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Tratamento inovador da compressão medular com reposição enzimática intratecal nas mucopolissacaridoses tipos I e VI : relato de uma série de casos / Innovative treatment of cord compression with trathecal enzyme replacement therapy in mucopolysaccharidoses I and VI: report of a case seriesMunõz Rojas, Maria Verônica January 2010 (has links)
As mucopolissacaridoses apresentam uma história natural progressiva, causada por defeitos no metabolismo dos glicosaminoglicanos. Frequentemente graves, as mucopolissacaridoses encurtam de forma considerável a expectativa de vida do paciente. Apesar de que em muitos casos a função intelectual é normal, morbidade neurológica considerável pode ser causada por compressão medular secundária ao acúmulo de glicosaminoglicanos nas meninges. O tratamento deste problema pode requerer a descompressão medular através de laminectomia cervical. A terapia de reposição enzimática endovenosa, para o tratamento de mucopolissacaridose, reduz o acúmulo lisossômico e alivia muitos dos sintomas da doença, porém não oferece benefício direto para o sistema nervoso central uma vez que não atravessa a barreira hemato-encefálica. Esta limitação da reposição enzimática endovenosa levou alguns pesquisadores a trabalhar com uma nova opção de via de liberação medicamentosa de alcance direto no sistema nervoso central, aproveitando o extenso contato que existe entre o líquido cefaloraquidiano e as meninges e com as granulações aracnoideas, para o tratamento de algumas doenças de depósito lisossomal. Estudos em modelos animais têm sido conduzidos e com resultados promissores. Este trabalho se propõe a estudar uma nova via de administração da enzima recombinante, diretamente no espaço liquórico que foi utilizada em dois pacientes com MPS I e em um paciente com MPS VI, com acesso a esta terapêutica através de uso compassivo individual aprovado pelo Comitê de Ética, no Hospital de Clínicas de Porto Alegre. Até então, apenas estudos animais haviam sido realizados abordando esta via de acesso em doenças de depósito lisossomal e estes pacientes foram os primeiros indivíduos com MPS no mundo a receber terapia de reposição intratecal para o tratamento de compressão medular sintomática por depósito de glicosaminoglicanos. Em 2005 um paciente adulto com MPS I apresentando compressão medular foi incluído em um protocolo de terapia de reposição enzimática intratecal por uso compassivo no Hospital de Clínicas de Porto Alegre. Em 2006 uma menina com MPS I apresentando compressão cervical medular sintomática também recebeu terapia de reposição enzimática intratecal por uso compassivo no Hospital de Clínicas de Porto Alegre. Em 2007 um menino com MPS VI e com compressão medular cervical também foi tratado através de reposição enzimática intratecal por uso compassivo neste mesmo hospital. / The mucopolysaccharidoses present a progressive natural course caused by defects on glycosaminoglycan degradation pathways. Usually severe, the mucopolysaccharidoses considerably shorten patient lifespan. Although in many cases the cognitive function is preserved, considerable neurological morbidity can be present due to spinal cord compression which is secondary to glycosaminoglycan storage in the meninges. Treatment for this complication usually requires surgical intervention with cervical laminectomy for thickened meninges removal. Enzyme replacement therapy used for the treatment of mucopolysaccharidoses reduces lysosomal storage and ameliorates many somatic symptoms but does not provide any direct benefit to central nervous system as the enzyme does not cross the blood-brain-barrier. Due to this limitation of intravenous enzyme replacement therapy some researchers have been working with an alternative option of enzyme delivery with direct action on central nervous system through the extensive close contact provided by cefalo-spinal fluid and meniniges and arachnoid villosities, to the treatment of some lysosomal disorders. Animal model studies have been conducted and some promising results have been achieved. This study intends to present an alternative route for the administration of a recombinant enzyme, directly in the cefalo-spinal fluid, which was used in two patients with mucopolysaccharidosis I and one patient with mucopolysaccharidois VI. These patients gained access to this therapy by individual compassionate use enrollment approved by local Ethics Board at Hospital de Clínicas de Porto Alegre. So far, only animal model trials had been conducted with the use of this administration route in lysosomal storage diseases, and these were the first three patients with mucopolysaccharidoses and cord compression to receive intrathecal enzyme replacement therapy in the world. In 2005, an adult mucopolysaccharidosis I patient presenting cervical cord compression was enrolled in a compassionate use trial of intrathecal enzyme replacement therapy, at the Hospital de Clínicas de Porto Alegre. In 2006, a girl with mucopolysaccharidosis I presenting spinal cord compression was also enrolled in a compassionate use trial of intrathecal enzyme replacement therapy, at the Hospital de Clínicas de Porto Alegre. In 2007, a boy with mucopolysaccharidosis VI and cord compression was enrolled in compassionate use trial of intrathecal enzyme replacement therapy in the same hospital.
