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2.
Nature ; 558(7711): 540-546, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29899452

RESUMO

CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.

3.
Hum Gene Ther ; 25(6): 506-16, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24524415

RESUMO

Mucopolysaccharidosis type IIIA is a severe degenerative disease caused by an autosomal recessive defect of a gene encoding a lysosomal heparan-N-sulfamidase, the N-sulfoglycosamine sulfohydrolase (SGSH), the catalytic site of which is activated by a sulfatase-modifying factor (SUMF1). Four children (Patients 1-3, aged between 5.5 and 6 years; Patient 4 aged 2 years 8 months) received intracerebral injections of an adeno-associated viral vector serotype rh.10-SGSH-IRES-SUMF1 vector in a phase I/II clinical trial. All children were able to walk, but their cognitive abilities were abnormal and had declined (Patients 1-3). Patients 1-3 presented with brain atrophy. The therapeutic vector was delivered in a frameless stereotaxic device, at a dose of 7.2×10(11) viral genomes/patient simultaneously via 12 needles as deposits of 60 µl over a period of 2 hr. The vector was delivered bilaterally to the white matter anterior, medial, and posterior to the basal ganglia. Immunosuppressive treatment (mycophenolate mofetil and tacrolimus) was initiated 15 days before surgery and maintained for 8 weeks (mycophenolate mofetil) or throughout follow-up (tacrolimus, with progressive dose reduction) to prevent elimination of transduced cells. Safety data collected from inclusion, during the neurosurgery period and over the year of follow-up, showed good tolerance, absence of adverse events related to the injected product, no increase in the number of infectious events, and no biological sign of toxicity related to immunosuppressive drugs. Efficacy analysis was necessarily preliminary in this phase I/II trial on four children, in the absence of validated surrogate markers. Brain atrophy evaluated by magnetic resonance imaging seemed to be stable in Patients 1 and 3 but tended to increase in Patients 2 and 4. Neuropsychological evaluations suggested a possible although moderate improvement in behavior, attention, and sleep in Patients 1-3. The youngest patient was the most likely to display neurocognitive benefit.


Assuntos
Dependovirus/genética , Terapia Genética , Hidrolases/genética , Mucopolissacaridose III/terapia , Sulfatases/genética , Ventrículos Cerebrais/patologia , Criança , Pré-Escolar , Feminino , Humanos , Injeções Intraventriculares , Masculino , Resultado do Tratamento
4.
Bull Cancer ; 99(6): 643-53, 2012 Jun.
Artigo em Francês | MEDLINE | ID: mdl-22645281

RESUMO

Allogeneic hematopoietic stem-cell transplant (allo-SCT) remains the only cure for many hematological malignancies and some benign and congenital diseases. Busulfan, proposed in its injectable form, has quickly become a mainstay of pharmacological and myeloablative (or non-myeloablative) conditioning. This is following the outbreak in 2010 of a multicenter international clinical phase II trial, we tested the robustness and reliability of our organization in a complex model of organization and multifactorial partnership. In this type "BuCy2" protocol based on a classical treatment duration of 4 consecutive days, the administration of IV busulfan is given in one single daily infusion instead of the conventional 16 infusions, while keeping the same total dose. Under these conditions, the treatment is totally secured using a therapeutic drug monitoring of busulfan, applied in real-time. The process is technically complex and requires the very close cooperation of the teams involved. A strength, weakness, opportunity and threat (SWOT) analysis has been constructed; it fully supports continuous quality improvement to the triple benefit of the nursing chain, the patients and their environment. Several critical points were identified and corrected. The experiment strongly contributes to the safety and security of the medication circuit at the hospital and, improves the performance of allo-SCT. It also contributes to the protection of all actors in the health field and their working environment via a well-functioning quality management system.


Assuntos
Bussulfano/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Relações Interinstitucionais , Agonistas Mieloablativos/administração & dosagem , Condicionamento Pré-Transplante/métodos , Adulto , Bussulfano/imunologia , Ensaios Clínicos Fase II como Assunto , Transplante de Células-Tronco Hematopoéticas/normas , Humanos , Infusões Intravenosas/métodos , Modelos Organizacionais , Estudos Multicêntricos como Assunto , Agonistas Mieloablativos/imunologia , Melhoria de Qualidade , Condicionamento Pré-Transplante/normas , Transplante Homólogo/normas
5.
Eur J Endocrinol ; 166(2): 333-9, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22048969

RESUMO

CONTEXT: Congenital hyperinsulinism (HI) is a common cause of hypoglycemia in infancy. The medical treatment of diazoxide-unresponsive HI is based on a somatostatin analogue. OBJECTIVE: This study aims at replacing three daily s.c. octreotide (Sandostatin, Novartis) injections by a single and monthly i.m. injection of long-acting release (LAR) octreotide (Sandostatin LP, Novartis) in HI patients. SUBJECTS AND METHOD: LAR octreotide was injected every 4 weeks during 6 months and s.c. octreotide injections were stopped after the third injection of LAR octreotide. After this 6-month study, LAR octreotide was continued, with an average follow-up of 17 months. Ten HI pediatric patients unresponsive to diazoxide and currently treated with s.c. octreotide were included in the trial. Glycemias and other parameters (HbA1c, IGF1, height, weight, quality of life (QoL), and satisfaction) were monitored at each monthly visit. RESULTS: For all ten patients, glycemias were maintained in the usual range, HbAlc (mean 5.5%; 95% CI: 4.6-6.2) and IGF1 (mean 89.7 ng/ml; 95% CI: 26-153) were unchanged. Patients gained height significantly (mean 2.7 cm; 95% CI: 1.9-3.4) and no side effect was noted during the study and the later follow-up. Plasma octreotide levels were stable under LAR octreotide. Parents' questionnaires of general satisfaction were highly positive whereas children's QoL evaluation remained unchanged. CONCLUSION: In these diazoxide-unresponsive HI patients, LAR octreotide was efficient, well tolerated and contributed to a clear simplification of the medical care.


