multicenter, randomized, double-blind, controlled study of the effect of Hépar on stool consistency and frequency in functional constipation included 226 outpatients. After washout, patients used 1.5 L of water daily, including 1 L of Hépar or of low-mineral water, during 14 d. In addition to a daily reporting of stool consistency by the patient, an expert investigator blindly analyzed stool consistency (Bristol stool scale) based on photographs taken by the patient. RESULTS: The primary endpoint was met. Treatment response was more frequent in the Hépar arm than in the control group at day 14 (50% versus 29%, respectively; Pâ¯=â¯0.001). Mean time to treatment response was shorter in the Hépar group (6.4 d) than in the control arm (7.3 d; Pâ¯=â¯0.013). Concomitant stool scoring was available for 60% of the patients. Scores given to 79% of the stools were similar between the patient and the expert (differences ≤1). Safety analyses showed excellent results. CONCLUSION: This study confirms the efficacy and safety of Hépar in the treatment of functional constipation and shows that it is associated with a response within 7 d. Hépar could be a safe response to the current absence of first-line medication in the treatment of functional constipation.
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Estreñimiento/terapia , Magnesio/uso terapéutico , Aguas Minerales/uso terapéutico , Minerales/uso terapéutico , Sulfatos/uso terapéutico , Adulto , Método Doble Ciego , Heces , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Tiempo , Tiempo de Tratamiento , Resultado del TratamientoRESUMEN
PURPOSES: Analyze the relationship and expectations of cancer patients towards the community pharmacist in a pharmaceutical care coordination project. METHODS: In November 2014, a questionnaire was distributed to ambulatory patients of a university hospital specialized in oncology. Thirteen questions explored the consumption habits and the usage of the pharmacy (typology of consumers, use of goods and benefits consumed), and collected their expectations for pharmaceutical benefits in the context of the management of their cancer. RESULTS: One thousand two hundred and seventy two patients were included for a final response rate of 78%. Characteristics of the respondents: 64% were women, 63% lived in Île-de-France and 49% took cancer-related treatments (anticancer drugs, supportive care medications). More than 84% of respondents went to pharmacies at least once a month and 95% reported resorting to a single pharmacy. 36% to be ready to share their hospital discharge report with their pharmacist and 61% to have their hospitalization order sent to their "referral" pharmacy to anticipate treatments. Discussion Community pharmacists were perceived positively by the respondents. Patients were willing to share information and be accompanied by this health professional in their cancer care. Their expectations were first and foremost the management of drug-related iatrogenic effects with a report of adverse effects to the hospital, and validated solutions for their management.
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Actitud , Neoplasias/tratamiento farmacológico , Neoplasias/psicología , Servicios Farmacéuticos/estadística & datos numéricos , Farmacias/estadística & datos numéricos , Farmacéuticos , Relaciones Profesional-Paciente , Adulto , Anciano , Anciano de 80 o más Años , Atención Ambulatoria , Antineoplásicos/efectos adversos , Femenino , Francia , Hospitales Universitarios , Humanos , Masculino , Persona de Mediana Edad , Encuestas y CuestionariosRESUMEN
Background Adverse drug events (ADEs) occur frequently in oncology and justify continuous assessment and monitoring. There are several methods for detecting them, but the trigger tool method seems the most appropriate. Although a generic tool exists, its use for ADEs in oncology has not been convincing. The development of a focused version is therefore necessary. Objective To provide an oncology-focused trigger tool that evaluates the prevalence, harm, and preventability in a standardised method for pragmatic use in ADE surveillance. Setting Hospitals with cancer care in France. Method The tool has been constructed in two steps: (1) constitution of an oncology-centred list of ADEs; 30 pharmacists/practitioners in cancer care from nine hospitals selected a list of ADEs using a method of agreement adapted from the RAND/UCLA Appropriateness Method; and (2) construction of three standardised dimensions for the characterisation of each ADE (including causality, severity, and preventability). Main outcome measure The main outcome measure was validation of the tool, including preventability criteria. Results The tool is composed of a final list of 15 ADEs. For each ADE, a 'reviewer form' has been designed and validated by the panel. It comprises (1) the trigger(s), (2) flowcharts to guide the reviewer, (3) criteria for grading harm, and (4) a standardised assessment of preventability with 6-14 closed sentences for each ADE in terms of therapeutic management and/or prevention of side-effects. Conclusion A complete 'ready-to-use' tool for ADE monitoring in oncology has been developed that allows the assessment of three standardised dimensions.