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Lipidomic Interrogation of Neonatal Progeroid Syndrome, Farber's Disease, and Spinal Muscular Atrophy with Progressive Myoclonic EpilepsyMcDowell, Graeme Stephen Vaughn 31 January 2024 (has links)
Spinal Muscular Atrophy with Progressive Myoclonic Epilepsy (SMA-PME), Farber Lipogranulomatosis (FL), and a rare variant form of Neonatal Progeroid Syndrome (NPS) are three monogenetic rare disorders caused by pathogenic variation in genes encoding lipid modifying proteins. FL and SMA-PME are caused by loss of function mutations in ASAH1, encoding the acid ceramidase (aCDase) enzyme. It is not, however, known how aCDase deficiency can produce either the isolated neurological symptoms of SMA-PME or the predominantly systemic symptoms of FL. Further, a recently identified variant form of NPS has been attributed to variants in ANO6, encoding a dual function calcium-activated chloride channel and glycerophosphoserine (GPS) scramblase. Here, it is not known how ANO6 mutation causes the premature aging phenotype that defines NPS. To address these questions, I sought to elucidate pathogenic changes in lipid metabolism that associate clinical phenotype. I show here that the different patient mutations in ANO6 cause a non-physiological gain of channel function and either a loss or gain of scramblase function depending on the variant expressed. Both variants, however, alter GPS metabolic homeostasis suggesting a common mechanism of action. To provide in vivo insight, I characterized a novel mouse model based on our NPS patient genetics, showing extremely low penetrance of disease symptoms in terms of live births yet confirming that affected animals show impaired GPS metabolism in affected organs. Next, I characterized the clinical presentation of six new patients with SMA-PME and identified distinct sphingolipid metabolic fingerprints in FL and SMA-PME cells. I show that FL is defined by a hypometabolic sphingolipid phenotype with cellular and molecular features of a classic lysosomal storage disorder. By contrast, SMA-PME has a hypermetabolic sphingolipid phenotype with features of non-classic lysosomal trafficking disorders. To provide clinical insight, I assessed the potential of enzyme replacement therapy, demonstrating a rescue of sphingolipid metabolism in SMA-PME patient cells. Together, this thesis identified changes in the cellular and tissue lipid profiles of patients with ANO6-NPS, SMA-PME, or FL, elucidating some of the lipid-centric pathomechanisms of these diseases.
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O tratamento da doença de Gaucher no Sistema Único de Saúde: o caso do Rio de JaneiroMagalhães, Tatiana de Sá Pacheco Carneiro de January 2013 (has links)
Made available in DSpace on 2014-08-26T17:31:46Z (GMT). No. of bitstreams: 2
license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5)
69585.pdf: 1181357 bytes, checksum: 50462d1ba789c7b199ee8460ca90f3b8 (MD5) / Fundação Oswaldo Cruz. Instituto Fernandes Figueira. Departamento de Ensino. Programa de Pós-Graduação em Saúde da Criança e da Mulher. Rio de Janeiro, RJ, Brasil / A Doença de Gaucher (DG) é uma Doença de Depósito Lisossômico (DDL) e
seu tratamento baseia
-
se na terapia de reposição enzimática. Tal terapia foi um marco na
vida de pacientes e especialistas, pois mudou a história da evolução da doença,
caracterizando um
a nova era na Genética Médica. Este trabalho tem como objeto
de
pesquisa as perspectivas trazidas por profissionais, com experiência em
trata
r a
Doença
de Gaucher no Sistema Único de Saúde
no estado do Rio de Janeiro. Uma vez que a
DG é a
única condição d
o grupo das DDL a ser contemplada por uma Política
Ministerial, promovendo acesso a drogas de alto custo através de um Protocolo Clínico
e Diretrizes Terapêuticas (PCDT).