Assuntos
Hiperinsulinismo Congênito/tratamento farmacológico , Octreotida/administração & dosagem , Transportadores de Cassetes de Ligação de ATP/genética , Criança , Pré-Escolar , Hiperinsulinismo Congênito/sangue , Hiperinsulinismo Congênito/genética , Hiperinsulinismo Congênito/metabolismo , Preparações de Ação Retardada , Feminino , Seguimentos , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/efeitos adversos , Humanos , Lactente , Injeções Intramusculares/efeitos adversos , Injeções Subcutâneas/efeitos adversos , Masculino , Octreotida/efeitos adversos , Octreotida/sangue , Octreotida/farmacocinética , Canais de Potássio Corretores do Fluxo de Internalização/genética , Receptores de Droga/genética , Receptores Sulfonilureia , Resultado do Tratamento
6.
Pediatr Res ; 70(6): 638-41, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21857385

RESUMO

Glycogen storage disease type III (GSD III) due to debranching enzyme deficiency presenting usually with hepatomegaly and hypoglycemia may be responsible for severe cardiomyopathy which is often fatal. Current treatment of GSD III is based on frequent high-carbohydrate meals that have no effect on the cardiomyopathy. We describe a 2-mo-old infant presenting with a familial form of GSD III complicated with cardiomyopathy. As conventional treatment was unable to improve his sister's cardiomyopathy who was deceased at age 11 mo, we proposed an experimental treatment combining the use of synthetic ketone bodies (D,L-3-OH butyrate) as an alternative energy source, 2:1 ketogenic diet to reduce glucose intake and high-protein diet to enhance gluconeogenesis. Twenty-four months after the onset of this treatment, echocardiography showed an improvement of cardiomyopathy. Growth and liver size remained normal, and no side effects were observed. Blood glucose levels remained within the normal range and insulin levels decreased. These findings show that synthetic ketone bodies as well as low-carbohydrate, high-lipid, and high-protein diet may be a more beneficial therapeutic choice therapeutic choice for GSD III patients with cardiomyopathy. These encouraging data need to be confirmed in more GSD III patients presenting with cardiac or muscular symptoms.


Assuntos
Ácido 3-Hidroxibutírico/farmacologia , Cardiomiopatias/dietoterapia , Cardiomiopatias/tratamento farmacológico , Dieta Cetogênica , Proteínas na Dieta/farmacologia , Doença de Depósito de Glicogênio Tipo III/complicações , Ácido 3-Hidroxibutírico/uso terapêutico , Glicemia/análise , Cardiomiopatias/etiologia , Creatina Quinase/sangue , Humanos , Lactente , Insulina/sangue , Corpos Cetônicos/sangue , Fígado/patologia , Masculino , Resultado do Tratamento , Triglicerídeos/sangue
7.
Antivir Ther ; 10(6): 769-76, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16218177

RESUMO

AIM: To evaluate the benefits of haematopoietic growth factors (HGFs) during the treatment of chronic hepatitis C virus (HCV) infection with severe haematotoxicity. METHODS: This was a 1-year retrospective study of HCV-positive patients receiving pegylated interferon and ribavirin. Patients received different HGFs, depending on certain criteria: they received erythropoietin (EPO) when their haemoglobin (Hb) levels were less than 10 g/dl and granulocyte colony-stimulating factor (G-CSF) when their neutrophil count was less than 750 cells/mm3. Haematological data, adherence and virological response were analysed and compared according to HGF use. RESULTS: In total, 132 patients were studied and 31 (23.5%) required HGF. Under multivariate analysis, baseline Hb levels of less than 13g/dl or a drop in Hb levels of over 2% per week predicted severe anaemia, and a baseline neutrophil count under 2900/mm3 predicted severe neutropaenia. HGF administration restored Hb values and the neutrophil count to above 10 g/dl and 1500 cells/mm3, respectively, in all 31 patients. Adherence to antiviral treatment was achieved in 25% of patients versus 58% of controls without severe haematotoxicity. The primary and sustained virological response did not differ statistically between HGF support and the control group (61% versus 57% and 32% versus 39%, respectively). CONCLUSION: HGF administration counteracts the severe haematological adverse effects which occur during antiviral therapy and maintains the rate of sustained response.


Assuntos
Antivirais/uso terapêutico , Eritropoetina/uso terapêutico , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Hepatite C Crônica/tratamento farmacológico , Interferon-alfa/uso terapêutico , Ribavirina/uso terapêutico , Idoso , Anemia/tratamento farmacológico , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Quimioterapia Combinada , Eritropoetina/administração & dosagem , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Hemoglobinas/metabolismo , Hepacivirus/efeitos dos fármacos , Hepatite C Crônica/virologia , Humanos , Interferon alfa-2 , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Masculino , Pessoa de Meia-Idade , Neutropenia/tratamento farmacológico , Polietilenoglicóis , RNA Viral/sangue , Proteínas Recombinantes , Ribavirina/administração & dosagem , Ribavirina/efeitos adversos , Resultado do Tratamento
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