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Sistemas de Registro de Reacción Adversa a Medicamentos/tendencias , Antineoplásicos/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Farmacéuticos , Servicio de Farmacia en Hospital/tendencias , Médicos , Antineoplásicos/uso terapéutico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Francia/epidemiología , Humanos , Errores de Medicación/prevención & control , Errores de Medicación/tendencias , Neoplasias/tratamiento farmacológico , Neoplasias/epidemiología , Servicio de Farmacia en Hospital/métodos , Encuestas y CuestionariosRESUMEN
In mice, the MPTP-induced striatal dopaminergic denervation is followed by a spontaneous partial DAT recovery and by serotoninergic hyperinnervation. We show that IL-1RI-deficient mice have a higher DAT decrease in the ventromedial striatum after MPTP and a higher basal serotoninergic innervation of the whole striatum. These data point to a possible role of IL-1RI in the early MPTP-induced structural or functional remodeling of the nigrostriatal dopamine system.
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Interleucina-1/fisiología , Intoxicación por MPTP/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Receptores de Interleucina-1/deficiencia , Análisis de Varianza , Animales , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Regulación de la Expresión Génica/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Piperazinas/farmacocinética , Unión Proteica/fisiología , ARN Mensajero/biosíntesis , Receptores de Interleucina-1/fisiología , Receptores Tipo I de Interleucina-1 , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Serotonina/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Factores de Tiempo , Tritio/farmacocinéticaRESUMEN
In young rodents, peripheral injection of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) results in a dopaminergic nigrostriatal denervation (during the first week after injection), followed by a spontaneous dopaminergic reinnervation. Sprouting from residual neurons has been proposed to account for this event. It has been shown that an inflammatory process takes place during striatal dopaminergic denervation but its consequences remain controversial. Some clues notably indicate that interleukin (IL)-1alpha may participate in MPTP-induced inflammation and promote recovery. We therefore studied the immunohistochemical localization of IL-1alpha expression in the striatum and ventral mesencephalon at different times (1, 3, 6, 16, and 30 days) after MPTP injection in mice. IL-1alpha-immunoreactivity (ir) was observed in striatum, substantia nigra pars compacta, and ventral tegmental area. Apart from a few localization in mesencephalic activated microglia, IL-1alpha was almost exclusively found in activated astrocytes. However, in the striatal parenchyma, another component of IL-1alpha-ir colocalized with tyrosine hydroxylase (TH)-ir, a marker for dopaminergic neurons. Moreover, some parenchymal TH-positive axons were also found to express the growth cone-associated protein (GAP)-43, a marker for axonal growth cones. In the striatum, IL-1alpha-ir was also detected in a non-astrocytic perivascular component, with a distribution similar to GAP-43-ir. IL-1alpha could thus directly or indirectly influence striatal reorganization after MPTP.
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Cuerpo Estriado/inmunología , Encefalitis/inmunología , Interleucina-1/metabolismo , Regeneración Nerviosa/inmunología , Plasticidad Neuronal/inmunología , Trastornos Parkinsonianos/inmunología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina/efectos adversos , Animales , Astrocitos/inmunología , Astrocitos/metabolismo , Biomarcadores/metabolismo , Cuerpo Estriado/metabolismo , Cuerpo Estriado/fisiopatología , Modelos Animales de Enfermedad , Dopamina/metabolismo , Encefalitis/metabolismo , Encefalitis/fisiopatología , Proteína GAP-43/metabolismo , Gliosis/inmunología , Gliosis/metabolismo , Gliosis/fisiopatología , Conos de Crecimiento/metabolismo , Conos de Crecimiento/ultraestructura , Inmunohistoquímica , Masculino , Ratones , Ratones Endogámicos C57BL , Trastornos Parkinsonianos/metabolismo , Trastornos Parkinsonianos/fisiopatología , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces dopaminergic neuron death in substantia nigra and dopamine loss in striatum, similar to those observed in Parkinson disease. Given MPTP can also induce alterations in brain cytokines and in peripheral immune parameters, we hypothesize that MPTP can induce an elevation of plasma cytokines. We have previously shown that cytokine production depends on behavioral lateralization in certain conditions. Therefore, we further postulate that the MPTP-induced plasma cytokines are related to behavioral lateralization. To answer these questions, C57BL/6J male mice, selected for paw preference, were injected with 25 mg/kg MPTP ip for five consecutive days and were decapitated at day 1, day 3, or day 14 after the last injection. Striatal DA and DOPAC concentration were measured by HPLC and plasma levels of IL-1beta and IL-6 were quantified by ELISA. The results showed that after MPTP treatment, striatal DA content was dramatically decreased, IL-1beta levels increased on day 3, while IL-6 levels increased on day 14. Interestingly, behavioral lateralization influenced DA/DOPAC ratio as well as plasma IL-1beta and IL-6 levels. In left-pawed mice, MPTP induced a higher decrease of DA/DOPAC ratio than in right-pawed mice. The increase of IL-1beta was observed in left-pawed but not in right-pawed mice. The elevation of IL-6 was higher in right-pawed mice than in left-pawed mice. These results have clearly demonstrated our hypotheses, that MPTP can induce increase of plasma IL-1beta and IL-6 levels in mice, and this effect is shaped by behavioral lateralization.