O o
bjetivo geral
foi a
nalisar a prática da aplicação do protocolo oficial de
tratame
nto da
DG
e o seu entendimento a partir da ótica dos médicos tratadores,
profissionais de saúde e gestores do Centro de Referência
,
o Instituto Estadual de
Hematologia Arthur de Siqueira Cavalcanti (HEMORIO).
Os objetivos específicos
foram primeiramente id
entificar
a formaçã
o profissional dos envolvidos no programa,
analisar a ótica desses profissionais
sob
re as recomendações do PCDT
e como estes
situam o Centro de Referência
(CR)
e
m
seu atual funcionamento
, e d
iscutir de maneira
crítica a visão dos profiss
i
onais a respeito dos benefícios e de
possíveis falhas do
programa.
Foram realizadas entrevistas temáticas semiestruturadas e a elas aplicou
-
se a
análise de conteúdo. No que tange ao entendimento sobre o PCDT
-
DG e o seu
viii
funcionamento, os resultados apontam
a importância da existência de um balizador, um
programa robusto governamental, revisado por especialistas bem capacitados no tema.
O PCDT
-
DG foi um avanço na saúde, oficializando e garantindo o acesso
à medicação
de maneira embasada, controlada por câmar
as técnicas estaduais,
permitindo a
efetuação de pregões públicos, uma maneira transparente de aquisiçã
o de drogas de alto
custo comparada
a medidas judiciais
. Os sujeitos da pesquisa são favoráveis ao
programa, no entanto possuem uma abordagem crítica ao
sistema de saúde no que diz
respeit
o a entraves na rede de assistência cirúrgica
e de reabilitação. Um grande gargalo
atualmente no SUS não é exclusivo ao programa da DG: certos questionamentos éticos
na fomentação do diagnóstico laboratorial por parte da
indústria farmacêutica, apesar de
haver
relações amigáveis entre esses dois atores no CR.
Concluímos que muitos avanços foram conquistados a partir da implementação
do protocolo e que talvez este possa servir como modelo para garantir acesso ao
tratamento
de outras DDL. Algumas incongruências do siste
ma são questionáveis e
discutida
s entre gestores, médicos e usuários, entretanto ainda são muito poucos os
estudos publicados no Brasil
sobre o tema
. / Gaucher disease (GD) is a
Lysosomal Storage Disease (LSD) and its
treatment is based on enzyme replacement therapy. Such therapy was a milestone in
patients
`s lives
and
experts in the field, changing
the
disease
natural history
. This work
aims at
present
ing
the treatment of GD in the Unified Health System i
n the state of Rio
de Janeiro,
as it is the only LSD to be
covered by a Ministerial policy
, which promotes
access to high cost drugs through a Clinical Gui
deline (CG)
.
The overall objective was to analyze
the practical application of the CG
protocol in the
treatment of GD, and how this guideline was interpreted and used by
the
medical c
haracters
, health professionals and ma
nagers of the Reference Center and
the
State Institute of Hematology Arthur
de Siquei
ra Cavalcanti (HEMORIO
). The specific
objectives were to identify the training of
those involved in the program,
to analyze how
professionals viewed the recommendations included in the CP, what they thought about
the
Reference Center for
GD and to critical
ly discuss
the benefits and possi
ble
shortcomings of the program
.
Thematic semi
-
structured interviews were conducted, and
the
content
analysis was applied. Regarding the understanding of the CP
-
GD and its op
eration,
the results point
the importance of t
he existence
of
a robust government program,
reviewed by
well
-
trained
experts
in the subject. The CP
-
GD was a
health`s
breakthrough
, ensuring access to medication, controlled by state technical chambers,
a
llowing the practice
of public auctions, a transpar
ent way of purchasing high
-
cost
drugs when compared to individual litigation. The
steakeholder`s research were
x
favo
rable to the program, although they criticized the
health network constraints for
specialized care, such as surgical services and rehabilitat
ion. Another major bottleneck
in the health system, not exclusive for G
D
is
ethical issues regarding
laboratory
diagnosis by the pharmaceutical industry.
We conclude
d
that many advances have been achieved from the
implementation of the CP, and that hopeful
ly this can serve as a model to ensure access
t
o treatment for other LSD.
Managers, physicians and users point out some
inconsistencies in the system
although there is still limited published data on this subject
in Brazil.
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Fonction auriculaire gauche dans la maladie de Fabry par analyse échocardiographique de la déformation myocardiquePichette, Maxime 04 1900 (has links)
Contexte: La maladie de Fabry (MF) se caractérise par l'accumulation de sphingolipides dans de multiples organes dont l'oreillette gauche (OG). La littérature existante ne permet pas d'établir si les fonctions réservoir, conduit et pompe de l'OG étudiées par échocardiographie de suivi des marqueurs acoustiques (speckle-tracking echocardiography, STE) sont affectées dans la MF et si la thérapie de remplacement enzymatique (TRE) permet d'améliorer la fonction de l'OG.
Méthodes: Dans cette étude de cohorte rétrospective, la déformation, le taux de déformation et les volumes phasiques de l'OG ont été étudiés chez 50 patients atteints de la MF et comparés à 50 contrôles sains.
Résultats: Les trois fonctions phasiques de l'OG étaient altérées. La déformation positive maximale (fonction réservoir) était de 38,9 ± 14,9 % vs. 46,5 ± 10,9 % (p=0,004) et la déformation télédiastolique (fonction pompe) était de 12,6 ± 5,9 % vs. 15,6 ± 5,3 % (p=0,010). Chez 15 patients ayant débuté la TRE pendant l'étude, la majorité des paramètres de fonction de l'OG se sont améliorés après un suivi d'un an (déformation positive maximale de 32,0 ± 13,5 % à 38,0 ± 13,5 %; p=0,006) alors qu'il y a eu une tendance vers une détérioration des paramètres chez 15 patients n'ayant jamais reçu de traitement (déformation positive maximale de 47,3 ± 10,8 % à 41,3 ± 9,3 %; p=0,058). Neuf patients atteints de la MF (21%) ont développé une fibrillation auriculaire ou un accident vasculaire cérébral pendant un suivi de quatre ans. La déformation positive maximale et la déformation protodiastolique étaient plus fortement associés aux événements cliniques que les paramètres cliniques et les paramètres échocardiographiques standards.
Conclusions: Les fonctions réservoir, conduit et pompe de l'OG par STE étaient affectées dans la MF. La TRE a permis d'améliorer la fonction de l'OG. Les paramètres de déformation de l'OG étaient associés à la survenue de fibrillation auriculaire et d'accidents vasculaires cérébraux. / Background: Fabry disease (FD) is characterized by the accumulation of sphingolipids in multiple organs including the left atrium (LA). It is uncertain if the LA reservoir, conduit and contractile functions evaluated by speckle-tracking echocardiography are affected in Fabry cardiomyopathy and whether enzyme replacement therapy can improve LA function.
Methods: In this retrospective cohort study, LA strain, strain rates and phasic LA volumes were studied in 50 FD patients and compared to 50 healthy controls.
Results: All three LA phasic functions were altered. The peak positive strain (reservoir function) was 38.9 ± 14.9 % vs. 46.5 ± 10.9 % (p=0.004) and the late diastolic strain (contractile function) was 12.6 ± 5.9 % vs. 15.6 ± 5.3 % (p=0.010). In 15 patients who started enzyme replacement therapy during the study, most of the LA parameters improved at one-year follow-up (peak positive strain from 32.0 ± 13.5 % to 38.0 ± 13.5 %; p=0.006) whereas there was a trend towards deterioration in 15 patients who never received treatment (peak positive strain from 47.3 ± 10.8 % to 41.3 ± 9.3 %; p=0.058). Nine FD patients (21%) experienced new-onset atrial fibrillation or stroke during four-year follow-up. By univariate analysis, peak positive strain and early diastolic strain demonstrated significant associations with clinical events, surpassing conventional echocardiographic parameters and clinical characteristics.
Conclusions: Left atrial reservoir, conduit and contractile functions by speckle-tracking echocardiography were all affected in FD. Enzyme replacement therapy improved LA function. Left atrial strain parameters were associated with atrial fibrillation and stroke.
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