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Encéfalo/inmunología , Encefalitis/inmunología , Lateralidad Funcional/efectos de los fármacos , Interleucina-1/inmunología , Interleucina-6/inmunología , Trastornos Parkinsonianos/inmunología , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/fisiopatología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cuerpo Estriado/fisiopatología , Modelos Animales de Enfermedad , Dopamina/metabolismo , Encefalitis/inducido químicamente , Encefalitis/fisiopatología , Miembro Anterior/inervación , Miembro Anterior/fisiología , Lateralidad Funcional/fisiología , Interleucina-1/sangre , Interleucina-6/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Movimiento/efectos de los fármacos , Movimiento/fisiología , Trastornos Parkinsonianos/inducido químicamente , Trastornos Parkinsonianos/fisiopatologíaRESUMEN
BACKGROUND: Drug-related iatrogenic effects are common in oncology because chemotherapy is toxic. The evaluation of the application of the guidelines may be a way to understand the occurrence of adverse drug-related event (ADE). There is no specific method for identifying ADEs and measuring harm to patients in oncology. OBJECTIVE: Our objective was to develop and test an Oncology Trigger Tool (OTT) for ADEs and to describe ADE characteristics and incidence. METHODS: A clinical advisory panel identified situations at high risk of ADE occurrence and built 22 triggers with, in each case, an analysis flowchart to confirm or refute occurrence. The OTT was used to review 288 random admissions (Oct. 2010-Sept. 2011) and measure ADE incidence and severity (CTCAE 4.03 - Common Terminology Criteria for Adverse Events). Tool feasibility (time required), inter-rater (IR) reproducibility and positive predictive value (PPV) were measured. RESULTS: Overall, 884 triggers were detected and 122 ADEs, with 42.4 ADEs/100 admissions or 46.0 ADEs/1000 patient-days, and a 31.1% rate of severe ADEs. The most common ADEs were hyperglycaemia (14.5%), unplanned drug-related admission within 30 days (13.7%) and opiate-induced constipation (12.1%). Unplanned drug-related admission was the most serious (82.4% incidence of severe harm). Mean time for OTT implementation was 21.8 min; IR reproducibility was high (κ=0.965 (trigger); κ=0.935 (ADE); κ=0.853 (harm)); PPV 22-trigger version was 20.7%. CONCLUSIONS: ADE analysis flowcharts coupled with standardised grading of harm considerably reduced IR variability, thus providing a robust oncology-focused trigger tool for use in ADE audits and hospital comparisons. The involvement of a clinical advisory panel in tool development should help drive changes for improving practice. Further research on the OTT is warranted.
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Antineoplásicos/efectos adversos , Monitoreo de Drogas/métodos , Prescripciones de Medicamentos/estadística & datos numéricos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/diagnóstico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Enfermedad Iatrogénica/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Adhesión a Directriz/estadística & datos numéricos , Humanos , Incidencia , Lactante , Recién Nacido , Tiempo de Internación/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: The uses of internet-based technologies (e.g. patient portals, websites and applications) by cancer patients could be strong drive for change in cancer care coordination practices. The goal of this study was to assess the current utilisation of internet-based technologies (IBT) among cancer patients, and their willingness to use them for their health, as well as analyse the influence of socio-demographics on both aspects. METHODS: A questionnaire-based survey was conducted in June 2013, over seven non-consecutive days within seven outpatient departments of Gustave Roussy, a comprehensive cancer centre (≈160,000 consultations yearly), located just outside Paris. We computed descriptive statistics and performed correlation analysis to investigate patients' usage and attitudes in correspondence with age, gender, socioeconomic status, social isolation, and place of living. We then conducted multinomial logistic regressions using R. RESULTS: The participation level was 85% (n=1371). The median age was 53.4. 71% used a mobile phone everyday and 93% had access to Internet from home. Age and socioeconomic status were negatively associated with the use of IBT (p<0.001). Regarding patients' expected benefits, a wide majority valued its use in health care, and especially, the possibility to enhance communication with providers. 84% of patients reported feeling comfortable with the use of such technologies but age and socioeconomic status had a significant influence. CONCLUSION: Most patients used IBTs every day. Overall, patients advocated for an extended use of IBT in oncology. Differences in perceived ease of use corresponding to age and socioeconomic status have to be addressed.
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Internet , Neoplasias/terapia , Telemedicina , Actitud , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Clase Social , Encuestas y CuestionariosRESUMEN
Injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice results in a retrograde nigrostriatal dopaminergic pathway denervation and subsequent tissue reorganization. Since the role of inflammatory mediators after MPTP remains unclear, proinflammatory cytokine and matrix metalloproteinase (MMP) expression were evaluated by comparative RT-PCR during denervation and tissue reorganization following a single-dose of MPTP (40 mg/kg, s.c.) in young (8-week-old) mice. The time-course of denervation/reorganization was assessed through [(3)H]GBR-12935 binding on dopamine transporter and tyrosine hydroxylase immunohistochemistry. In the striatum, TNF-alpha, IL-1alpha, IL-1beta, IL-6 and MMP-9 mRNA expression peaked on day 1. In the ventral mesencephalon, cytokines (TNF-alpha, IL-1alpha, IL-1beta) and MMP-9 mRNA expression peaked on day 3. During tissue reorganization (day 6 through 16), the only change observed in the striatum consisted of IL-1alpha mRNA and protein overexpression together with MMP-2 downregulation. Whereas the early expression of proinflammatory cytokines and MMP might participate in the retrograde nigrostriatal denervation, the late component of IL-1alpha expression suggests a possible role for this cytokine in the subsequent striatal reorganization.
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Citocinas/genética , Encefalitis/fisiopatología , Metaloproteinasas de la Matriz/genética , Glicoproteínas de Membrana , Neostriado/fisiopatología , Proteínas del Tejido Nervioso , Vías Nerviosas/fisiopatología , Trastornos Parkinsonianos/fisiopatología , Sustancia Negra/fisiopatología , Animales , Modelos Animales de Enfermedad , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Encefalitis/enzimología , Encefalitis/inmunología , Mediadores de Inflamación/metabolismo , Interleucina-1/genética , Masculino , Proteínas de Transporte de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Neostriado/enzimología , Neostriado/inmunología , Vías Nerviosas/enzimología , Vías Nerviosas/inmunología , Trastornos Parkinsonianos/enzimología , Trastornos Parkinsonianos/inmunología , Piperazinas/farmacología , ARN Mensajero/metabolismo , Tiempo de Reacción/fisiología , Sustancia Negra/enzimología , Sustancia Negra/inmunología , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
IMPORTANCE OF THE FIELD: The oxazaphosphorines (cyclophosphamide, ifosfamide and trofosfamide) are widely used in clinical practice for their antitumor and immunomodulatory activities. However, their use is associated with toxicities. The metabolism of oxazaphosphorines involves cytochrome P450 biotransformations, leading to highly reactive metabolites such as acrolein and chloroacetaldehyde responsible for urotoxicity, neurotoxicity and nephrotoxicity. While the mechanisms behind these toxicities remain under investigation, some advances have been made, as exemplified by the use of mesna to limit acrolein related urotoxicity. AREAS COVERED IN THIS REVIEW: This review highlights potential strategies for limiting side effects commonly associated with the oxazaphosphorine drugs, through pharmacological or medicinal chemistry-based approaches. WHAT THE READER WILL GAIN: The readers will gain a comprehensive review of these approaches to treatment in terms of: i) pharmacology: use of antidotes and modification of metabolism through inhibition/induction of CYP enzymes or use of gene therapy; and ii) medicinal chemistry: the design of new drugs to target cancer cells and avoid CYP biotransformation with pre-activated prodrugs or with side-chain substituted analogues. TAKE HOME MESSAGE: An increased knowledge of oxazaphosphorines' metabolism and toxicity may allow the development of new anticancer drugs combined with drug delivery systems to circumvent drug toxicity, providing increased tumoral specificity and greater anticancer activity.
Asunto(s)
Ciclofosfamida/farmacología , Diseño de Fármacos , Ifosfamida/farmacología , Animales , Antineoplásicos Alquilantes/efectos adversos , Antineoplásicos Alquilantes/metabolismo , Antineoplásicos Alquilantes/farmacología , Ciclofosfamida/efectos adversos , Ciclofosfamida/análogos & derivados , Ciclofosfamida/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Sistemas de Liberación de Medicamentos , Terapia Genética/métodos , Humanos , Ifosfamida/efectos adversos , Ifosfamida/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/fisiopatologíaRESUMEN
PURPOSE: We describe drug-drug interactions (DDIs) encountered with antifungals in clinical practice. METHODS: Retrospective observational study of hospitalized adults receiving systemic antifungal treatment in the intensive care unit (ICU) and in the infectious diseases unit (IDU) of the University Hospital of Bordeaux, France between 1996 and 2001. All treatment episodes with antifungal agent were examined and all prescribed concomitant medication identified for potential drug-drug interactions (PDDI)-serious events occurring during treatment were adjudicated for clinical DDI. RESULTS: There were 150 treatment episodes with antifungal agent in 105 patients. Fluconazole was used in 48% of the treatment episodes, amphotericin B in 46%, itraconazole in 4.7% and flucytosine in 1.3%. One hundred and sixteen PDDIs were identified related to the use of amphotericin B (81.0%), fluconazole (17.2%) or itraconazole (1.7%). Of these, 22 were associated with a clinical evidence of adverse interaction (hypokalemia, increased creatininemia or nephrotoxicity). All these clinical drug-drug interactions (CDDIs) were with amphotericin B. They were due to furosemide (36.4%), cyclosporine (31.8%) and hydrocortisone (18.2%). PDDIs were mostly associated with leukaemia (40.4%), HIV infection (24.6%) and cancer (10.5%). CONCLUSIONS: In ICU and IDU, systemic antifungal treatments lead to many PDDIs, mainly related to the type of antifungal used and to the pathology treated. Clinical DDI seem more common with amphotericin.
Asunto(s)
Anfotericina B/efectos adversos , Antifúngicos/efectos adversos , Fluconazol/efectos adversos , Itraconazol/efectos adversos , Adulto , Anciano , Anfotericina B/farmacología , Antifúngicos/farmacología , Creatinina/sangre , Ciclosporina/efectos adversos , Ciclosporina/farmacología , Interacciones Farmacológicas , Femenino , Fluconazol/farmacología , Francia , Furosemida/efectos adversos , Furosemida/farmacología , Infecciones por VIH/tratamiento farmacológico , Hospitales Universitarios , Humanos , Hidrocortisona/efectos adversos , Hidrocortisona/farmacología , Hipopotasemia/inducido químicamente , Unidades de Cuidados Intensivos , Itraconazol/farmacología , Enfermedades Renales/inducido químicamente , Leucemia/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
The central nervous system can regulate the peripheral immune system. Moreover, differences between left and right hemispheres (neurochemical brain asymmetries) and behavioral lateralization (functional brain asymmetries) affect immune responses. The molecular basis of brain-immune interactions remains insufficiently understood. Cytokines regulate immune responses, possibly through activation of the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis activities are related to behavioral lateralization and brain asymmetry. Given IL-6 plays a role in asymmetrical brain immunomodulation, one might expect the IL-6 distribution in brain to be asymmetrical and to depend on behavioral lateralization. In order to start to test this hypothesis, male C57BL/6J mice were selected for paw preference and assessed for IL-6 levels in right and left cortex and hippocampus by enzyme linked immunosorbent assay. The results showed asymmetrical distribution of brain IL-6 in left-pawed animals and ambidextrous animals, but not in right-pawed animals, both in cortex and hippocampus. Furthermore, we found a correlation between IL-6 hemispheric distribution and the degree of behavioral lateralization both in cortex and hippocampus. Altogether, these results suggest that brain IL-6 could be a mediator of asymmetrical immunomodulation by the central nervous system.
Asunto(s)
Corteza Cerebral/inmunología , Lateralidad Funcional/fisiología , Hipocampo/inmunología , Interleucina-6/metabolismo , Neuroinmunomodulación/inmunología , Animales , Química Encefálica/genética , Química Encefálica/inmunología , Corteza Cerebral/anatomía & histología , Ensayo de Inmunoadsorción Enzimática , Miembro Anterior/inervación , Miembro Anterior/fisiología , Hipocampo/anatomía & histología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
The syntthesis of new N-propargyl-3-pyrrol-1-ylindanamine derivatives, analogues of rasagiline, is described in ten steps starting from the corresponding arylaldehydes via the corresponding cis-3-pyrrol-1-ylindanamines. The cis-configuration of some intermediates has been established using X-ray analysis and NOE experiments. The new N-propargyl-3-pyrrol-1-ylindanamine derivatives were evaluated for their potential MAO-B inhibitor activity in an in vivo model of MPTP-induced Parkinsonism in mice with respect to the potent MAO-B inhibitor rasagiline.